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Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC.

We evaluated tissue tumor mutational burden (tTMB) and mutations in This retrospective exploratory analysis evaluated prevalence of high tTMB and Among patients with evaluable data from whole-exome sequencing for evaluation of tTMB (KEYNOTE-189, These findings support pembrolizumab-combination as first-line treatment in patients with metastatic NSCLC and do not suggest the utility of tTMB,

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era The European EXOTIC Registry.

Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range 0%-95%) and mean tumor mutational burden was 7.06 (range 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival ( EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Effect of Exosomal lncRNA MALAT1miR-370-3pSTAT3 Positive Feedback Loop on PI3KAkt Pathway Mediating Cisplatin Resistance in Cervical Cancer Cells.

Exosomes can encapsulate lncRNA to mediate intercellular communication in cancer progression. Our study devoted to research the effect that long noncoding RNA Metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) influence on cervical cancer (CC). MALAT1 and miR-370-3p levels in CC was assessed using qRT-PCR. CCK-8 assay and flow cytometry were devoted to confirm the influence on MALAT1 influencing the proliferation in cisplatin-resistant CC cells. Futher more, MALAT1, combined with miR-370-3p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. In CC tissues, MALAT1 turned into substantially expressed, cisplatin-resistant cell lines, as well as exosomes. Cell proliferation was restrained and cisplatin-induced apoptosis was promoted by way of Knockout MALAT1. And promoted the miR-370-3p level, MALAT1 targeted miR-370-3p. Promoting effect of MALAT1 on cisplatin resistance of CC was partially reversed through miR-370-3p. In addition, STAT3 may induce up-regulation of MALAT1 expression in cisplatin-resistant CC cells. It was further confirmed that the effect of MALAT1 on cisplatin-resistant CC cells was achieved by activating PI3KAkt pathway. The positive feedback loop of exosomal MALAT1miR-370-3pSTAT3 mediates the cisplatin resistance of cervical cancer cells affecting PI3KAkt pathway. Exosomal MALAT1 may become a promising therapeutic target for treating cervical cancer.

A prediction model for in-hospital mortality in intensive care unit patients with metastatic cancer.

To identify predictors for in-hospital mortality in patients with metastatic cancer in intensive care units (ICUs) and established a prediction model for in-hospital mortality in those patients. In this cohort study, the data of 2,462 patients with metastatic cancer in ICUs were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied to identify the predictors for in-hospital mortality in metastatic cancer patients. Participants were randomly divided into the training set ( In total, 656 (26.65%) metastatic cancer patients were dead in hospital. Age, respiratory failure, the sequential organ failure assessment (SOFA) score, the Simplified Acute Physiology Score II (SAPS II) score, glucose, red cell distribution width (RDW) and lactate were predictors for the in-hospital mortality in patients with metastatic cancer in ICUs. The equation of the prediction model was ln( The prediction model for in-hospital mortality in ICU patients with metastatic cancer exhibited good predictive ability, which might help identify patients with high risk of in-hospital death and provide timely interventions to those patients.

Therapeutic efficacy of platinumetoposide regimens in the treatment of advanced poorly differentiated neuroendocrine carcinomas of the lung A retrospective analysis.

Lung neuroendocrine neoplasms (NENs) are rare malignancies developed from bronchial mucosa. Because of its rarity and complex histopathology, there is limited data on the role of chemotherapy in this subset of tumors. Few studies regarding the treatment of poorly differentiated lung NENs, known as neuroendocrine carcinomas (NECs), are available and many limits are detectable as heterogeneity of tumor samples including different origins and different clinical behaviors, moreover, no evidence of therapeutic advances have been achieved along the last thirty years. We performed a retrospective analysis of 70 patients affected by poorly differentiated lung NECs half of patients underwent a first line therapy with a combination of cisplatin plus etoposide the remaining patients receiving carboplatin instead of cisplatin, plus etoposide. Results In our analysis, the outcomes of patients treated with either cisplatin or carboplatin schedule are similar in terms of ORR (44% versus 33%), DCR (75% versus 70%), PFS (6.0 versus 5.0 months) and OS (13.0 versus 10 months). Median number of chemotherapy cycles was 4 (range 1-8). The 18% of patients required a dose reduction. Main toxicities reported were hematological (70.5%), gastrointestinal (26.5%) and fatigue (18%). Survival rate in our study suggests that high grade lung NENs are characterized by an aggressive behavior and a poor prognosis, despite the treatment with platinumetoposide according to available data. Clinical results of present study contribute to strengthen available data on the usefulness of platinumetoposide regimen in the treatment of poorly differentiated lung NENs.

SLC3A2 Promotes Tumor Associated Macrophage Polarization via Metabolic Reprogramming in Lung Cancer.

Tumor associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidences indicate that altered metabolic properties in cancer cell support the tumorigenic functions of TAMs. However, mechanisms and mediators underly crosstalk between cancer cell and TAMs remain largely unknown. In present study, we revealed that high Solute Carrier Family 3 Member 2 (SLC3A2) expression in lung cancer patients were associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in co-culture system. By using metabolome analysis, we identified that knockdown SLC3A2 altered metabolism of lung cancer cells and changed multiple metabolites including arachidonic acid in the tumor microenvironment. More importantly, we demonstrated that arachidonic acid was responsible for SLC3A2 mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAMs polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming via arachidonic acid.

An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers.

T cell-based immunotherapy has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions remain rare, particularly in gastrointestinal cancers like colorectal cancer (CRC). B7-H3 is overexpressed in multiple cancer entities including CRC on both, tumor cells and tumor vasculature, the latter facilitating influx of effector cells into the tumor site upon therapeutic targeting. We generated a panel of T cell-recruiting B7-H3xCD3 bispecific antibodies (bsAbs) and show that targeting a membrane-proximal B7-H3 epitope allows for a 100-fold reduction of CD3 affinity. In vitro, our lead compound CC-3 showed superior tumor cell killing, T cell activation, proliferation and memory formation, whereas undesired cytokine release was reduced. In vivo, CC-3 mediated potent antitumor activity in three independent models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors. Thus, fine-tuning of both, target and CD3 affinities as well as binding epitopes allowed for the generation of a B7-H3xCD3 bsAb with promising therapeutic activity. CC-3 is presently undergoing GMP production to enable evaluation in a clinical first in human study in CRC.

HDAC inhibitor ITF2357 reduces resistance of mutant-KRAS non-small cell lung cancer to pemetrexed through a HDAC2miR-130a-3p-dependent mechanism.

Histone deacetylases (HDAC) contribute to oncogenic program, pointing to their inhibitors as a potential strategy against cancers. We, thus, studied the mechanism of HDAC inhibitor ITF2357 in resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem). We first determined the expression of NSCLC tumorigenesis-related HDAC2 and Rad51 in NSCLC tissues and cells. Next, we illustrated the effect of ITF2357 on the Pem resistance in wild type-KARS NSCLC cell line H1299, mut-KARS NSCLC cell line A549 and Pem-resistant mut-KARS cell line A549R in vitro and in xenografts of nude mice in vivo. Expression of HDAC2 and Rad51 was upregulated in NSCLC tissues and cells. Accordingly, it was revealed that ITF2357 downregulated HDAC2 expression to diminish the resistance of H1299, A549 and A549R cells to Pem. HDAC2 bound to miR-130a-3p to upregulate its target gene Rad51. The in vitro findings were reproduced in vivo, where ITF2357 inhibited the HDAC2miR-130a-3pRad51 axis to reduce the resistance of mut-KRAS NSCLC to Pem. Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Detection of solid and subsolid pulmonary nodules with lung MRI performance of UTE, T1 gradient-echo, and single-shot T2 fast spin echo.

Although MRI is a radiation-free imaging modality, it has historically been limited in lung imaging due to inherent technical restrictions. The aim of this study is to explore the performance of lung MRI in detecting solid and subsolid pulmonary nodules using T1 gradient-echo (GRE) (VIBE, Volumetric interpolated breath-hold examination), ultrashort time echo (UTE) and T2 Fast Spin Echo (HASTE, Half fourier Single-shot Turbo spin-Echo). Patients underwent a lung MRI in a 3 T scanner as part of a prospective research project. A baseline Chest CT was obtained as part of their standard of care. Nodules were identified and measured on the baseline CT and categorized according to their density (solid and subsolid) and size (> 4 mm ≤ 4 mm). Nodules seen on the baseline CT were classified as present or absent on the different MRI sequences by two thoracic radiologists independently. Interobserver agreement was determined using the simple Kappa coefficient. Paired differences were compared using nonparametric Mann-Whitney U tests. The McNemar test was used to evaluate paired differences in nodule detection between MRI sequences. Thirty-six patients were prospectively enrolled. One hundred forty-nine nodules (100 solid49 subsolid) with mean size 10.8 mm (SD 9.4) were included in the analysis. There was substantial interobserver agreement (k 0.7, p 0.05). Detection for all nodules, solid and subsolid nodules was respectively UTE 71.8%71.0%73.5% VIBE 61.6%65%55.1% HASTE 72.4%72.2%72.7%. Detection rate was higher for nodules > 4 mm in all groups UTE 90.2%93.4%85.4%, VIBE 78.4%88.5%63.4%, HASTE 89.4%93.8%83.8%. Detection of lesions ≤4 mm was low for all sequences. UTE and HASTE performed significantly better than VIBE for detection of all nodules and subsolid nodules (diff 18.4 and 17.6%, p < 0.01 and p 0.03, respectively). There was no significant difference between UTE and HASTE. There were no significant differences amongst MRI sequences for solid nodules. Lung MRI shows adequate performance for the detection of solid and subsolid pulmonary nodules larger than 4 mm and can serve as a promising radiation-free alternative to CT.

Is prior cancer history a hindrance for non-small cell lung cancer patients to participate in clinical trials

This study aimed to explore the effect of a prior cancer history on the survivals of resected non-small cell lung cancer (NSCLC) patients. Kaplan-Meier method with a log-rank test was used to compare overall survival (OS) and disease-free survival (DFS) between groups. Propensity score matching (PSM) method was used to reduce bias. The least absolute shrinkage and selection operator (LASSO)-penalized Cox multivariable analysis was used to identify the prognostic factors. A total of 4,102 eligible cases were included in this study. The rate of patients with a prior cancer was 8.2% (3384,102). Patients with a prior cancer tended to be younger and have early-stage tumors when compared with those without prior cancer. Before PSM, the survivals of the patients with a prior cancer were similar to those of the patients without prior cancer (OS P 0.591 DFS P 0.847). After PSM, patients with a prior cancer and those without prior cancer still had comparable survival rates (OS P 0.126 DFS P 0.054). The LASSO-penalized multivariable Cox analysis further confirmed that a prior cancer history was not a prognostic factor for both OS and DFS. A prior cancer history was not associated with resected NSCLC patients survivals, and we proposed that it might be reasonable for clinical trials to enroll the NSCLC patients with a prior cancer.

Brief Report Declining Rates of SARS-CoV-2 Vaccine Uptake Among Patients With Thoracic Malignancies.

• Patients with primary thoracic malignancies are at increased risk of complications and death from COVID-19. Multiple studies have demonstrated humoral immune responses to SARS-CoV-2 vaccinations in patients with cancer, though the degree of immunogenicity varies. Over the last year the United States CDC has issued recommendations for multiple additional ‘booster’ vaccine doses for patients with cancer for protection against severe disease. • In this study, we found that among 242 patients with primary thoracic malignancies who underwent initial vaccination against SARS-CoV-2, there was a marked decline in uptake of each subsequent additional vaccine dose. Specifically, among patients who received an initial mRNA-based vaccination series (mRNA-1273 or BNT162b2), 75% of eligible patients received the recommended third dose, 39% received the recommended fourth dose, and 5% received the recommended fifth dose at the time of data cutoff. Of note, we assessed serologic responses in a subset of patients receiving booster vaccinations and found that additional vaccinations increased humoral immunity, as expected. • With the recent CDC recommendation of novel bivalent mRNA-based vaccine booster doses for all individuals over the age of 12, our findings highlight the need for further understanding of the reasons behind decreased vaccine uptake and emphasize the importance of counseling by providers regarding public health recommendations for patients with lung cancer.

Improving lung cancer diagnosis with cancer, fungal, and imaging biomarkers.

Indeterminate pulmonary nodules (IPNs) represent a significant diagnostic burden in health care. We aimed to compare a combination clinical prediction model (Mayo Clinic model), fungal (histoplasmosis serology), imaging (computed tomography CT radiomics), and cancer (high-sensitivity cytokeratin fraction 21 hsCYFRA 21-1) biomarker approach to a validated prediction model in diagnosing lung cancer. A prospective specimen collection, retrospective blinded evaluation study was performed in 3 independent cohorts with 6- to 30-mm IPNs (n 281). Serum histoplasmosis immunoglobulin G and immunoglobulin M antibodies and hsCYFRA 21-1 levels were measured and a validated CT radiomic score was calculated. Multivariable logistic regression models were estimated with Mayo Clinic model variables, histoplasmosis antibody levels, CT radiomic score, and hsCYFRA 21-1. Diagnostic performance of the combination model was compared with that of the Mayo Clinic model. Bias-corrected clinical net reclassification index (cNRI) was used to estimate the clinical utility of a combination biomarker approach. A total of 281 patients were included (111 from a histoplasmosis-endemic region). The combination biomarker model including the Mayo Clinic model score, histoplasmosis antibody levels, radiomics, and hsCYFRA 21-1 level showed improved diagnostic accuracy for IPNs compared with the Mayo Clinic model alone with an area under the receiver operating characteristics curve of 0.80 (95% CI, 0.76-0.84) versus 0.72 (95% CI, 0.66-0.78). Use of this combination model correctly reclassified intermediate risk IPNs into low- or high-risk category (cNRI benign 0.11 and cNRI malignant 0.16). The addition of cancer, fungal, and imaging biomarkers improves the diagnostic accuracy for IPNs. Integrating a combination biomarker approach into the diagnostic algorithm of IPNs might decrease unnecessary invasive testing of benign nodules and reduce time to diagnosis for cancer.

Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.

Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence. PDACs (n284 discovery cohort) were classified according to recurrence site as liver (n9333%), lung (n4917%), local (n3111%), peritoneal (n3813%) and no-recurrence (n7326%). Spatial compartments were identified by fluorescent imaging as pancytokeratin (PanCK) No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin Our findings demonstrate distinct inflammatorystromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvantneoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.

Upregulation of KLHL17 promotes the proliferation and migration of non-small cell lung cancer by activating the RasMAPK signaling pathway.

