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Recognising the importance of chronic lung disease a consensus statement from the Global Alliance for Chronic Diseases (Lung Diseases group).

Chronic respiratory diseases are disorders of the airways and other structures of the lung, and include chronic obstructive pulmonary disease (COPD), lung cancer, asthma, bronchiectasis, interstitial lung diseases, occupational lung diseases and pulmonary hypertension. Through this article we take a broad view of chronic lung disease while highlighting (1) the complex interactions of lung diseases with environmental factors (e.g. climate change, smoking and vaping) and multimorbidity and (2) proposed areas to strengthen for better global patient outcomes. We suggest new directions for the research agenda in high-priority populations and those experiencing health disparities. We call for lung disease to be made a research priority with greater funding allocation globally.

Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIPTGF-β1Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis. CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.

Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction.

The leading cause of cancer-related mortality worldwide is lung cancer, and its clinical outcome and prognosis are still unsatisfactory. The understanding of potential molecular targets is necessary for clinical implications in precision diagnostic andor therapeutic purposes. Histone deacetylase 6 (HDAC6), a major deacetylase enzyme, is a promising target for cancer therapy however, the molecular mechanism regulating cancer pathogenesis is largely unknown. The clinical relevance of HDAC6 expression levels and their correlation with the overall survival rate were analyzed based on the TCGA and GEO databases. HDAC6 expression in clinical samples obtained from lung cancer tissues and patient-derived primary lung cancer cells was evaluated using qRT-PCR and Western blot analysis. The potential regulatory mechanism of HDAC6 was identified by proteomic analysis and validated by immunoblotting, immunofluorescence, microtubule sedimentation, and immunoprecipitation-mass spectrometry (IP-MS) assays using a specific inhibitor of HDAC6, trichostatin A (TSA) and RNA interference to HDAC6 (siHDAC6). Lung cancer cell growth was assessed by an in vitro 2-dimensional (2D) cell proliferation assay and 3D tumor spheroid formation using patient-derived lung cancer cells. HDAC6 was upregulated in lung cancer specimens and significantly correlated with poor prognosis. Inhibition of HDAC6 by TSA and siHDAC6 caused downregulation of phosphorylated extracellular signal-regulated kinase (p-ERK), which was dependent on the tubulin acetylation status. Tubulin acetylation induced by TSA and siHDAC6 mediated the dissociation of p-ERK on microtubules, causing p-ERK destabilization. The proteomic analysis demonstrated that the molecular chaperone glucose-regulated protein 78 (GRP78) was an important scaffolder required for p-ERK localization on microtubules, and this phenomenon was significantly inhibited by either TSA, siHDAC6, or siGRP78. In addition, suppression of HDAC6 strongly attenuated an in vitro 2D lung cancer cell growth and an in vitro 3D patient derived-lung cancer spheroid growth. HDAC6 inhibition led to upregulate tubulin acetylation, causing GRP78-p-ERK dissociation from microtubules. As a result, p-ERK levels were decreased, and lung cancer cell growth was subsequently suppressed. This study reveals the intriguing role and molecular mechanism of HDAC6 as a tumor promoter, and its inhibition represents a promising approach for anticancer therapy.

Arginase-1 inhibition reduces migration ability and metastatic colonization of colon cancer cells.

Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer. We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro. Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular L-arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells. Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.

Patient-reported outcome (PRO) measurements in chronic and malignant diseases ten years experience with PRO-algorithm-based patient-clinician interaction (telePRO) in AmbuFlex.