Analysis of the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that Kelch-like 17 (KLHL17) is overexpressed in non-small cell lung cancer (NSCLC) including adenocarcinoma (ADC) and squamous cell carcinoma (SCC). We therefore explored the role of KLHL17 in the development and progression of NSCLC. Immunohistochemistry and western blotting showed that KLHL17 expression was significantly higher in the tumor tissues from 173 patients with NSCLC, compared with the corresponding non-neoplastic tissue. In addition, upregulated KLHL17 expression was positively correlated with tumor size, lymph node metastasis and tumor node metastasis (TNM) stage, and affected the overall survival (OS) of patients with NSCLC. Consistent with clinical samples, in vitro studies demonstrated that KLHL17 expression was higher in various cell lines of NSCLC (A549, H1299, H460 and SK cells) as compared to normal human bronchial epithelial cells (HBE cells). Overexpression of KLHL17 in the cell lines of NSCLC with KLHL17-Flag plasmid promoted the proliferation and migration of tumor cells, which was associated with elevated activation of Rat sarcomaMitogen-activated protein kinases (RasMAPK) signaling and increased expression of cyclin D1, cyclin D-dependent kinases 4 (CDK4), matrix metalloproteinase 2 (MMP2) and Ras homolog gene family member A (RhoA). In contrast, knockdown of KLHL17 in the cell lines of NSCLC using KLHL17 small interfering RNA suppressed the proliferation and migration of tumor cells, in association with reduced activation of RasMAPK signaling and decreased expression of cyclin D1, CDK4, MMP2 and RhoA. Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced RasMAPK activity as well as tumor proliferation and migration. These results suggest that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating RasMAPK signaling pathway. Therefore, KLHL17 may be a novel therapeutic target for the treatment of NSCLC. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with limited treatment options. This study elucidates the role of KLHL17 in the development and progression of NSCLC using clinical samples and NSCLC cell lines. The results show that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating RasMAPK signaling pathway, and suggest that KLHL17 may be a novel therapeutic target for the treatment of NSCLC.

CircRNA-ST6GALNAC6 increases the sensitivity of bladder cancer cells to erastin-induced ferroptosis by regulating the HSPB1P38 axis.

Previous studies have demonstrated that circST6GALNAC6 is a tumor suppressor in bladder cancer. However, the role of circST6GALNAC6 in ferroptosis remains unclear. In the current study, ferroptosis was induced in bladder cancer cells by erastin. Functional experiments showed that overexpression of circST6GALNAC6 promoted ferroptosis of bladder cancer cells in vitro and in vivo. Mechanistic studies revealed that circST6GALNAC6 bound to the N-terminus of small heat shock protein 1 (HSPB1) and thus blocked the erastin-induced phosphorylation of HSPB1 at the Ser-15 site, a phosphorylation site in the protective response to ferroptosis stress. In addition, protein kinase C inhibited circST6GALNAC6-induced ferroptosis by increasing the overall phosphorylation level of HSPB1, further demonstrating the role of phosphorylation activation of HSPB1 in resistance to ferroptosis. Finally, the involvement of the HSPB1p38 MAPK pathway in the downstream signal transduction of circST6GALNAC6 in bladder cancer ferroptosis regulation was determined. The regulatory mechanism of ferroptosis sensitivity dependent on circST6GALNAC6 expression levels in bladder cancer was revealed as circRNA regulation of various protein functions. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by occupying the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Therefore, enhancing the expression of circST6GALNAC6 to promote ferroptosis or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity is of considerable importance to the development and application of ferroptosis intervention methods in bladder cancer. The authors describe a regulatory mechanism for ferroptosis sensitivity that is dependent on circST6GALNAC6 expression levels in bladder cancer. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by blocking the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Enhancing the expression of circST6GALNAC6 to promote ferroptosis, or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity, is significant for the development and application of ferroptosis intervention methods.

Primary small cell neuroendocrine cancer of adrenal gland a rare extrapulmonary small cell cancer.

Small cell cancer is an aggressive neoplasm of neuroendocrine origin that is most commonly found in the lungs. However, up to 5% of cases can be extrapulmonary. These have been reported to be located in the gastrointestinal and genitourinary systems and rarely in other locations. Only five prior cases of small cell cancer have been reported where the primary lesion is at the adrenal gland. Here we present the case of a female patient in her mid-50s who presented with right upper quadrant pain and was diagnosed with metastatic small cell carcinoma of the adrenal gland. The patient received palliative chemotherapy for her metastatic cancer and was ultimately admitted to hospice after progression of her disease. This case and the accompanying literature review highlight a rare manifestation of extrapulmonary small cell cancer.

Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors a systematic review.

Quantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here, we explore the value of changes in ctDNA levels in response to immune checkpoint inhibitors (ICIs). We searched MEDLINE (host PubMed) for trials of ICIs in advanced solid tumors in which outcomes were reported based on change in ctDNA levels. ctDNA reduction was defined as reported in individual trials. Typically, this was either >50% reduction or a reduction to undetectable levels. We extracted HRs and related 95% CIs andor p values comparing ctDNA reduction versus no reduction for progression-free survival (PFS) andor overall survival (OS). Data were then pooled in a meta-analysis. Variation in effect size was examined using subgroup analyses. Eighteen trials were included in the meta-analysis. ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. A reduction in ctDNA measured 6-16 weeks after starting treatment was associated with significantly better PFS (HR 0.20 95% CI, 0.14 to 0.28 p<0.001). Similarly, OS was superior in patients with reduced ctDNA levels (HR 0.18 95% CI, 0.12 to 0.26 p<0.001). The results were consistent across all disease sites, lines of treatment, magnitude of change (to undetectable vs >50% reduction) and whether treatment exposure comprised single or combination ICIs. In advanced solid tumors, a reduction in ctDNA levels in response to ICIs is associated with substantial improvements in outcome. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs or support treatment de-escalation strategies.

Lung Squamous Cell Carcinoma with EML4-ALK Fusion and TP53 Co-mutation Treated with Ensartinib A Case Report and Literature Review.

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Thus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V1) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 19 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease. . 【中文题目：恩沙替尼治疗EML4-ALKTP53共突变 肺鳞癌1例并文献复习】 【中文摘要：肺鳞癌约占非小细胞肺癌（non-small cell lung cancer, NSCLC）的30%，是第二常见的肺癌组织学类型。具有间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合突变的NSCLC仅占所有NSCLC病例的2%-5%，且几乎只存在于肺腺癌患者中。因此ALK检测在肺鳞癌患者中不常规进行，个别见于报道的ALK融合突变肺鳞癌患者的靶向治疗效果也不清楚。本例晚期肺鳞癌患者通过二代测序发现存在棘皮动物微管相关蛋白样4（echinoderm microtubule associated protein like 4, EML4）-ALK（V1）和 TP53共突变，2020年12月3日开始口服恩沙替尼，疗效评价为部分缓解（partial response, PR），无进展生存期（progression-free survival, PFS）达19个月，疾病进展后改为洛拉替尼。其中一线恩沙替尼治疗创造了有文献报道以来ALK突变肺鳞癌患者靶向治疗最长的PFS。本文报道了1例接受恩沙替尼治疗的EML4-ALK和TP53共突变肺鳞癌患者，并回顾相关文献，对此类罕见患者的治疗进行了讨论。 】 【中文关键词：ALK融合基因；肺肿瘤；TP53；恩沙替尼；洛拉替尼】.

Advances of Immunotherapy Resistance and Coping Strategies in Non-small Cell Lung Cancer.

Immunotherapy has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC), however, along with the popularization of immunotherapy, immune resistance has become an unavoidable problem. Immunotherapy can induce extensive cellular and molecular alterations in the tumor microenvironment. Considering the mechanisms of immune resistance are not yet fully understood and the efficacy of standard chemotherapy regimens is limited, more effective coping strategies based on resistance mechanisms are urgently needed. In this review, we intend to summarize the known mechanisms of immune resistance and feasible strategies, so as to provide a foundation for clinicians to develop more individualized and precise regimens and finally improve patients prognosis. . 【中文题目：非小细胞肺癌免疫耐药机制及应对策略 的研究进展】 【中文摘要：免疫治疗对非小细胞肺癌（non-small cell lung cancer, NSCLC）有显著的临床益处，然而，随着NSCLC免疫治疗的广泛应用，免疫耐药成为不可避免的问题。免疫治疗诱导肿瘤微环境发生广泛的细胞和分子改变，其耐药机制目前尚未完全明确，且耐药后标准化疗方案的疗效有限，亟待探索基于耐药机制的更有效的应对策略。本文拟对目前已知的免疫治疗耐药机制及应对策略进行综述，为临床医生制定更加个体化、精准化的治疗方案以及改善患者预后提供基础。 】 【中文关键词：免疫治疗；免疫耐药；肺肿瘤；应对策略】.

Recent Progress of Nano-drug Combined with Chimeric Antigen Receptor T Cell Therapy in the Treatment of Soild Tumors.

Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable success in treating hematological malignancies. However, CAR-T therapy for solid tumors is still limited due to the unique solid-tumor microenvironment and heterogeneous target antigen expression, which leads to an urgent need of combining other therapies. At present, nano delivery system has become one of the most promising directions for the development of anti-tumor drugs. Based on the background of CAR-T and tumor treatment, we focus on the research progress of nanomedicine combined with CAR-T therapy, and systematically review the strategies and examples in recent years in the aspects of in vivo delivery of mRNA, regulation of tumor microenvironment, combination with photothermal therapy. And we also look forward to the future direction of this filed. . 【中文题目：纳米药物联合CAR-T疗法在实体肿瘤治疗中 的研究进展】 【中文摘要：嵌合抗原受体T细胞（chimeric antigen receptor T cell, CAR-T）疗法在血液系统肿瘤治疗中已取得巨大成功，但由于实体肿瘤特殊的肿瘤微环境和缺乏特异性的抗原靶点，CAR-T疗法在实体肿瘤中的治疗效果并不理想，联合其他疗法是目前的迫切需要。当前，纳米递送系统已经成为抗肿瘤药物研发最活跃的方向之一，本文在介绍CAR-T疗法与实体肿瘤治疗相关的背景基础上，重点关注纳米药物联合CAR-T疗法以增强肿瘤治疗的研究进展，从体内递送mRNA、调节肿瘤微环境、联合光热治疗等方面，较为系统地综述了近年来纳米递送系统联合CAR-T疗法的策略与典例，同时对该领域的未来方向进行展望。 】 【中文关键词：纳米递送系统；嵌合抗原受体T细胞疗法；实体肿瘤】.

Research Progress of DNA Methylation in Cisplatin Resistance in Lung Cancer.

As one of the most common malignant tumors, lung cancer poses a serious threat to human life and health. The platinum-based drug cisplatin (DDP) is used as the first-line treatment for lung cancer. The poor prognosis of lung cancer is mostly due to developed resistance to cisplatin, which poses a serious treatment challenge. The mechanism of cisplatin resistance is complex and unclear. Numerous studies have shown that DNA methylation plays a crucial role in the emergence of lung cancer cisplatin resistance. DNA hypermethylation results in the deactivation of numerous drug resistance genes and tumor suppressor genes through a change in chromatin conformation. Finding new therapeutic targets and indicators to predict the therapeutic effect can be aided by elucidating the complex mechanism. In order to discover novel strategies to overcome cisplatin resistance in lung cancer, this paper discusses DNA methylation-mediated cisplatin resistance and offers an overview of current demethylation procedures. . 【中文题目：DNA甲基化在肺癌顺铂耐药中的研究进展】 【中文摘要：肺癌作为最常见的恶性肿瘤之一，严重威胁人类的生命健康。铂类药物如顺铂（cisplatin, DDP）是肺癌的一线治疗药物，但其获得性耐药是肺癌治疗的主要难题，也是预后不良的关键原因。顺铂耐药的发生机制较为复杂，确切机制尚未明确。大量研究表明DNA甲基化在肺癌顺铂耐药过程中发挥关键作用，DNA异常高甲基化使染色质构象发生变化，导致多种耐药基因和抑癌基因失活。阐明其复杂机制有望为寻找预测疗效的生物标志物和治疗新靶点的确定提供依据。因此，本文就DNA甲基化在肺癌顺铂耐药过程中的作用和机制做一综述，并总结近年来的去甲基化策略，为逆转肺癌顺铂耐药提供新思路。 】 【中文关键词：肺肿瘤；DNA甲基化；去甲基化；顺铂；耐药性】.

Advances in the Study of Chemokine-like Factor Superfamily Members in Tumors.

Chemokine-like factor-like MARVEL transmembrane domain containing memberchemokine-like factor superfamily member (CMTMCKLFSF) including CKLF and CMTM1-CMTM8 are a new family of proteins linking chemokines and transmembrane superfamilies. CMTM not only have broad chemotactic activities, but also associate with hematopoietic system, immune system, and tumor development and metastasis closely. CMTM proteins are involved in key biological processes of cancer development, which include activation and recycling of growth factor receptors, cell proliferation and metastasis, and regulation of the tumor immune microenvironment. This is a new focus of research on the relationship between CMTM and tumors, because CMTM4CMTM6 can be considered as a regulator for programmed cell death ligand 1 (PD-L1). This paper reviews the role of CMTM family members on cancer, especially in tumor growth, metastasis and immune escape, summarize the latest findings on the relationship between CMTM and non-small cell lung cancer, and explores the potential clinical value of CMTM as a novel drug target or biomarker. . 【中文题目：趋化素样因子超家族成员在肿瘤中的 研究进展】 【中文摘要：趋化素样因子超家族成员（chemokine-like factor-like MARVEL transmembrane domain containing memberchemokine-like factor superfamily member, CMTMCKLFSF）是连接趋化因子和跨膜超家族的一组新的蛋白家族，包括CKLF和CMTM1-CMTM8。CMTM除了具有广泛的趋化活性外，还与造血系统、免疫系统以及肿瘤的发生、发展和转移密切相关。CMTM蛋白参与癌症发展中的关键生物学过程，包括生长因子受体的激活和循环、细胞的增殖与转移以及肿瘤免疫微环境的调节。随着研究发现CMTM4、CMTM6可作为程序性死亡配体1（programmed cell death ligand 1, PD-L1）的调控器，关于CMTM与肿瘤之间的关系重新成为研究热点。本文对CMTM家族成员在癌症中作用进行综述，特别是在肿瘤生长、转移和免疫逃逸中的研究进展，并总结CMTM与非小细胞肺癌之间关系的最新研究结果，探讨CMTM作为新型药物靶点或生物标志物的潜在临床价值。 】 【中文关键词：趋化素样因子；CKLF；CMTM；肿瘤；生物标志物】.

Research Progress of Role and Mechanism of SETD7 in Tumor Occurrence and Progression.

The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. This article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis. . 【中文题目：SETD7在肿瘤发生发展中的作用及机制 的研究进展】 【中文摘要：肿瘤的发生是个复杂的过程，不仅取决于本身基因的突变或缺失，还受表观遗传调控的影响。近年来研究表明甲基化修饰在转录调控、异染色质的形成、X染色体失活、DNA损伤、肿瘤的发生发展等众多过程中均发挥着重要作用。含SET域赖氨酸甲基转移酶7（SET domain containing lysine methyltransferase 7, SETD7）是体内一种重要的赖氨酸甲基转移酶，可甲基化组蛋白，也可使非组蛋白甲基化。这种修饰调节方式一旦发生紊乱可直接导致细胞异常，从而引起多种疾病的发生。研究表明SETD7与多种肿瘤的发生发展具有相关性，但是有关SETD7甲基化底物位点及其在相应肿瘤中的调控机制并未完全阐明。本文将就SETD7对组蛋白及非组蛋白的甲基化修饰在肿瘤中发挥的作用及调控分子机制等方面的研究进展加以概述，以期为肿瘤的发病机制及诊疗研究提供新的治疗靶点。 】 【中文关键词：SETD7；甲基化；组蛋白及非组蛋白底物；肿瘤进展】.

Research Progress in Imaging-based Diagnosis of Benign and Malignant Enlarged Lymph Nodes in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) can be detected with enlarged lymph nodes on imaging, but their benignity and malignancy are difficult to determine directly, making it difficult to stage the tumor and design radiotherapy target volumes. The clinical diagnosis of malignant lymph nodes is often based on the short diameter of lymph nodes ≥1 cm or the maximum standard uptake value ≥2.5, but the sensitivity and specificity of these criteria are too low to meet the clinical needs. In recent years, many advances have been made in diagnosing benign and malignant lymph nodes using other imaging parameters, and with the development of radiomics, deep learning and other technologies, models of mining the image information of enlarged lymph node regions further improve the diagnostic accuracy. The purpose of this paper is to review recent advances in imaging-based diagnosis of benign and malignant enlarged lymph nodes in NSCLC for more accurate and noninvasive assessment of lymph node status in clinical practice. . 【中文题目：基于影像学诊断非小细胞肺癌肿大淋巴结 良恶性的研究进展】 【中文摘要：非小细胞肺癌（non-small cell lung cancer, NSCLC）在影像学上可见肿大淋巴结，但其良恶性难以直接判断，为肿瘤分期及设计放疗靶区带来了困难。临床上常依据淋巴结短径≥1 cm或最大标准摄取值≥2.5诊断淋巴结为恶性，但这些诊断标准敏感性和特异性均较低，难以满足临床需要。近年来，基于其他影像学参数诊断淋巴结良恶性取得了众多进展，同时随着影像组学、深度学习等技术的发展，通过挖掘肿大淋巴结区域的影像信息建立模型进而提升淋巴结良恶性诊断准确性展现出巨大的应用前景。本文旨在综述近年来基于影像学诊断NSCLC肿大淋巴结良恶性的研究进展，以便临床工作中更准确且无创地评估淋巴结状态。 】 【中文关键词：肺肿瘤；影像学；淋巴结；影像组学；深度学习】.

Advances in the Study of Invasive Non-mucinous Adenocarcinoma with Different Pathological Subtypes.

Lung cancer is the leading cause of cancer death in the world today, and adenocarcinoma is the most common histopathological type of lung cancer. In May 2021, World Health Organization (WHO) released the 5th edition of the WHO classification of thoracic tumors, which classifies invasive non-mucinous adenocarcinoma (INMA) into lepidic adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, solid adenocarcinoma, and micropapillary adenocarcinoma based on its histological characteristics. These five pathological subtypes differ in clinical features, treatment and prognosis. A complete understanding of the characteristics of these subtypes is essential for the clinical diagnosis, treatment options, and prognosis predictions of patients with lung adenocarcinoma, including recurrence and progression. This article will review the grading system, morphology, imaging prediction, lymph node metastasis, surgery, chemotherapy, targeted therapy and immunotherapy of different pathological subtypes of INMA. . 【中文题目：不同病理亚型浸润性非黏液腺癌的研究进展】 【中文摘要：肺癌是当今世界癌症死亡的首要原因，腺癌是肺癌中最常见的组织病理学类型。2021年5月世界卫生组织（World Health Organization, WHO）发布第5版《WHO胸部肿瘤分类》，根据组织学特点将浸润性非黏液腺癌（invasive non-mucinous adenocarcinoma, INMA）分为贴壁生长型腺癌、腺泡型腺癌、乳头型腺癌、实体型腺癌和微乳头型腺癌。这5种病理亚型在临床特征、治疗及预后等方面均有所差异，充分了解不同病理亚型的特点对肺腺癌患者的临床诊断、治疗方案的选择及疾病复发、进展等预后情况的判断具有至关重要的作用。本文将就不同病理亚型的INMA的分级系统、形态学、影像学预测、淋巴结转移、手术、化疗、靶向及免疫治疗做一综述。 】 【中文关键词：肺肿瘤；浸润性腺癌；浸润性非黏液腺癌；病理亚型】.

Application of Three-dimensional Computed Tomography Bronchography and Angiography Combined with Perfusion Area Identification Technique in Uniport Thoracoscopic Complex Segmentectomy.

With the extensive application of segmental lung resection in the treatment of early-stage lung cancer, how to complete segmentectomy more accurately and minimally invasively has become a research hotspot. The aim of this study is to explore the application of three-dimensional computed tomography bronchography and angiography (3D-CTBA) combined with perfusion area recognition technique in single-hole thoracoscopic complex segmentectomy. From January 2021 to January 2022, the clinical data of 112 consecutive patients undergoing single-port thoracoscopic complex segmentectomy in the Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The three-dimensional reconstruction combined with perfusion area identification technique was used to perform the operation and the clinical data were analyzed. The average operation time was (141.1±35.4) min the initial time of intersegmental plane display was (12.5±1.7) s the maintenance time of intersegmental plane was (114.3±10.9) s the intersegmental plane was clearly displayed (100%) the amount of bleeding was 10 (10, 20) mL the total postoperative drainage volume was (380.5±139.7) mL the postoperative extubation time was (3.9±1.2) d and the postoperative hospitalization time was (5.2±1.6) d. Postoperative complications occurred in 8 cases. The advantages of 3D-CTBA combined with perfusion area recognition technique are fast, accurate and safe in identifying intersegmental boundary in single-port thoracoscopic complex segmentectomy, which could provide guidances for accuratding resection of tumors, shortening operation time and reducing surgical complications. 【中文题目：3D-CTBA结合灌注区识别技术 在单孔胸腔镜复杂肺段切除术中的应用】 【中文摘要：背景与目的 随着肺段切除术在早期肺癌治疗中的广泛应用，如何更加精准和微创地完成肺段切除成为研究热点。本研究旨在探讨三维计算机断层支气管血管成像（three-dimensional computed tomography bronchography and angiography, 3D-CTBA）结合灌注区识别技术在单孔胸腔镜复杂肺段切除术中的应用价值。方法 回顾性分析2021年1月-2022年1月首都医科大学宣武医院胸外科单诊疗组连续112例单孔胸腔镜复杂肺段切除术患者的资料，总结采用三维重建结合灌注区识别技术完成手术并分析其临床数据。结果 本组病例平均手术时间为（141.1±35.4）min，段间界显示初始时间为（12.5±1.7）s，段间界维持时间为（114.3±10.9）s，肺段间界均清晰显示（100%），出血量为［10 (10, 20)］mL，术后总引流量为（380.5±139.7）mL，术后拔管时间为（3.9±1.2）d，术后住院时间为（5.2±1.6）d。8例出现术后并发症。结论 3D-CTBA结合灌注区识别技术在单孔胸腔镜复杂肺段切除术中对段间界识别具有快速、准确和安全的优点，为精准切除肿瘤、减少手术时间及降低手术并发症提供指导。 】 【中文关键词：肺肿瘤；单孔胸腔镜；肺段切除术；段间界；灌注区；识别技术】.

PHF5A Promotes Proliferation and Migration of Non-Small Cell Lung Cancer by Regulating of PI3KAKT Pathway.

There have been many significant advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC). However, the mechanism underlying the progression of NSCLC is still not clear. Plant homodomain finger-like domain-containing protein 5A (PHF5A) plays an important role in processes of chromatin remodeling, morphological development of tissues and organs and maintenance of stem cell pluripotency. This study aims to investigate the role of PHF5A in the proliferation and migration of NSCLC. A549 and PC-9 PHF5A overexpression cell lines were constructed. PHF5A expression was decreased in H292 and H1299 cells by using siRNA. Flow cytometry was used to detect the cell cycle. MTT assay and clone formation assay were used to examine the proliferative ability of NSCLC, while migration assay and wound healing assay were performed to evaluate the ability of migration. Western blot analysis was used to measure the expressions of PI3K, p-AKT and the associated downstream factors. Up-regulation of PHF5A in A549 and PC-9 cells increased the proliferation rate, while down-regulation of PHF5A in H292 and H1299 cells inhibited the proliferation rate at 24 h, 48 h and 72 h (P<0.05). The metastatic ability was elevated in the PHF5A-overexpresion groups, while reduced in the PHF5A-down-regulation group (P<0.05). In addition, reduced expression of PHF5A induced cell cycle arrest at G1S phase (P<0.05). Furthermore, decreased expression of PHF5A reduced the expression levels of PI3K, phosphorylation of AKT, c-Myc (P<0.05) and elevated the expression of p21 (P<0.05). These results demonstrated that PHF5A may play an important role in progression of NSCLC by regulating the PI3KAKT signaling pathway. 【中文题目：PHF5A通过调节PI3KAKT通路 促进非小细胞肺癌的增殖和迁移】 【中文摘要：背景与目的 非小细胞肺癌（non-small cell lung cancer, NSCLC）的诊断及治疗仍然是目前研究的热点与难点，探索NSCLC增殖和转移的分子机制及寻找新的靶点是当前研究的焦点。PHD锌指结构域蛋白5A（plant homodomain finger-like domain-containing protein 5A, PHF5A）在维持正常细胞的基本生物学功能中起重要作用。本研究旨在探讨PHF5A在NSCLC细胞增殖、转移中的作用及分子机制。方法 采用慢病毒转染方法构建A549、PC-9 PHF5A稳定过表达细胞株；采用siRNA技术构建PHF5A抑制的H292和H1299细胞株。利用流式细胞技术检测细胞周期。采用克隆形成、MTT法、细胞增殖计数检测细胞增殖情况，采用细胞迁移实验及细胞划痕实验检测细胞体外迁移能力变化。利用A459稳定过表达细胞株构建裸鼠成瘤模型，并观察比较PHF5A过表达细胞与对照组细胞的成瘤能力。用Western blot方法分析细胞内PHF5A及PI3KAKT通路及其下游p21、c-Myc的表达变化。结果 与对照组相比，PHF5A过表达组的PHF5A表达明显增加，PHF5A抑制组的PHF5A表达明显减少（P<0.05）；PHF5A过表达组24 h、48 h、72 h细胞增殖率均明显升高，抑制PHF5A表达组24 h、48 h、72 h细胞增殖率明显下降（P<0.05）。成瘤实验中，与对照组相比，PHF5A过表达组成瘤速度明显加快，瘤体体积明显增加（P<0.05）。利用Transwell迁移实验以及划痕实验证实PHF5A过表达组细胞的迁移能力较对照组明显增加，抑制PHF5A的表达可以降低细胞的迁移能力（P<0.05）。同时，抑制PHF5A的表达使细胞周期被抑制在G1期S期，PI3K、磷酸化AKT和下游c-Myc表达明显减少（P<0.05），p21表达明显升高（P<0.05）。结论 PHF5A表达增加可以促进NSCLC细胞增殖及迁移，PI3KAKT信号通路可能是其作用的机制之一。 】 【中文关键词：PHF5A；肺肿瘤；增殖；迁移】.

China National Lung Cancer Screening Guideline with Low-dose Computed Tomography (2023 Version).

Lung cancer is the leading cause of cancer-related death in China. The effectiveness of low-dose computed tomography (LDCT) screening has been further validated in recent years, and significant progress has been made in research on identifying high-risk individuals, personalizing screening interval, and management of screen-detected findings. The aim of this study is to revise China national lung cancer screening guideline with LDCT (2018 version). The China Lung Cancer Early Detection and Treatment Expert Group (CLCEDTEG) designated by the Chinas National Health Commission, and China Lung Oncolgy Group experts, jointly participated in the revision of Chinese lung cancer screening guideline (2023 version). This revision is based on the recent advances in LDCT lung cancer screening at home and abroad, and the epidemiology of lung cancer in China. The following aspects of the guideline were revised (1) lung cancer risk factors besides smoking were considered for the identification of high risk population (2) LDCT scan parameters were further classified (3) longer screening interval is recommended for individuals who had negative LDCT screening results for two consecutive rounds (4) the follow-up interval for positive nodules was extended from 3 months to 6 months (5) the role of multi-disciplinary treatment (MDT) in the management of positive nodules, diagnosis and treatment of lung cancer were emphasized. This revision clarifies the screening, intervention and treatment pathways, making the LDCT screening guideline more appropriate for China. Future researches based on emerging technologies, including biomarkers and artificial intelligence, are needed to optimize LDCT screening in China in the future. . 【中文题目：中国肺癌低剂量CT筛查指南（2023年版）】 【中文摘要：肺癌是导致中国癌症死亡的首要原因。近年来低剂量计算机断层扫描（low-dose computed tomography, LDCT）筛查的效果进一步被证实，并且在高危人群选择、筛查间隔及结节管理的研究方面取得了显著进展。本研究的目的是对2018年中国肺癌LDCT筛查指南进行修订。由国家卫健委任命的中国肺癌早诊早治专家组专家及中国西部肺癌研究协作中心部分专家，共同参与了2023版中国肺癌筛查指南的修订工作。专家们根据近年来国内外LDCT肺癌筛查进展，结合我国肺癌流行病学特征，共同修订了本次肺癌筛查指南。本指南对以下方面进行了修订：（1）高危人群定义中考虑了除吸烟外其他肺癌危险因素；（2）对LDCT扫描参数进行了修改和补充；（3）扩大了部分筛查阴性个体的筛查间隔；（4）将部分阳性结节的随访时间由3个月调整为6个月；（5）强调了多学科诊疗（multi-disciplinary treatment, MDT）在阳性结节管理、肺癌诊断和治疗中的作用。本次修订将使得LDCT筛查指南更适应我国国情，并使筛查、干预与治疗路径更为明确。未来应进一步基于新兴技术，包括生物标志物及人工智能研究，优化肺癌LDCT筛查方法及技术。 】 【中文关键词：肺肿瘤；筛查；低剂量计算机断层扫描；指南】.

Cellular atlas of senescent lineages in radiation- or immunotherapy-induced lung injury by single-cell RNA-sequencing analysis.

Although the combination of immunotherapy and radiotherapy (RT) to treat various malignancies is rapidly expanding, concerns regarding increased pulmonary toxicities remain. The mechanisms of immunotherapy- and irradiation-induced lung injury involve a complex interplay of cell types and signaling pathways, much of which remains to be elucidated. C57BL6 mice were treated with a single fraction (20 Gy) of RT to the right lung or 200 μg anti-PD1 antibody twice a week. At 7, 30, and 60 days post-treatment, the lung tissues were obtained for unbiased single-cell RNA sequencing or histological staining. The Seurat analysis pipeline, Cellchat, Monocol, and SCENIC were used to define cell types, mechanisms, and mediators driving pathological remodeling in response to this lung injury. RT-PCR, immunofluorescent staining, and multiplex immunohistochemistry were applied to validate the key results. Thirty distinct cell subsets encompassing 75,396 cells were identified. A comprehensive investigation of cell-cell crosstalk revealed that monokine signals derived from senescent fibroblasts were substantially elevated after lung injury. Independent analytic strategies revealed that senescence-like subtypes of fibroblasts, alveolar epithelial cells, B cells, and myeloid immune cells were functionally pathological, with high expression of senescence-signature proteins, especially ApoE, during injury response. Senescence markers were also elevated in irradiated human cell lines (HBE), mouse cell lines (B3T3 and L929), and the publicly available human pulmonary fibrosis dataset. These findings demonstrate that the accumulation of senescence-like fibroblasts, macrophages, and alveolar epithelial cells is the primary common pathological mechanism of immunotherapy- and irradiation-induced lung injury. This high-resolution transcriptomic data provide novel insights into therapeutic opportunities in order to predict or prevent therapy-induced lung injury.

Cisplatin and albumin-based gold-cisplatin nanoparticles enhance ablative radiotherapy-induced antitumor immunity in local and distant tumor microenvironment.

Ablative radiotherapy (RT) is an important strategy to eliminate primary tumor and can potentially induce the abscopal effect. Human serum albumin (HSA) nanoparticle (NP) was used for controlled release of cisplatin to decrease cisplatins systemic toxicity, and gold (Au) was added to increase RT-induced immunogenic cell death and potentiate the abscopal antitumor immunity. The designed albumin-based cisplatin-conjugated AuNPs were administered concurrently with ablative RT. C57BL6 mice implanted with syngeneic murine Lewis lung carcinoma (LLC) or murine MB49 tumor models were treated with ablative RT (12 Gy per fraction for 2 fractions, total 24 Gy), cisplatin, or Au-cisplatin NPs. Combining ablative RT with cisplatin or Au-cisplatin NPs both destroyed the primary tumor effectively and elicited immunogenic cell death (ICD) accompanied by release of danger-associated molecular patterns. This enhanced recruitment of effector tumor-infiltrating immune cells (TIIs), including NKT cells and CD8 T cells, and elicited an increased percentage of professional antigen-presenting cells (APCs) CD11c dendritic cells. Transient weight loss, accompanying hepatotoxicity, nephrotoxicity, and hematopoietic suppression, was observed as a systemic adverse event in the cisplatin but not the Au-cisplatin NPs group. Cisplatin and Au-cisplatin NPs both showed equivalent ability to reduce metastatic potential when combined with ablative RT, confirmed by suppressed un-irradiated flank tumor growth and decreased metastatic lung tumor burden, which translated to improved survival. Mobilization and abundance of effector TIIs including CD8 T cells and dendritic cells were observed in the distant lung tumor microenvironment after ablative RT with cisplatin or Au-cisplatin NPs, demonstrating increased antitumor immunotherapeutic activity as an abscopal effect. Compared to cisplatin, the albumin-based Au-cisplatin NPs exhibited equivalent but no superior antitumor immunotherapeutic activity while reducing systemic adverse events, and can be safely administered concurrently with ablative RT. Alternative nanoparticle formulations may be designed to further improve anticancer outcomes.

Avocado peel extract loaded on chitosan nanoparticles alleviates urethane toxicity that causes lung cancer in a mouse model.

Lung cancer progresses without obvious symptoms and is detected in most patients at late stages, causing a high rate of mortality. Avocado peels (AVP) were thought to be biowaste, but they have antioxidant and anticancer properties in vitro. Chitosan nanoparticles (Cs-NPs) were loaded with various plant extracts, increasing their in vitro and in vivo anticancer activities. Our goal was to load AVP onto Cs-NPs and determine the role of AVP-extract or AVP-loaded Cs-NPs in controlling the progression of lung cancer caused by urethane toxicity. The AVP-loaded chitosan nano-combination (CsAVP NC) was synthesized and characterized. Our in vitro results show that CsAVP NC has higher anticancer activity than AVP against three human cancer cell lines. The in vivo study proved the activation of apoptosis in lung cancer cells with the CsAVP NC oral treatment more than the AVP treatment. Additionally, CsAVP NC-treated animals showed significantly higher p53 and Bax-expression levels and lower NF-κB p65 levels in their lung tissues than in positive control animals. In conclusion, our study demonstrated the superior anticancer potency of CsAVP NC over AVP extract and its ability to inhibit lung cancer proliferation. Therefore, oral consumption of CsAVP NC might be a promising treatment for lung cancer.

Changes in the treatment rate of patients newly diagnosed with stage IV cancer near the end of life from 2012 to 2017 in Korea.

This study aimed to evaluate changes in the cancer treatment rate among patients newly diagnosed with stage IV cancer using sociodemographic and clinical subgroups in a nationwide cohort of Korean patients. This retrospective, national-level study used the Korea Central Cancer Registry (KCCR), which is linked to the National Health Insurance Service (NHIS) database, from January 1, 2012 to December 31, 2017. The records of patients newly diagnosed with stage IV of the 5 cancers with the highest cancer-related mortality rate were identified to analyze changes in the treatment rate. The main outcome examined in this study was the change in the cancer treatment rate between 2012 and 2017, as measured using the annual percent change (APC). A total of 106,082 patients with newly diagnosed gastric, colorectal, liver, pancreatic, and lung cancers at the end of life (EoL) were identified from the KCCR-NHIS database. Of these patients, 76,533 (72.1%) received cancer treatment. Over the study period (2012-2017), the proportion of patients who received cancer treatment at EoL decreased by 8.3%, with an APC of -2.1% (95% confidence interval, -2.6% to -1.6%). This declining trend of cancer treatment among patients with advanced cancer stage at EoL was consistent among sociodemographic and clinical subgroups. The proportion of untreated patients with stage IV cancer is increasing in the Republic of Korea. For patients who are not undergoing standard cancer treatment near EoL, an alternative care plan, such as early palliative care, should be considered.

EGFR-TKI Combined with Pemetrexed Versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC A Prospective, Randomized, Exploratory Study.

We aimed to evaluate whether the addition of pemetrexed is effective in improving progression free survival in EGFR-mutated patients with or without concomitant alterations. This multicenter clinical trial was conducted in China from June 15, 2018 to May 31, 2019. A total of 92 NSCLC patients harboring EGFR sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-TKI monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 11. Progression free survival (PFS) was recorded as the primary endpoint. The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p0.21 and p0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p0.0021). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. EGFR-TKI monotherapy is applicable to EGFR sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Small Cell Lung Cancer in LightNever Smokers - A Role for Molecular Testing

This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor-sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have lightnever smoking histories in order to help understand the incidence and ultimate optimal management strategies.

Dual-quenching electrochemiluminescence resonance energy transfer system from CoPd nanoparticles enhanced porous g-C

For the diagnosis and therapy of small cell lung cancer (SCLC), the accurate and sensitive determination of neuron-specific enolase (NSE) content is crucial. This work outlines a dual-quenching electrochemiluminescence resonance energy transfer (ECL-RET) immunosensor based on the double quenching effects of iron base metal organic frameworks (FeMOFs) loaded with small sized CuO nanoparticles (FeMOFs-sCuO) towards CoPd nanoparticles (CoPdNPs) enhanced porous g-C

Efficacy of blonanserin transdermal patch on terminal delirium in patients with respiratory diseases.

Delirium is a common distressing symptom observed in patients with terminal respiratory diseases and is treated with antipsychotic medications such as haloperidol. Its management is difficult, especially in palliative home care, because its administration is limited to oral or injection methods. Recently, the blonanserin transdermal patch was developed as the first antipsychotic percutaneous agent. After it became available, we recognized its potential for the management of delirium and the alleviation of uncontrolled dyspnea in clinical practice. Thus, this study aimed to assess its efficacy in patients with terminal respiratory diseases. This retrospective study included 113 patients with respiratory diseases who were cared for at home. The efficacy was evaluated through the prevalence of terminal delirium before and after its treatment initiation for uncontrolled dyspnea. Blonanserin transdermal patch treatment for uncontrolled dyspnea improved the prevalence and severity of terminal delirium (from 70.4% to 16.3%, p < 0.001) and reduced the number of doctors visits to patients homes within a week before their death (from 4.0 to 3.0, p 0.086). A sub-group analysis of 23 patients with interstitial pneumonia revealed that the treatment prevented dyspnea progression by inhibiting terminal delirium. Blonanserin transdermal patch performed similarly to haloperidol, as previously reported, for managing terminal delirium. Our study suggests that a blonanserin transdermal patch potentially prevents terminal delirium and alleviates uncontrolled dyspnea in patients with respiratory diseases. Our findings encourage clinical trials to evaluate the safety and efficacy of blonanserin transdermal patches for patients with terminal illnesses.

LDANet Automatic lung parenchyma segmentation from CT images.

Automatic segmentation of the lung parenchyma from computed tomography (CT) images is helpful for the subsequent diagnosis and treatment of patients. In this paper, based on a deep learning algorithm, a lung dense attention network (LDANet) is proposed with two mechanisms residual spatial attention (RSA) and gated channel attention (GCA). RSA is utilized to weight the spatial information of the lung parenchyma and suppress feature activation in irrelevant regions, while the weights of each channel are adaptively calibrated using GCA to implicitly predict potential key features. Then, a dual attention guidance module (DAGM) is designed to maximize the integration of the advantages of both mechanisms. In addition, LDANet introduces a lightweight dense block (LDB) that reuses feature information and a positioned transpose block (PTB) that realizes accurate positioning and gradually restores the image resolution until the predicted segmentation map is generated. Experiments are conducted on two public datasets, LIDC-IDRI and COVID-19 CT Segmentation, on which LDANet achieves Dice similarity coefficient values of 0.98430 and 0.98319, respectively, outperforming a state-of-the-art lung segmentation model. Additionally, the effectiveness of the main components of LDANet is demonstrated through ablation experiments.

Dual kinase inhibitor for EGFR mutants and ErbB2 limit breast cancer.

Mutations in the epidermal growth factor receptor (EGFR) have been found in more than 10% of non-small cell lung cancer (NSCLC) patients in North America. The vast majority of these differences are L858R point mutations in Exon 21. Currently, monoclonal antibodies directed against the extracellular domain of EGFR or small moleculetyrosine kinase inhibitors (TKI) are the stalwarts of NSCLC therapy. Resistance, however, gradually develops because of the T790 mutation towards first and second generation TKIs. The third generation TKI AZD9291 (Osimertinib) has a high affinity for both activating and the acquired resistant mutation (T790 M) in EGFR, with a low affinity towards wild-type EGFR. Recent research, however, suggests that the EGFR (C797S) mutation in the tyrosine kinase domain is a likely cause of resistance to AZD9291. Another significant transformation mechanism associated with this resistance is erbB2 amplification. Our laboratory has developed a small kinase inhibitor, ER121 (MW ∼500), that inhibits the erbB2HER2 tyrosine kinases in addition to the EGFR C797S mutations. We have identified a TKI, ER121 targeting the mutant EGFR(T790 M). Using in vitro and in vivo models, examined the efficacy of ER121 on mutant EGFR cell lines. This has enabled us to establish that ER121 is well tolerated when administered orally and produces significant inhibitory activity against human cancers generated by mutant EGFR and amplified ErbB2.

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa ZD1839 AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. Efficacy was similar for the 250- and 500-mgd groups. Objective tumor response rates were 18.4% (95% confidence interval CI, 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9) among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1) median progression-free survival times were 2.7 and 2.8 months and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mgd) and 85.7% (500 mgd) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mgd, respectively. Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mgd, gefitinib had a favorable AE profile. Gefitinib 250 mgd is an important, novel treatment option for patients with pretreated advanced NSCLC.

Investigating gene-diet interactions impacting the association between macronutrient intake and glycemic traits.

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed N33,187 diabetes-free participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g. for hemoglobin A1c HbA1c, -0.013 %HbA1c per 250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that over 150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry.

Assessing the Contribution of Scanned Outside Documents to the Completeness of Real-World Data Abstraction.

Electronic health record (EHR) data are widely used in precision medicine, quality improvement, disease surveillance, and population health management. However, a significant amount of EHR data are stored in unstructured formats including scanned documents external to the treatment facility presenting an informatics challenge for secondary use. Studies are needed to characterize the clinical information uniquely available in scanned outside documents (SODs) to understand to what extent the availability of such information affects the use of these real-world data for cancer research. Two independent EHR data abstractions capturing 30 variables commonly used in oncology research were conducted for 125 patients treated for advanced non-small-cell lung cancer at a comprehensive cancer center, with and without consideration of SODs. Completeness and concordance were compared between the two abstractions, overall, and by patient groups and variable types. The overall completeness of the data with SODs was 77.6% as compared with 54.3% for the abstraction without SODs. The differences in completeness were driven by data related to biomarker tests, which were more likely to be uniquely available in SODs. Such data were prone to missingness among patients who were diagnosed externally. There were no major differences in completeness between the two abstractions by demographics, diagnosis, disease progression, performance status, or oral therapy use. However, biomarker data were more likely to be uniquely contained in the SODs. Our findings may help cancer centers prioritize the types of SOD data being abstracted for research or other secondary purposes.

Epidemiology and psychiatric correlates of cancer among homeless and unstably housed veterans in the VA healthcare system.

This study examined the incidence and correlates of cancer among homeless and unstably housed (HUH) veterans as compared to stably housed (SH) veterans. Using VA administrative data from 564,563 HUH and 5,213,820 SH veterans in 2013 and 2014, we examined the types and stages of 69 different types of cancer diagnosed among HUH and SH veterans. Sociodemographic and psychiatric characteristics associated with cancer were also examined. The one-year incidence rate of cancer was 21.5% lower among HUH veterans than SH veterans (0.68% and 0.86% respectively). There was no difference in the most common stages and types of cancer among HUH and SH veterans. The most common primary sites of cancer were in the prostate, lung, and bronchus. HUH veterans were more likely than SH veterans to have cancer of the liver and intrahepatic bile ducts (∆4.79%). Among HUH veterans, older age and alcohol use disorder were associated with greater risk for any incident cancer while suicidal ideationbehaviors were associated with lower risk. Psychiatric conditions were often diagnosed before cancer diagnosis for SH and HUH veterans rates of substance use disorders and suicidal ideationbehaviors decreased in HUH veterans after cancer diagnosis. The VA healthcare system serves many HUH veterans with cancer. Mental health and substance use disorders are important to treat in veterans at risk of cancer and as potential sequalae of cancer. The high prevalence of psychiatric disorders in HUH populations is important to consider in the diagnosis and treatment of cancer in these populations.

Inflammatory and Nested Testicular Sex Cord Tumor A Novel Neoplasm With Aggressive Clinical Behavior and Frequent EWSR1ATF1 Gene Fusions.

A subset of malignant testicular sex cord tumors (TSCTs), heretofore interpreted as Sertoli cell tumors, not otherwise specified, exhibits distinctive morphologic features that partially overlap with those of seminoma. In this study, we evaluated the clinicopathologic and molecular characteristics of 13 such tumors. The patients were 20 to 73 years old (median, 36 y), and all with available data presented with testicular masses (median size, 3 cm), with 2 having synchronous retroperitoneal metastases. All 11 patients with available follow-up developed metastases to retroperitoneal lymph nodes, nonretroperitoneal lymph nodes, bone, contralateral testis, andor lung. Microscopically, the tumors showed solid nests and sheets of epithelioid cells with granular, eosinophilic to clearvacuolated cytoplasm, admixed in most (1213) cases with variable proportions of lymphocytes, plasma cells, eosinophils, and neutrophils. Additional features included intracytoplasmic hyaline inclusions and a prominent collagenous, sometimes hyalinized stroma. Mitotic activity was relatively low (median, 1 mitosis10 HPF), but tumor necrosis was frequent (1113). Local invasion of adjacent structures and lymphovascular invasion were noted in some tumors (49 cases with available data for each feature). All were α-inhibin-positive and lacked nuclear reactivity for β-catenin. In addition, all tested cases were positive for epithelial membrane antigen (99) and steroidogenic factor-1 (88), and 810 expressed CD30. Two index cases were initially analyzed using a DNA sequencing panel, which identified EWSR1ATF1 fusions in both. Subsequently, EWSR1ATF1 fusions were demonstrated in 8 of the remaining 11 cases using fluorescence in situ hybridization or DNA sequencing. One of the 3 cases that were negative for EWSR1ATF1 harbored ATF1 amplification. This study, therefore, shows that a group of malignant TSCTs resembling seminoma is characterized by α-inhibin and steroidogenic factor-1 positivity, no expression of nuclear β-catenin, frequent CD30 positivity and recurrent EWSR1ATF1 fusions. We have descriptively termed these neoplasms inflammatory and nested TSCT. Importantly, inflammatory and nested TSCTs show significant differences in morphology, immunoprofile, molecular biology, and, likely, clinical behavior from Sertoli cell tumors, not otherwise specified and should be classified separately.

Conditioned media from human pluripotent stem cell-derived cardiomyocytes inhibit the growth and migration of lung cancer cells.

Conditioned media (CM) from various cell types contain significant levels of paracrine factors. Recently, therapeutic properties of CM derived from stem cells have been revealed. Based on the fact that heart cancer is extremely rarely, we hypothesized that the CM obtained from human pluripotent stem cell-derived cardiomyocytes might inhibit cancer cell growth and survival. To this end, lung cancer cell line A549 along with human foreskin fibroblasts (HFF) were treated with serial concentrations of cardiomyocyte CM (CCM) or fibroblast CM (FCM). We found that CCM markedly reduced the viability of lung cancer cells, while FCM did not compromise the viability of neither cancer cells nor HFF cells. Furthermore, we determined an optimized CCM concentration, 30 mgmL, at which the growth, clonogenicity, and migration of A549 and Calu6 lung cancer cell lines were substantially impaired, whereas FCM did not influence these properties. Moreover, lung cancer cells exhibited cell cycle regulation upon treatment with CCM and the rate of apoptosis was markedly increased by cardiomyocyte CM in both lung cancer cell lines tested. Finally, in response to CCM treatment, A549 and Calu6 cells expressed lower levels of antiapoptotic and stemness genes, but higher levels of proapoptotic genes. In conclusion, this study provides cellular and molecular evidence for the antitumor ability of secretome obtained from stem cell-derived cardiomyocytes.

ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via

Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, understanding the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investigated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-κB) and Activator protein 1 (AP1) are major transcriptional regulators of

Non-Lobe Specific Metastases in Occult N2 after Lobectomy for Clinical N0 Non-Small Cell Lung Cancer.

Non-small cell lung cancer can spread into lobe specific stations and non-lobe-specific mediastinal lymph nodes. We evaluated frequency and features of non-lobe specific nodal metastases, focusing especially on the prognostic value of only non-lobe specific N2-metastases after lobectomy. We performed a retrospective review of 550 patients with non-small cell lung cancer with clinical N0, undergoing lobectomy and systematic or lobe specific node dissection. We evaluated disease free and overall survival rates using Kaplan-Meier method and significance was tested by log-rank test. Occult N2 disease was detected in 68 patients (8.1%), 26 of them (38.2%) had metastases in non-lobe specific stations. Comparing patients with lobe and non-lobe specific lymph node metastases, 3-years DFS rate was 44.4% In patients with occult N2 disease, the finding of a metastatic lymph node in a non-lobe specific station relates with significant lower survival rate. The subset of patients who presented only non-lobe specific node metastases showed a significant lower survival rate compared to the remaining occult N2.

Ginsenoside Rg3 enhances the radiosensitivity of lung cancer A549 and H1299 cells via the PI3KAKT signaling pathway.

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths in the world. Radiation is widely used for the treatment of lung cancer. However, radioresistance and toxicity limit its effectiveness. Ginsenoside Rg3 (Rg3) is a positive monomer extracted from ginseng and has been shown to the anti-cancer ability on many tumors. The aim of the present study was to ascertain whether Rg3 is able to enhance the radiosensitivity of lung cancer cells and investigate the underlying mechanisms. The effect of Rg3 on cell proliferation was examined by Cell Counting Kit-8 (CCK-8) and radiosensitivity was measured by colony formation assay. Flow cytometry, transwell, and wound healing assay were used to determine apoptosis, cell cycle, and metastasis. Western blot was used to detect the main protein levels of the PI3KAKT signaling pathway. We found that Rg3 inhibited cell proliferation, promoted apoptosis, and suppressed migration and invasion in radio-induced lung cancer cells. In addition, Rg3 increased the proportion of G2M phase cells and inhibited the formation of cell colonies. Moreover, Rg3 decreased the expression levels of PI3K, p-AKT, and PDK1 in radio-induced cells. These findings indicate that Rg3 may be able to enhance the radiosensitivity in lung cancer cells by the PI3KAKT signaling pathway. These results demonstrate the therapeutic potential of Rg3 as a radiosensitizer for lung cancer.

Comparative study of radon sources and associated health risk in four underground uranium mines.

This paper presents a comparative study of the quantitative estimation of

Cyclin-dependent kinase (CDK) 46 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations.

Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 46 inhibitor, simultaneously with osimertinib in vitro. Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n 27 pStage 0-I, n 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p 0.02), lymph node metastasis (p 0.001), and lymphatic invasion (p 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. Combination therapy with CDK46 inhibitors and EGFR-TKIs may be a promising approach.

Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2.

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

An ordinal radiomic model to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma based on low-dose computed tomography in lung cancer screening.

To construct a radiomic model of low-dose CT (LDCT) to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma (IPA) and compare its diagnostic performance with quantitative-semantic model and radiologists. A total of 682 pulmonary nodules were divided into the primary cohort (181 grade 1 254 grade 2 64 grade 3) and validation cohort (69 grade 1 99 grade 2 15 grade 3) according to scanners. The radiomic and quantitative-semantic models were built using ordinal logistic regression. The diagnostic performance of the models and radiologists was assessed by the area under the curve (AUC) of the receiver operating characteristic curve and accuracy. The radiomic model demonstrated excellent diagnostic performance in the validation cohort (AUC, 0.900 (95%CI 0.847-0.939) for Grade 1 vs. Grade 2Grade 3 AUC, 0.929 (95%CI 0.882-0.962) for Grade 1Grade 2 vs. Grade 3 accuracy, 0.803 (95%CI 0.737-0.857)). No significant difference in diagnostic performance was found between the radiomic model and radiological expert (AUC, 0.840 (95%CI 0.779-0.890) for Grade 1 vs. Grade 2Grade 3, p 0.130 AUC, 0.852 (95%CI 0.793-0.900) for Grade 1Grade 2 vs. Grade 3, p 0.170 accuracy, 0.743 (95%CI 0.673-0.804), p 0.079), but the radiomic model outperformed the quantitative-semantic model and inexperienced radiologists (all p < 0.05). The radiomic model of LDCT can be used to predict the differentiation grade of IPA in lung cancer screening, and its diagnostic performance is comparable to that of radiological expert. • Early identifying the novel differentiation grade of invasive non-mucinous pulmonary adenocarcinoma may provide guidance for further surveillance, surgical strategy, or more adjuvant treatment. • The diagnostic performance of the radiomic model is comparable to that of a radiological expert and superior to that of the quantitative-semantic model and inexperienced radiologists. • The radiomic model of low-dose CT can be used to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma in lung cancer screening.

Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade.

Concurrent PD-1 blockade and thoracic radiotherapy is being investigated in clinical trials for locally advanced, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), despite a potential overlapping risk of cardiotoxicity. Our prior studies demonstrate that cardiotoxicity from concurrent cardiac irradiation and anti-PD-1 administration in a mouse model is CD8 T cell-dependent. The objective of this study was to determine if humoral immunity contributed to the observed cardiac tissue damage, as measured by creatine kinase MB and cardiac troponin 1 release and decline in cardiac function. In the current study, we demonstrate the presence of cardiac autoantibodies, which were essential for the occurrence of cardiotoxicity from the combined therapy. Mice subjected to cardiac irradiation, while being treated with anti-PD-1, developed high levels of antibodies that reacted with cardiac tissues in vivo and cardiac antigens in vitro. Moreover, mice deficient in B cells were protected against cardiotoxicity, whereas the transfer of autoantibody-containing sera from mice that had received combined treatment reproduced the same pathological phenotype in mice exposed to cardiac irradiation but was not observed in normal recipients. The cardiotoxic effect of the sera, which associated with CD8 T-cell accumulation in cardiac tissue, was limited by IgG depletion. In conclusion, concurrent cardiac irradiation and PD-1 blockade leads to production of cardiac autoantibodies, likely due to antigen exposure within the irradiated cardiac tissues, which play a key role in the resulting cardiotoxicity.

Fine needle aspirational cytology of metastatic tumours to the thyroid.

Metastasis to the thyroid gland from non-thyroid sites is relatively rare and often poses a diagnostic difficulty on fine-needle aspiration cytology as it often mimics primary thyroid neoplasms. All cases of fine needle aspiration cytology (FNAC) of metastasis to the thyroid gland ( 2014 to 2022) were selected from the pathology database. The detailed cytopathological features and histopathology of the cases were studied. There was a total of 18 cases of secondary tumours of the thyroid. All cases had confirmed histopathological data. The commonest sites of the primary tumours in our study were squamous cell carcinoma of the oesophagus (9) followed by infiltrating ductal carcinoma of the breast (4), and one case each of renal cell carcinoma, neuroendocrine carcinoma of the lung, carcinoma stomach and malignant melanoma and squamous cell carcinoma from vallecula. Metastasis to thyroid carcinoma is relatively uncommon. The history of malignancy, the presence of malignant cells amid benign thyroid follicular cells, unusual malignancy in FNAC smear and immunocytochemistry are helpful in diagnosing such cases.

Tomographic pleuropulmonary manifestations in rheumatoid arthritis a pictorial essay.

Rheumatoid arthritis (RA) is an autoimmune inflammatory and heterogeneous disease that affects several systems, especially the joints. Among the extra-articular manifestations of RA, pleuropulmonary involvement occurs frequently, with different presentations, potentially in all anatomic thoracic compartments, and may determine high morbidity and mortality. The most common pleuropulmonary manifestations in patients with RA include interstitial lung disease (ILD), pleural disease, pulmonary arterial hypertension, rheumatoid lung nodules, airway disease (bronchiectasis and bronchiolitis), and lymphadenopathy. Pulmonary hypertension and ILD are the manifestations with the greatest negative impact in prognosis. HRCT of the chest is essential in the evaluation of patients with RA with respiratory symptoms, especially those with higher risk factors for ILD, such as male gender, smoking, older age, high levels of rheumatoid factor, or positive anti-cyclic citrullinated peptide antibody results. Additionally, other etiologies that may determine tomographic pleuropulmonary manifestations in patients with RA are infections, neoplasms, and drug-induced lung disease. In these scenarios, clinical presentation is heterogeneous, varying from being asymptomatic to having progressive respiratory failure. Knowledge on the potential etiologies causing tomographic pleuropulmonary manifestations in patients with RA coupled with proper clinical reasoning is crucial to diagnose and treat these patients.

Risk of Tract Seeding Following Laser Interstitial Thermal Therapy for Brain Tumors.

The management of intracranial oncological disease remains a significant challenge despite advances in systemic cancer therapy. Laser interstitial thermal therapy (LITT) represents a novel treatment for local control of brain tumors through photocoagulation with a stereotactically implanted laser fiber. Because the use of laser interstitial thermal therapy continues to increase within neurosurgery, characterization of LITT is necessary to improve outcomes. To quantify the risk of tumor seeding along the laser fiber tract in patients receiving LITT for primary or metastatic brain tumors at a high-volume treatment center. We retrospectively reviewed all patients receiving LITT from 2015 to 2021 at our medical center. Patients with biopsy-confirmed tumors were included in this study. Tract seeding was identified as discontinuous, newly enhancing tumor along the LITT tract. Fifty-six patients received LITT for biopsy-confirmed tumors from 2015 to 2021, with tract seeding identified in 3 (5.4%). Twenty-nine (51.8%) patients had gliomas, while the remainder had metastases, of which lung was the most common histology (20 patients, 74%). Tract seeding was associated with ablation proceeding inward from superficial tumor margin closest to the cranial entry point (P .03). Patients with tract seeding had a shorter median time to progression of 1.1 (0.1-1.3) months vs 4.2 (2.2-8.6) months (P .03). Although the risk of tract seeding after LITT is reassuringly low, it is associated with decreased progression-free survival. This risk may be related to surgical technique or experience. Follow-up radiosurgery to the LITT tract has the potential to prevent this complication.

Personalized Treatment for Patients With Lung Cancer.

Lung cancer is the most common cause of death among all types of cancer in Germany, with an annual death rate of 45 000 patients. Over the past 15 years, innovations in diagnosis and treatment have prolonged the survival of patients with non-small-cell lung cancer in all tumor stages. This review of the diagnosis and treatment of lung cancer is based on current national and international guidelines, and on prospective trials with the highest possible level of evidence that were retrieved by a selective search of the literature. Improved outcomes in patients with non-small-cell lung cancer (85% of new diagnoses) were achieved with the aid of precise diagnostic techniques, including functional imaging and endobronchial procedures for localized disease stage. Contemporary surgical and radio-oncological technologies reduce the morbidity and expand the boundaries of local therapy. Molecular pathology, including the assessment of predictive biomarkers, is an integral part of the diagnostic evaluation of non-small-cell lung cancer in all tumor stages it enables stratified cytotoxicmolecularly targeted treatments and immunotherapies and improves patient-reported outcomes. The percentage of long-term survivors in the metastatic stage has doubled by the introduction of immunotherapy. In contrast, there has been no major improvement in the survival of patients with small-cell lung cancer (15% of new diagnoses). In addition to the implementation of lung cancer screening in high-risk populations, the further development and consistent implementation of personalized diagnosis and treatment in certified lung cancer centers can be expected to prolong survival and improve the patients quality of life.

Full cost of diagnostic pathology for lung carcinoma in Italy results from four Pathology Units.

To calculate the full cost of diagnostic pathology tests for Non-Small Cell Lung Cancer (NSCLC) across four Italian Pathology Units. Pathology Units were located in private (2) and public (2) hospitals distributed across the Italian territory (North 2 Centre 1 South 1). Pathologists provided via questionnaire data on tests on NSCLC samples along with the identification and quantification of the necessary healthcare resources (diagnostic technologies, laboratory instruments and personnel). Resources were valued according to hospital-specific unit, yearly and hourly costs (disposables technologies professional clusters). The full cost per NSCLC tissue sample included histopathological immunophenotypic and required molecular analysis. Overall, it reached € 659.77 and it was mainly composed of direct costs (77.69%). The processing of a NSCLC tissue sample was labour intensive, as a relevant share of the full cost (44.98%) was actually due to personnel costs, with laboratory technicians, biologists and pathologist driving this finding (17.09%,12.43% and 10.81%, respectively). The results of this research can facilitate the negotiation of new dedicated tariffs for NSCLC sample processing with the national or local third party-payers.

The Association between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients with Non-Small Cell Lung Cancer Treated with a PD-1L1 Blocking Antibody using Real-World and Trials Data.

Clinical trials have demonstrated the benefit of PD-1L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1L1 blocking antibodies in real-world data (RWD patient-level data from electronic-health records) and pooled clinical trials data submitted to the FDA. The Kaplan-Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and holds promise to complement trial data in better understanding populations not represented in clinical trials.

Seasonal effects on cancer incidence and prognosis.

It is unknown if the reduction in the expected number of cancer cases diagnosed during Swedish holidays are due to diagnostic delays, how different cancers are affected, and if the season of diagnosis influences long-term cancer survival. We aimed to quantify seasonal trends in incidence and excess mortality for a wide range of malignancies, requiring more or less urgent clinical management. This nationwide cohort study included all Swedish residents aged 20-84 in 1990-2019. Incidence and relative survival in pancreatic, colorectal, lung, urothelial, breast, and prostate cancer, together with malignant melanoma, non-Hodgkin lymphoma, and acute leukemia diagnosed during holiday and post-holiday were compared to working (reference) season. Incidence rate ratios (IRR) were estimated using Poisson regression and excess (cancer) mortality rate ratios using flexible parametric models. We identified 882,980 cancer cases. Incidence declined during holiday season for all malignancies and the IRR ranged from 0.58 (95% CI 0.57-0.59 in breast to 0.92 (95% CI 0.89-0.94) in pancreatic cancer. A post-holiday increase was noted for acute leukemia, pancreatic, and lung cancer. For all malignancies except lung cancer, non-Hodgkin lymphoma, and acute leukemia, the excess mortality at 2 years from diagnosis was higher among those diagnosed during the holiday season. A tendency toward elevated short-term (0.5 years) excess mortality was noted in the post-holiday group, but long-term effects only persisted in breast cancer. This study demonstrates lower holiday detection rates and higher mortality rates in various cancer types diagnosed during holiday season. Healthcare systems should offer a uniform level of cancer care independent of calendar season.

Cardiac metastasis from a squamous cell carcinoma of the tongue presenting with symptoms of endocarditis a case report.

Cardiac metastasis of squamous cell carcinoma (SCC) of the tongue is rare. This report presents a known case of SCC of the tongue in a patient who was admitted with an initial diagnosis of pneumonia and endocarditis and had received wide spectrum antibiotics. Due to the lack of an appropriate response, surgical valve replacement was initially considered, but further evaluation by cardiac MRI revealed multiple cardiac, lung and paravertebral metastases, most probably from the previous SCC and as such the patient was managed conservatively. This case report highlights the importance of cardiac MRI for evaluating head and neck tumors and choosing optimal treatment plans. Mouth cancer (also known as oral squamous cell carcinoma can spread to other areas of the body, including the heart – this is referred to as cardiac metastases. Although cardiac metastases is rare, it can change the surgical plan and prognosis of the disease. A young woman with a prior history of tongue squamous cell carcinoma was admitted with what was believed to be an infection of the inner surface of the heart, this is also known as infective endocarditis. However, a technique used to assess the function and structure of the cardiovascular system inside the heart called cardiac MRI, showed that the cancer had spread to multiple areas of the heart. With this knowledge the patient was managed conservatively but passed away one month later.

Comparison of treatment strategies for resectable locally advanced primary mucinous adenocarcinoma of the lung.

Primary pure mucinous adenocarcinoma (PMA) is a rare type of lung cancer with unique clinical and prognostic features. Previous studies have shown that PMA have more early-stage cancer compared with other adenocarcinoma (ADC) subtypes. The clinicopathological features and optimal treatment strategies of resectable locally advanced mucinous adenocarcinoma lack evidence and require further study. In this study, we collected information from patients with stage III-N2 PMA who underwent radical surgery between 2004 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. The clinicopathological parameters, treatments, overall survival (OS), and cancer-specific survival (CSS) were evaluated. Of 242,699 eligible lung adenocarcinoma patients, 124 with PMA and 3405 with other ADCs of stage III-N2 received radical surgery were identified. Compared with other ADCs, PMA tended to appear more in the lower lobes, with higher degree of differentiation, less early T stage, and more positive lymph nodes numbers. Patients with PMA had significantly worse survival than other ADCs (OS 45.0 vs. 57.1 months, p 0.005, CSS 51.8 vs. 65.5 months, p 0.017). We explored the benefit population of postoperative radiotherapy (PORT) and found that the population with ≤7 positive lymph nodes could benefit from PORT, and OS was significantly improved (41.2 vs. 69.3 months, p 0.034). For patients with >7 positive lymph nodes, PORT did not provide a survival benefit, while chemotherapy improved OS (10.9 vs. 23.3 months, p 0.041). Multivariate analysis showed that race, tumor location, number of positive lymph nodes, and PORT were independent prognostic factors in patients with postoperative III-N2 lung PMA. The prognosis of patients with resectable III-N2 primary lung PMA was significantly worse than that of other ADCs, and PORT was an independent prognostic factor. Patients with ≤7 positive lymph nodes could benefit from PORT and those with >7 positive lymph nodes could benefit from chemotherapy.

Real-world maintenance therapy and survival outcomes for pembrolizumab plus pemetrexed and platinum for non-small-cell lung cancer in USA.

What is this article about KEYNOTE-189 was a research study (i.e., clinical trial) that compared two different combinations of medicine to treat patients with advanced non-squamous (NSQ) non-small-cell lung cancer (NSCLC). This was the first treatment after being diagnosed for all patients, and they received one of two combinations – either pembrolizumab, pemetrexed, plus a platinum-based chemotherapy (pembropemplat) or placebo plus pemetrexed plus a platinum-based chemotherapy. After receiving these combinations four-times, patients were switched to maintenance therapy with pembro andor pem. In general, patients first treated with pembropemplat survived longer than those treated with placebo plus pemetrexed-platinum. In the current study, researchers wanted to learn if the same results can be expected for patients being treated in the community. What are the results Patients who completed four sessions of pembropemplat and continued on maintenance therapy survived for 21.0 months and those who completed four sessions of pembropemplat but did not continue on maintenance therapy survived for 9.1 months. What do the results of the study mean Patients in the community who were treated with pembropemplat and continued on maintenance therapy survived as long as those in the KEYNOTE-189 study.

Progression patterns and site-specific responses in advanced gastric cancer patients treated with nivolumab.

While the efficacy of immune checkpoint inhibitors (ICIs) reportedly varies among metastatic sites and progression patterns (classified as systemic progression SP or mixed progression MP), the clinical efficacy of ICIs against gastric cancer remains unclear. The response to nivolumab depending on metastatic site and clinical outcomes according to progression pattern in patients with advanced gastric cancer was investigated retrospectively. Seventy-four advanced gastric cancer patients with measurable lesions who received nivolumab monotherapy between 2015 and 2020 were enrolled. Progression-free survival (PFS), overall survival, response at each metastatic site, and clinical outcomes according to progression pattern were analyzed retrospectively. SP and MP were defined as progression in more than half of the lesions and progression in half or fewer of the lesions, respectively, in cases evaluated as progressive disease. Thirty-five (47%) and 27 (36%) patients had SP and MP, respectively, and 12 (16%) patients experienced no progression. The progression rates of target lesions in the lung (44%) and liver (57%) were significantly higher than that in the lymph nodes (18%) (lung vs. lymph node, p < 0.001 liver vs. lymph node, p 0.03). Patients with MP had superior PFS to those with SP (median, 2.6 vs. 1.5 months HR, 0.42 95% CI, 0.23-0.76 p 0.004). In MP group, patients with treatment beyond progression (TBP) with nivolumab had a trend of longer post-progression survival than those without TBP (median, 8.0 vs. 4.0 months HR, 0.55 95% CI, 0.23-1.29 p 0.161). Patients with MP had a longer PFS than those with SP. Lung and liver metastases had a poorer response to an ICI than lymph node metastases.

Excellent response of refractory triple-negative breast cancer to sintilimab plus chemotherapy a case report.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high propensity for invasion and a high incidence of lymph node metastasis. Systemic chemotherapy is considered the primary treatment for patients with TNBC however, immune checkpoint inhibitors in addition to chemotherapy have been associated with better outcomes. Sintilimab, an anti-PD-1 antibody, was developed in China. Herein, the authors report a 49-year-old woman diagnosed with TNBC with extensive lung and sternal metastases. Treatment with sintilimab plus paclitaxel and carboplatin was found highly effective after failure of first-line chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no target for endocrine or targeted therapy, and the standard treatment for patients with TNBC was chemotherapy alone. Recent studies have suggested that immune checkpoint inhibitors plus chemotherapy might be effective and safe for advanced TNBC. Pembrolizumab and atezolizumab have been approved by the US FDA for the treatment of PD-L1-positive TNBC patients. Sintilimab, a Chinese immune checkpoint inhibitor, has not been reported in the treatment of TNBC. This case report presents excellent outcomes of a patient with TNBC who received sintilimab plus chemotherapy after the failure of standard chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials.

Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase III trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. Two doses of nivolumab (3 mgkg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS HR, 0.61 95% confidence interval (CI), 0.15-2.44 and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 611 patients without MPR experienced tumor relapse, and 3 died. Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

Spatial patterns of the cap-binding complex eIF4F in human melanoma cells.

As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. Since different subsets of mRNAs are translated in distinct subcellular compartments, understanding the distribution of translation initiation factors in the cell is of major interest. Here, we developed an

High post-chemotherapy TIL and increased CD4TIL are independent prognostic factors of surgically resected NSCLC following neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NCT) has significantly improved the overall survival of patients with operable non-small cell lung cancer (NSCLC). Chemotherapy can remodel the tumor immune microenvironment (TIME) and has an important influence on antitumor immunity. For patients who underwent surgery for resected NSCLC following NCT (NCT-NSCLC), a prognostic value comparison between naïve and post-chemotherapy TIME is absent. We enrolled 89 patients with NCT-NSCLC in this study the tumor-infiltrating lymphocyte (TIL), CD4TIL, and CD8TIL levels in naïve and post-chemotherapy tumor tissues were detected using immunohistochemistry staining and divided into high and low groups. Kaplan-Meier analysis revealed that major pathology response, pathological tumor, node, and metastasis stage post-NCT (ypTNM), high post-chemotherapy TIL, high post-chemotherapy CD8TIL, low naïve CD4TIL, low naïve CD4CD8TIL ratio, and increased CD4TIL levels post-chemotherapy were favorable prognostic factors in patients with NCT-NSCLC. Multivariate Cox analysis found that ypTNM, high post-chemotherapy TIL, and increased CD4TIL levels post-chemotherapy were independent prognostic factors in patients with NCT-NSCLC. These results indicate that a TIME remodeled by chemotherapy plays an important role in antitumor immunity and has a better prognostic value than the naïve TIME.

Safety Profiling of Tumor-targeted T Cell-Bispecific Antibodies with Alveolus Lung- and Colon-on-Chip.

Traditional drug safety assessments often fail to predict complications in humans, especially when the drug targets the immune system. Rodent-based preclinical animal models are often ill-suited for predicting immunotherapy-mediated adverse events in humans, in part because of the fundamental differences in immunological responses between species and the human relevant expression profile of the target antigen, if it is expected to be present in normal, healthy tissue. While human-relevant cell-based models of tissues and organs promise to bridge this gap, conventional in vitro two-dimensional models fail to provide the complexity required to model the biological mechanisms of immunotherapeutic effects. Also, like animal models, they fail to recapitulate physiologically relevant levels and patterns of organ-specific proteins, crucial for capturing pharmacology and safety liabilities. Organ-on-Chip models aim to overcome these limitations by combining micro-engineering with cultured primary human cells to recreate the complex multifactorial microenvironment and functions of native tissues and organs. In this protocol, we show the unprecedented capability of two human Organs-on-Chip models to evaluate the safety profile of T cell-bispecific antibodies (TCBs) targeting tumor antigens. These novel tools broaden the research options available for a mechanistic understanding of engineered therapeutic antibodies and for assessing safety in tissues susceptible to adverse events. Graphical abstract Figure 1. Graphical representation of the major steps in target-dependent T cell-bispecific antibodies engagement and immunomodulation, as performed in the Colon Intestine-Chip.

Cancer, diabetes, survival and glycemic control a large multisite analysis.

To determine overall survival (OS) and glycemic control in patients with cancer and diabetes. Patients of our institution with breast, colon, lung, pancreas and prostate cancer were retrospectively reviewed. OS was compared between matched patients with and without diabetes, and changes in glucose value over time were assessed. For 3934 patients each with and without diabetes, adjusted analysis showed no difference in OS according to diabetes status (hazard ratio 1.07 95% CI 0.96-1.20). Mean glucose values decreased over time in patients with and without diabetes (p 0.01). In this large study of patients with five common cancers, the co-occurrence of diabetes did not affect OS. Cancer did not adversely affect glucose levels. The aim of this study was to evaluate survival and glucose control in patients with cancer and diabetes at three separate geographic locations in a single health system. From an institutional cancer registry, we identified patients with breast, colon, lung, pancreas and prostate cancers. Patients with and without diabetes were matched by age, sex, cancer type, staging, geographic location and year of cancer diagnosis. In this study, the co-occurrence of diabetes did not affect overall survival. Cancer did not adversely affect glucose levels.

Comparing Gefitinib and Traditional Chemotherapy for Better Survival in Patients With Non-Small Cell Lung Cancer A Systematic Review.

Current non-small cell lung cancer (NSCLC) treatment consists of various combinations of surgery, chemotherapy, andor radiation, depending on the tumor stage. Individuals with stage II-IIIa NSCLC undergo surgery, followed by combination chemotherapy containing cisplatin, such as vinorelbine cisplatin. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, act by inhibiting any signaling pathway containing the EGFR mutation and inhibiting the growth of NSCLC. TKI is a treatment option in advanced NSCLC, resulting in more prolonged progression-free survival (PFS). This manuscript aims to evaluate the influence of utilizing gefitinib - either alone or in combination with conventional chemotherapeutic drug regimens upon NSCLC patient profile survival parameters. A systematic literature review was conducted across multiple scientific literature repositories. The review was performed using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020. There were six randomized clinical trials (RCT) and five retrospective studies. The overall consensus based on the end outcome of each published journal on the effectiveness of gefitinib as a treatment option for NSCLC indicated that there was a notable difference in overall survival (OS) and progression-free survival (PFS) and disease-free survival (DFS) datasets. Gefitinib use correlated with increased timeframes for multiple patient survival parameters within articles shortlisted in this investigation. However, more comprehensive investigations are required to validate such correlations. Gefitinib did demonstrate the potential to provide beneficial effects and counteract NSCLC within such patients.

Impact of KRAS Mutation on Survival Outcome of Patients With Metastatic Colorectal Cancer in Jordan.

Background Colorectal cancer (CRC) is the most prevalent cancer in males, with an incidence rate (IR) of 13.1%, and the second most prevalent cancer in females, with an IR of 8.4%, coming after breast cancer in Jordan. The present study was motivated by conflicting clinical data regarding the prognostic impact of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in patients with metastatic colorectal cancer (mCRC). Our study aimed to investigate if KRAS mutation conferred a negative prognostic value in Jordanian patients with mCRC. Materials and methods The current study is a retrospective study that collected data from a cohort of 135 mCRC patients diagnosed between 1 January 2017 and 1 January 2022 at our Oncology Department at the Jordanian Military Cancer Center (MCAC) using our patients electronic medical records. The last follow-up date was 1 September 2022. From the cohort, we obtained data regarding age, sex, date of diagnosis, metastatic spread, KRAS status, either mutated KRAS or wild-type KRAS, and location of the primary tumor. All patients underwent tumor tissue biopsies to determine KRAS mutational status based on quantitative polymerase chain reaction and reverse hybridization from an accredited diagnostic laboratory at Jordan University Hospital. Statistical analysis was carried out to address the associations between

Unusual Urologic Metastasis From Gastrointestinal Cancers A Compilation of Case Reports and Literature Review.

Gastrointestinal cancers are highly prevalent around the world. In the metastatic setting, the most usual sites for metastases are the liver, lymph nodes, peritoneum, and lung. Urologic metastases are very rare. We report a case series of three patients with gastrointestinal tumours in different topographies (stomach, colon, and rectum) with urological metastases. In all cases, the patients were initially treated with curative intent. Two of the patients presented with bladder metastases, and the third had penile metastases in addition to pulmonary metastases. Haematuria was the most common symptom at presentation. One of the patients had a good overall survival and is still undergoing palliative intent chemotherapy. In the literature, there are few reported cases of urological metastases from gastrointestinal cancers, and that is the aim of this publication.

Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from anomalous accumulation of pathogenic CD1a

A novel, accurate, and non-invasive liquid biopsy test to measure cellular immune responses as a tool to diagnose early-stage lung cancer a clinical trials study.

Lung cancer remains the leading cause of death from cancer, worldwide. Developing early detection diagnostic methods, especially non-invasive methods, is a critical component to raising the overall survival rate and prognosis for lung cancer. The purpose of this study is to evaluate two protocols of a novel in vitro cellular immune response test to detect lung cancer. The test specifically quantifies the glycolysis metabolism pathway, which is a biomarker for the activation level of immune cells. It summarizes the results of two clinical trials, where each deploys a different protocols version of this test for the detection of lung cancer. In the later clinical trial, an improved test protocol is applied. The test platform is based on changes in the metabolic pathways of the immune cells following their activation by antigenic stimuli associated with Lung cancer. Peripheral Blood Mononuclear Cells are loaded on a multiwell plate together with various lung tumor associated antigens and a fluorescent probe that exhibits a pH-dependent absorption shift. The acidification process in the extracellular fluid is monitored by a commercial fluorescence plate reader device in continuous reading for 3 h at 37 °C to document the fluorescent signal received from each well. In the later clinical trial, an improved test protocol was applied and resulted in increased test accuracy. Specificity of the test increased to 94.0% and test sensitivity increased to 97.3% in lung cancer stage I, by using the improved protocol. The improved protocol of the novel cellular immune metabolic response based test detects stage I and stage II of lung cancer with high specificity and sensitivity, with low material costs and fast results.

EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy.

Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome traffickingturnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.

Investigation of Shared Genetic Risk Factors Between Parkinsons Disease and Cancers.

Epidemiological studies that examined the association between Parkinsons disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinsons Disease PD, N 16,519) and EPITHYR (differentiated thyroid cancer, N 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium PD, N 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. We confirmed a previously reported positive genetic correlation of PD with melanoma (G We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Clinical Concept-Based Radiology Reports Classification Pipeline for Lung Carcinoma.

Rising incidence and mortality of cancer have led to an incremental amount of research in the field. To learn from preexisting data, it has become important to capture maximum information related to disease type, stage, treatment, and outcomes. Medical imaging reports are rich in this kind of information but are only present as free text. The extraction of information from such unstructured text reports is labor-intensive. The use of Natural Language Processing (NLP) tools to extract information from radiology reports can make it less time-consuming as well as more effective. In this study, we have developed and compared different models for the classification of lung carcinoma reports using clinical concepts. This study was approved by the institutional ethics committee as a retrospective study with a waiver of informed consent. A clinical concept-based classification pipeline for lung carcinoma radiology reports was developed using rule-based as well as machine learning models and compared. The machine learning models used were XGBoost and two more deep learning model architectures with bidirectional long short-term neural networks. A corpus consisting of 1700 radiology reports including computed tomography (CT) and positron emission tomographycomputed tomography (PETCT) reports were used for development and testing. Five hundred one radiology reports from MIMIC-III Clinical Database version 1.4 was used for external validation. The pipeline achieved an overall F1 score of 0.94 on the internal set and 0.74 on external validation with the rule-based algorithm using expert input giving the best performance. Among the machine learning models, the Bi-LSTMdropout model performed better than the ML model using XGBoost and the Bi-LSTMsimple model on internal set, whereas on external validation, the Bi-LSTMsimple model performed relatively better than other 2. This pipeline can be used for clinical concept-based classification of radiology reports related to lung carcinoma from a huge corpus and also for automated annotation of these reports.

Digital Quantification of Tumor Cellularity as a Novel Prognostic Feature of Non-Small Cell Lung Carcinoma.

Non-small cell lung carcinoma is currently staged based on the size and involvement of other structures. Tumor size may be a surrogate measure of the total number of tumor cells. A recently revised reporting system for adenocarcinoma incorporates high-risk histologic patterns, which may have increased cellular density. Modern digital image analysis tools can be utilized to automate the quantification of cells. In this study, we tested the hypothesis that tumor cellularity can be used as a novel prognostic tool for lung cancer. Digital slides from The Cancer Genome Atlas lung adenocarcinoma (ADC) data set (n 213) and lung squamous cell carcinoma (SCC) data set (n 90) were obtained and analyzed using QuPath. The number of tumor cells was normalized with the surface area of the tumor to provide a measure of tumor cell density. Tumor cellularity was calculated by multiplying the size of the tumor with the cell density. Major histologic patterns and grade were compared with the tumor density of the lung ADC and lung SCC cases. The overall and progression-free survival were compared between groups of high and low tumor cellularity. High-grade histologic patterns in the ADC and SCC cases were associated with greater tumor densities compared with low-grade patterns. Cases with lower tumor cellularity had improved overall and progression-free survival compared with cases with higher cellularity. These results support tumor cellularity as a novel prognostic tool for non-small cell lung carcinoma that considers tumor stage and grade elements.

Genomic Profiling With Large-Scale Next-Generation Sequencing Panels Distinguishes Separate Primary Lung Adenocarcinomas From Intrapulmonary Metastases.

The distinction between different separate primary lung cancers (SPLCs) and intrapulmonary metastases (IPMs) is a challenging but clinically significant issue. Histopathology-based classification is the current practice however, it is subjective and affected by interobserver variability. Recently, next-generation sequencing (NGS) panels have been used in lung cancer diagnostics. This study aimed to investigate the value of large-scale NGS panels for distinguishing between SPLCs and IPMs. A total of 32 patients with 69 lung adenocarcinomas were included. Comprehensive histopathologic assessments of multiple pulmonary adenocarcinomas were performed independently by 3 pathologists. The consensus of histopathologic classification was determined by a majority vote. Genomic analysis was performed using an amplicon-based large-scale NGS panel, targeting single-nucleotide variants and short insertions and deletions in 409 genes. Tumor pairs were classified as SPLCs or IPMs according to a predefined molecular classification algorithm. Using NGS and our molecular classification algorithm, 97.6% of the tumor pairs can be unambiguously classified as SPLCs or IPMs. The molecular classification was predictive of postoperative clinical outcomes in terms of overall survival (P .015) and recurrence-free interval (P .0012). There was a moderate interobserver agreement regarding histopathologic classification (κ 0.524 at the tumor pair level). The concordance between histopathologic and molecular classification was 100% in cases where pathologists reached a complete agreement but only 53.3% where they did not. This study showed that large-scale NGS panels are a powerful modality that can help distinguish SPLCs from IPMs in patients with multiple lung adenocarcinomas and objectively provide accurate risk stratification.

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets.

Basal cell carcinomas (BCCs) are human beings most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAPTAZ-binding domain of TEAD genes. Accordingly, YAPTAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3‑kinase (PI3K)protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3KAKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the natureorigin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.

Diagnostic Accuracy of GATA6 Immunostaining in Sebaceous Tumors of the Skin.

The accurate diagnosis of skin adnexal neoplasms is sometimes challenging but is necessary because medical management and follow-up may differ between tumors. GATA6 transcription factor has been identified as a new marker of the upper folliculosebaceous compartment (lower infundibulum, junctional zone and isthmus, and upper sebaceous gland) in the human skin. We aimed to determine the diagnostic accuracy of GATA6 immunostaining to diagnose sebaceous tumors compared with that to diagnose other adnexal and nonadnexal cutaneous neoplasms. We conducted a retrospective, evaluator-nonblinded study comparing the reference standard (diagnosis by an expert dermatopathologist) with GATA6 immunostaining to identify sebaceous tumors in a cohort containing 234 different tumors. The GATA6 expression score was significatively higher in sebaceous than that in nonsebaceous tumors. In addition, tumors originating from the upper hair follicle showed positive results for GATA6 staining however, they showed lower GATA6 expression scores. Detection of sebaceous tumors using GATA6 positivity had a sensitivity of 95.7% (95% confidence interval 95% CI, 85.8-99.2), specificity of 80.8% (95% CI, 74.5-85.8), positive predictive value of 55.6% (95% CI, 44.7-65.9), and negative predictive value of 98.7% (95% CI, 95.4-99.8). GATA6 showed similar sensitivity to adipophilin, the reference marker however, the specificity of GATA6 was higher, as observed in a cohort of 106 tumors enriched in squamous cell carcinomas with clear-cell histology. In addition, GATA6 positivity was assessed in 39 sebaceous carcinomas and compared with epithelial membrane antigen (EMA), CK7, and androgen receptor (AR) staining results. Although CK7 staining displayed lower diagnostic performances, GATA6 staining showed comparable results as EMA and AR. Finally, we found GATA6 expression in skin metastases of gastrointestinal origin, whereas GATA6 was absent in metastases originating from breast or lung cancers. Overall, our work identified GATA6 immunostaining as a new diagnostic tool for sebaceous tumors.

Identifying SOX17 as a Sensitive and Specific Marker for Ovarian and Endometrial Carcinomas.

Similar to PAX8, SOX17 was recently identified as a master transcription factor of ovarian cancer based on RNA sequencing data. We explored SOX17 utility in diagnosing ovarian tumors and other gynecologic tumors. We systematically evaluated SOX17 expression on tissue microarrays of 398 ovarian tumors of various types, 93 endometrial carcinomas, 80 cervical carcinomas, and 1371 nongynecologic carcinomas, such as those of kidney, thyroid, breast, colon, bladder, liver, bile duct, adrenal gland, pancreas, brain, and lung and malignant melanoma. In addition, we evaluated SOX17 expression in whole tissue sections from 60 gynecologic carcinomas and 10 angiosarcomas. The results demonstrated that SOX17 was highly expressed in most ovarian and endometrial tumors with strong intensity. However, unlike PAX8, it was predominately negative in other tested tumor types, including kidney and thyroid tumors. In particular, SOX17 was highly expressed in the following pathologic subtypes of ovarian tumors serous carcinoma, clear cell carcinoma, endometrioid carcinoma, and germ cell tumors. SOX17 was mostly negative in mucinous carcinoma and sex cord stromal tumors. In addition, SOX17 was expressed in vascular endothelial cells and was positive in all tested angiosarcomas. In summary, our results demonstrate that SOX17 is a sensitive and specific marker for ovarian nonmucinous carcinomas and endometrial carcinomas. For ovarian germ cell tumors and angiosarcomas, SOX17 demonstrates higher specificity than PAX8, with comparable sensitivity. Furthermore, SOX17 positivity in endothelial cells serves as an internal positive control, making it an excellent marker.

Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non-Small Cell Lung Cancer.

Our understanding of the molecular mechanisms underlying postsurgical recurrence of non-small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P .031 and P .024, respectively), along with an increase in regulatory T cells (Treg) (P .018), antigen-experienced T cells (P .025), and effector-memory T cells (P .041). Spatial analysis revealed that a higher level of infiltration of PD-L1

Evidence base for exercise prehabilitation suggests favourable outcomes for patients undergoing surgery for non-small cell lung cancer despite being of low therapeutic quality a systematic review and meta-analysis.

The aim of this systematic review was to evaluate whether exercise prehabilitation programs reduce postoperative complications, postoperative mortality, and length of hospital stay (LoS) in patients undergoing surgery for non-small cell lung cancer (NSCLC), thereby accounting for the quality of the physical exercise program. Two reviewers independently selected randomized controlled trials (RCTs) and observational studies and assessed them for methodological quality and therapeutic quality of the exercise prehabilitation program (i-CONTENT tool). Eligible studies included patients with NSCLC performing exercise prehabilitation and reported the occurrence of 90-day postoperative complications, postoperative mortality, and LoS. Meta-analyses were performed and the certainty of the evidence was graded (Grading of Recommendations Assessment, Development and Evaluation (GRADE)) for each outcome. Sixteen studies, comprising 2,096 patients, were included. Pooled analyses of RCTs and observational studies showed that prehabilitation reduces postoperative pulmonary complications (OR 0.45), postoperative severe complications (OR 0.51), and LoS (mean difference -2.46 days), but not postoperative mortality (OR 1.11). The certainty of evidence was very low to moderate for all outcomes. Risk of ineffectiveness of the prehabilitation program was high in half of the studies due to an inadequate reporting of the dosage of the exercise program, inadequate type and timing of the outcome assessment, and low adherence. Although risk of ineffectiveness was high for half of the prehabilitation programs and certainty of evidence was very low to moderate, prehabilitation seems to result in a reduction of postoperative pulmonary and severe complications, as well as LoS in patients undergoing surgery for NSCLC.

Esophageal Glomus Tumors Rare Neoplasms with Aggressive Clinical Behavior.

Glomus tumors are neoplasms with perivascular smooth muscle differentiation, which rarely occur in the esophagus and may behave aggressively in this site based upon prior case reports. This study describes the clinicopathologic features of 3 esophageal glomus tumors diagnosed at 2 large academic institutions between 1984 and 2022. Three cases of esophageal glomus tumors were identified. Patients included 2 females and 1 male, with an age range of 19-65 years. All 3 tumors behaved in a malignant fashion, with metastases to various sites (lymph nodes, lung, pericardium, pleura, diaphragm, scalp). One patient developed an aorto-esophageal fistula, resulting in a fatal hemorrhage. Tumors ranged in size from 4.5 to 8.1 cm. Histologically, all tumors had a multinodular, perivascular growth pattern. The neoplasms showed varying degrees of cytologic atypia and spindling, elevated mitotic activity (2-12 mitotic figures per 10 high-power fields), and necrosis was seen in in 2 cases. All tumors expressed smooth muscle actin by immunohistochemistry, and harbored NOTCH gene alterations (MIR143NOTCH2 fusion in 2 cases NOTCH3 rearrangement and NOTCH1 point mutation in 1 case). An ATRX splicing mutation in exon 10 was also identified in 1 case. Esophageal glomus tumors pose diagnostic challenges given their rarity at this site but can be recognized by their characteristic perivascular growth pattern, round central nuclei, and supportive ancillary studies. Given the propensity for aggressive behavior in this location, we recommend management by a multidisciplinary sarcoma team for optimal outcome.

Clonal expansion of resident memory T cells in peripheral blood of patients with non-small cell lung cancer during immune checkpoint inhibitor treatment.

Immune checkpoint inhibitors (ICIs) are an essential treatment for non-small cell lung cancer (NSCLC). Currently, the tumor-related intrinsic factors in response to ICIs have mostly been elucidated in tissue samples. However, tissue immune status and changes in the immune microenvironment can also be reflected and monitored through peripheral blood. Single-cell RNA and T cell receptor (scTCR) sequencing were conducted using peripheral blood mononuclear cells (PBMCs) from 60 patients with stage IV NSCLC. Those samples were prospectively acquired from patients treated with anti-PD(L)-1 therapy for advanced lung cancer. Based on the clinical outcomes, samples were classified as durable clinical benefit (DCB) and non-durable clinical benefit (NCB). The samples constituted paired longitudinal samples, consisting of pre-treatment and on-treatment. Additionally, PBMC samples from 60 healthy donors from the Asian Immune Diversity Atlas project were used as a control. The dynamic changes in major cell types between pre-treatment and on-treatment PBMCs were associated with an increase in proliferating T cells and NK cells in both DCB and NCB groups. Among T cell subtypes, effector memory CD8 A transitioning T cell subtype identified in PBMCs might be related to the prolonged ICI response. From our study, expansion of effector memory CD8

Rare recurrence of malignant mesothelioma spreading to the perineum.

Malignant mesothelioma is a rare aggressive tumour of the mesothelium with a propensity to spread locally and, rarely, to distant organs. The latest advances in its diagnosis and treatment have led to an increase in unusual disease presentations. Although a direct invasion of the perineum has been previously described in a men, a malignant mesothelioma spreading to the perianal region was never reported in a women. We presented a rare case of malignant mesothelioma recurrence spreading from the peritoneal cavity to the perineum through the rectovaginal space.

Combining Radiation Therapy with Immune Checkpoint Blockade for the Treatment of Small Cell Lung Cancer.

The addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy has been shown to improve survival in patients with metastatic small cell lung cancer. However, the benefit is modest and there remains an unmet need for novel therapeutic approaches to enhance the effectiveness of immunotherapy in this disease, both in the early and late stages. Ionizing radiation, which is a standard treatment for small cell lung cancer, is known to trigger immunogenic cell death in tumor cells, making it an attractive partner for ICB therapies in multiple solid tumor types. However, the optimal radiation dosage and fractionation scheme, target sites for radiation, and sequencing of radiation in relation to ICB treatment are still unclear. In this review we discuss the molecular biology underlying radiation-induced tumor immunity as well as pre-clinical and clinical studies combining radiation with ICB treatments, with a focus on translational and clinical trials in small cell lung cancer.

Empirical relationship between chromosomal damage and airborne particulate matter A systematic review and meta-analysis of studies in exposed populations.

Ambient particulate matter (PM) has gained significant attention as an environmental risk factor for human health. Although the association between ambient PM and micronucleus (MN) induction has been investigated, the quantitative association of PM and genomic instability is inconclusive. We conducted a systematic review and meta-analysis to study the association between PM exposure and MN endpoint. Four databases were systematically searched for studies published up to November 2022, to find papers investigating the relationship between ambient PM and MN induction. Random effect models were conducted to estimate the overall effect based on the Ratio of Means (RoM) with 95% confidence intervals (95% CIs). Subgroup analysis, funnel plot, and Egger and Begg tests, were also performed. Twenty-three studies across nine countries, including 4,524 participants, were included. A meta-RoM of 2.13 for MN (95% CI 1.63-2.79) was observed for individuals exposed to ambient PM compared to non-exposed. A significant difference in the subgroup test was found for buccal cells (3.16, 95% CI 2.20-4.52) and low economy level (3.61, 95% CI 1.44-9.01). Our meta-analysis suggests the presence of an association between PM exposure and the frequency of MN and identified the kind of cells and economic status as possible effect modifiers. The use of effective methods, such as the MN assay, enables identification of early genetic damage in humans, which in turn may anticipate the risk of developing respiratory diseases, including lung cancer.

CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.

Rare Co-Infection of the Lungs with EBV and Pneumocystis Carinii in a Patient with Kidney Cancer a Case Report.

Epstein-Barr virus (EBV) is the primary agent of infectious mononucleosis, lymphoma, and naso-pharyngeal carcinoma, but rarely involves the lungs. Pneumocystis carinii is commonly found in patients with HIV infection and is not pathogenic when the host is healthy, but opportunistic infections can occur when the body is immunocompromised, causing pneumocystis pneumonia (PCP). It is rare for both diseases to occur in the lungs of the same patient. Next-generation sequencing (NGS), laboratory examination, chest CT scan, electronic bronchoscopy, and pathogenetic examination were used in this study. Laboratory tests showed (1-3)-β-D-glucan of 889.47 pgmL, negative human immunodeficiency virus (HIV) antibody, and negative Aspergillus immunological test. Chest CT showed multiple high-density shadows in both lungs, and EBV infection combined with Pneumocystis carinii pneumonia was confirmed by bronchoscopic biopsy and NGS examination. Elevated serum (1-3)-β-D-glucan is not a specific index for infectious diseases. Bronchoscopy and the NGS has high specificity in pathogen detection of infectious diseases.

Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy an observational study from central Switzerland.

In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology IO group, n 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval CI 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype.

Comprehensive analysis of BUBs gene family in lung adenocarcinoma with immunological analysis.

Lung adenocarcinoma (LUAD) is one of the most commonly malignant tumors, and major challenges remain in the treatment of LUAD. Budding uninhibited by benzimidazole 13 (BUB13) play significant roles in the process of spindle-assembly checkpoint (SAC) during mitosis. However, their roles in LUAD have not been established. Here, we performed an immunological analysis of BUB13 in LUAD using a comprehensive bioinformatics approach, quantitative real-time-PCR and Western blotting technique. Our results indicated that the expression levels of BUB1 and BUB3 in LUAD samples were higher than the expression levels in the control groups and were associated with some clinicopathologic parameters in patients with LUAD. BUB13 and their related genes were enriched in cell immune, and the immune infiltration analysis revealed that the BUB13 expression profile was significantly correlated with characteristics of immune cell infiltration. Survival analysis showed that the disease-free survival and overall survival of patients with LUAD decreased with an increase in the BUB13 expression levels. The mRNA and protein expression levels of BUB1 and BUB3 in each of the LUAD cell lines were upregulated to varying degrees. BUB1 and BUB3 are the potential immunological therapeutic intervention targets for patients with LUAD.

Lobar emphysema ratio of more than 1% in the lobe with lung cancer as poor predictor for recurrence and overall survival in patients with stage I non-small cell lung cancer.

The purpose of this study was to examine the relationship between the lobar emphysema ratio (LER) and tumor recurrence and survival in patients with stage I non-small cell lung cancer (NSCLC). We enrolled 258 patients with surgically proven stage I NSCLC. These patients underwent noncontrast chest CT, and pulmonary lobe segmentation and lobar emphysema quantification were performed using commercially available software. We assessed the LER in the lobe with lung cancer. We divided the patients into two groups according to the LER, and the cut-off value was 1. Furthermore, we analyzed the disease-free survival of high LER and other clinical factors after surgical resection. The 258 patients were divided into two groups low LER (n 195) and high LER (n 63). The right upper lobe was the most frequent location in lung cancer and the most severe location in emphysema. In the Kaplan‒Meier curve, high LER showed a significantly lower disease-free survival (8.21 ± 0.27 years vs 6.53 ± 0.60 years, p 0.005) and overall survival (9.56 ± 0.15 years vs. 8.51 ± 0.49 years, p 0.011) than low LER. Stage Ib (2.812 1.661-4.762, p<0.001) and high LER (2.062 1.191-3.571, p 0.010) were poor predictors for disease-free survival in multivariate Cox regression analysis. Stage Ib (4.729 1.674-13.356, p 0.003) and high LER (3.346 1.208-9.269, p 0.020) were significant predictors for overall survival in multivariate Cox regression analysis. A LER of more than 1% in the lobe with lung cancer is a poor predictor for cancer recurrence and overall survival in patients with stage I NSCLC.

Mental health, cancer risk, and the mediating role of lifestyle factors in the CARTaGENE cohort study.

Evidence on the association between mental health disorders and cancer risk is inconclusive, despite well-established associations between mental health disorders and lifestyle factors such as smoking. This study examines the relationships between depression, anxiety and cancer risk, and the potential mediating effects of lifestyle factors. A study of 34,571 participants aged 40-69 years in the CARTaGENE cohort was conducted. Depression was defined by questionnaire (PHQ-9), antidepressant use, and a composite of questionnaire, antidepressant use, or lifetime self-reported physician diagnosis. Anxiety was defined by questionnaire (GAD-7). Co-morbid depression and anxiety was also assessed. Cox regression models were used to investigate associations between mental health and risk of prostate, lung, and all cancers combined. Mediating effects of lifestyle factors were assessed using Baron and Kenny mediation criteria. There were positive associations between mental health disorders, all cancers and lung cancer risk, however with the exception of anxiety and lung cancer in women (Hazard Ratio HR 1.67, 95% CI 1.01-2.76), associations were attenuated with adjustment for sociodemographics, health status and lifestyle factors. In the mediation analysis, smoking accounted for 27%, 18%, and 26%, of the total effect between depression (PHQ-9), anxiety, and co-morbidity and lung cancer, respectively in women. In men, smoking accounted for 17% of the total effect between depression (PHQ-9, antidepressant, or lifetime self-report of physician diagnosis) and all cancers. Positive associations were observed between mental health disorders, all cancer and lung cancer risk, however most relationships were attenuated with adjustment for lifestyle factors. Smoking status mediated a significant proportion of the relationships between mental health disorders and cancer risk.

Characteristics of the microbiome in lung adenocarcinoma tissue from patients in Kunming city of southwestern China.

The purpose of this study is to identify the characteristics of microbial communities in the lung cancer tissues from patients in Kunming sity of southwestern China and to compare the microbial differences at different clinical stages of lung cancer to uncover potential microbial biomarkers. In total, 40 tissue samples of primary lung adenocarcinoma were collected and further performed by 16S rRNA gene sequencing. The subjects were grouped according to TNM stages (T and N group), clinical stage, and smoke status, and the microbial differences in each group were compared. Analysis of sequence data to determine beta diversity, the UniFrac distance was calculated by QIIME and visualized by principal coordinate analysis (PCoA) using R (version 2.15.3). Microbiome abundance and diversity between different groups were calculated by t test or Wilcoxon rank sum test and drawn by R. The linear discriminant analysis effect size (LEfSe) method was utilized to compare relative abundances of all bacterial taxa between groups. A total of 951 OTUs were identified in the cancer tissues. No significant difference has been found in the alpha diversity within all the groups. Beta diversity significantly differed in the N, T, and clinical stage groups. By LEfSe analysis, eight differential taxa including Bifidobacterium were identified in the N group. In the T1 and T2 group, the LEfSe result identified five phyla and ten genera. The differential genera were Moraxella, Dolosigranulum, unidentifiedCorynebacteriaceae, and Citrobacter in the T2 group and Bifidobacterium, Alistipes, Akkermansia, Blautia, Lactobacillus, as well as Faecalibaculum in the T1 group. Differential bacterial composition and abundance were also observed in the clinical stage group. This study confirmed that by 16S rRNA sequencing, we identified the dominant microbe of lung cancer tissue in different groups. Bifidobacterium may play an essential role in lymph node metastasis and tumor progression, providing a specific potential microbial biomarker for lung adenocarcinoma. PCR products were subject to vertical electrophoresis on 2% agarose gels, and a colloid recovery kit (Qiagen, Valencia, CA) was applied to recover the target bands. Libraries were generated by the TruSeq DNA PCR-Free Sample Preparation Kit (Illumina, San Diego, USA), and the concentrations were quantitated with a Qubit fluorometer. Finally, the qualified libraries were sequenced by NovaSeq6000 (Illumina).

LncRNA PCAT6 promotes proliferation, migration, invasion, and epithelial-mesenchymal transition of lung adenocarcinoma cell by targeting miR-545-3p.

Lung cancer is a high incidence cancer on a worldwide basis and has become a major public health problem. Lung adenocarcinoma (LUAD) makes up approximately half of all lung cancers and is a threat to human health. Long non-coding RNAs (lncRNAs) is an important regulator of the development and progression of lung adenocarcinoma. In this manuscript we examined the role and potential mechanism of lncRNA PCAT6 in the development of LUAD. Differences in lncRNA PCAT6 levels between LUAD samples and normal samples were first explored in the GEPIA database. We found that lncRNA PCAT6 expression was elevated, which was also validated in lung adenocarcinoma tissues and cell lines. Using western blotting, CCK-8, EdU, wound healing and transwell assays, we found that knockdown of lncRNA PCAT6 inhibited EMT, proliferation, migration, and invasion of LUAD cells. We noted a predicted a binding site for lncRNA PCAT6 and miR-545-3p through conducting bioinformatic analyses, and their binding was subsequently verified by a dual-luciferase reporter assay. Rescue experiments confirmed that miR-545-3p inhibitor partially abolished the inhibition function of lncRNA PCAT6 knockdown on LUAD cells. In addition, we predicted the downstream target genes of miR-545-3p and verified them by RT-qPCR. We found that EGFR was reduced in the silence of lncRNA PCAT6 and upregulated after miR-545-3p inhibition. This study demonstrates that lncRNA PCAT6 promotes a more aggressive LUAD phenotype by sponging miR-545-3p. This finding may provide new ideas for the treatment of lung cancer.

Defining the learning curve of robotic portal segmentectomy in small pulmonary lesions a prospective observational study.

Although robotic segmentectomy has been applied for the treatment of small pulmonary lesions for many years, studies on the learning curve of robotic segmentectomy are quite limited. Thus, we aim to investigate the learning curve of robotic portal segmentectomy with 4 arms (RPS-4) using prospectively collected data in patients with small pulmonary lesions. One hundred consecutive patients with small pulmonary lesions who underwent RPS-4 between June 2018 and April 2021 were included in the study. Da Vinci SiXi systems were used to perform RPS-4. The mean operative time, console time, and docking time for the entire cohort were 119.2 ± 41.6, 85.0 ± 39.6, and 6.6 ± 2.8 min, respectively. The learning curve of RPS-4 can be divided into three different phases 1-37 cases (learning phase), 38-78 cases (plateau phase), and > 78 cases (mastery phase). Moreover, 64 cases were required to ensure acceptable surgical outcomes. The total operative time (P < 0.001), console time (P < 0.001), blood loss (P < 0.001), and chest tube duration (P 0.014) were reduced as experience increased. In conclusion, the learning curve of RPS-4 could be divided into three phases. 37 cases were required to pass the learning phase, and 78 cases were needed to truly master this technique.

Transcriptome of Lung Cancer Cells Resistant to the Cytotoxic Activity of Macrophages.

The role of the immune system in tumor progression has been the subject of research for more than 100 years since Paul Ehrlich hypothesized that the presence of the immune system limits the occurrence of cancer. One of the mechanisms hindering the initiation and progression of the tumor is the cytotoxic activity of macrophages however, in some cases, it is not sufficient to control tumorigenesis. This may be due to both the development of resistance of tumor cells to the antitumor activity of macrophages and the development of a tolerant phenotype of macrophages that do not have sufficient antitumor activity. In this work, the lung cancer cells resistant to the cytotoxic action of macrophages were obtained and characterized for the first time, and the genes associated with the observed changes were identified. Understanding the mechanisms of resistance of tumor cells to the cytotoxic activity of macrophages and the peculiarities of its manifestation in a tumor environment is critically important for improving the effectiveness of the existing methods of cancer treatment and developing novel methods for tumor immunotherapy.

The role of brain radiotherapy for EGFR- and ALK-positive non-small-cell lung cancer with brain metastases a review.

Non-small cell lung cancer (NSCLC) is frequently complicated by central nervous system (CNS) metastases affecting patients life expectancy and quality. At the present clinical trials including neurosurgery, radiotherapy (RT) and systemic treatments alone or in combination have provided controversial results. CNS involvement is even more frequent in NSCLC patients with EGFR activating mutations or ALK rearrangement suggesting a role of target therapy in the upfront treatment in place of loco-regionals treatments (i.e. RT andor surgery). So far clinical research has not explored the potential role of accurate brain imaging (i.e. MRI instead of the routine total-body contrast CT andor PETCT staging) to identify patients that could benefit of local therapies. Moreover, for patients who require concomitant RT there are no clear guidelines on the timing of intervention with respect to innovative precision medicine approaches with Tyrosine Kinase Inhibitors, ALK-inhibitors andor immuno-oncological therapies. On this basis the present review describes the therapeutic strategies integrating medical and radiation oncology in patients with metastatic NSCLC (mNSCLC) adenocarcinoma with CNS involvement and EGFR activating mutations or ALK rearrangement.