Patient-reported Outcome (PRO) measures may be used as the basis for out-patient follow-up instead of fixed appointments. The patients attend follow-up from home by filling in questionnaires developed for that specific aim and patient group (telePRO). The questionnaires are handled in real time by a specific algorithm, which assigns an outcome color reflecting clinical need. The specific questionnaires and algorithms (named solutions) are constructed in a consensus process with clinicians. We aimed to describe AmbuFlex telePRO solutions and the algorithm outcomes and variation between patient groups, and to discuss possible applications and challenges. TelePRO solutions with more than 100 processed questionnaires were included in the analysis. Data were retrieved together with data from national registers. Characteristics of patients, questionnaires and outcomes were tabulated for each solution. Graphs were constructed depicting the overall and within-patient distribution of algorithm outcomes for each solution. From 2011 to 2021, 29 specific telePRO solutions were implemented within 24 different ICD-10 groups. A total of 42,015 patients were referred and answered 171,268 questionnaires. An existing applicable instrument with cut-off values was available for four solutions, whereas items were selected or developed ad hoc for the other solutions. Mean age ranged from 10.7 (Pain in children) to 73.3 years (chronic kidney disease). Mortality among referred patients varied between 0 (obesity, asthma, endometriosis and pain in children) and 528 per 1000 patient years (Lung cancer). There was substantial variation in algorithm outcome across patient groups while different solutions within the same patient group varied little. TelePRO can be applied in diseases where PRO can reflect clinical status and needs. Questionnaires and algorithms should be adapted for the specific patient groups and clinical aims. When PRO is used as replacement for clinical contact, special carefulness should be observed with respect to patient safety.

At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC.

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1-PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.

Discovery of rafoxanide as a novel agent for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases, is associated with a poor outcome. Rafoxanide is an anthelmintic drug that inhibits tumor growth in certain malignancies. However, its impact on NSCLC remains unknown. In this study, we examined the effect of rafoxanide on NSCLC and dissected the underlying mechanism. The results showed that rafoxanide significantly inhibited the growth, invasion, and migration of NSCLC cells. Besides, rafoxanide can induce NSCLC cell apoptosis and cell cycle arrest in a dose-dependent manner. RNA-seq analysis revealed that genes associated with endoplasmic reticulum stress (ER) stress responses were activated. Mechanistically, we found Rafoxanide can induce ER stress and activate the unfolded protein response (UPR). Apoptosis was activated by excessive ER stress, and autophagy was activated to partially alleviate ER stress. In vivo, we found that rafoxanide inhibited the growth of A549 and H1299 xenograft mouse models without severe side effects. Collectively, the present study indicates that rafoxanide may be a candidate drug for the treatment of NSCLC.

Betulinaldehyde exhibits effective anti-tumor effects in A549 cells by regulating intracellular autophagy.

It is of great significance to find new effective drugs for an adjuvant therapy targeting lung cancer to improve the survival rate and prognosis of patients with the disease. Previous studies have confirmed that certain Chinese herbal extracts have clear anti-tumor effects, and in our preliminary study, betulinaldehyde was screened for its potential anti-tumor effects. The current study thus aimed to confirm the anti-tumor effect of betulinaldehyde, using in vitro experiments to explore its underlying molecular mechanism. It was found that betulinaldehyde treatment significantly inhibited the viability, proliferation, and migration of A549 cells in a dose-dependent manner. In addition, betulinaldehyde inhibited the activation of Akt, MAPK, and STAT3 signaling pathways in A549 cells in a time-dependent manner. More importantly, betulinaldehyde also decreased the expression level of SQSTM1 protein, increased the expression level of LC3 II, and increased the autophagy flux in A549 cells. The pretreatment of A549 cells with the autophagy inhibitor, 3-methyladenine, could partially negate the anti-tumor effects of betulinaldehyde. These findings suggest that betulinaldehyde could significantly inhibit the oncological activity of A549 cells by regulating the intracellular autophagy level, making it a potentially effective option for the adjuvant therapy used to treat lung cancer in the future.

Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.

Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviralanti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.

RBM4 regulates cellular senescence via miR1244SERPINE1 axis.

Cellular senescence serves as a powerful tumor suppressing mechanism that inhibits the proliferation of cancer cells bearing oncogenic mutations at the initial stage of cancer development. RNA-binding proteins (RBPs) play important roles in cancer progression and treatment through distinct functions. However, functions and mechanisms of RNA binding proteins in regulating senescence remain elusive. Here we reported that the RNA binding protein RBM4 contributed to cellular senescence. Depletion of RBM4 induced senescence in different types of cells, including multiple cancer cells. Meanwhile, RBM4 ablation inhibited cancer cell progression both in vitro and in vivo. Specifically, knockdown of RBM4 significantly increased the level of SERPINE1, a known promoter of senescence, thereby inducing the senescence of lung cancer cells. Mechanistically, miR-1244 bound to the 3-UTR of SERPINE1 to suppress its expression, whereas depletion of RBM4 reduced the level of miR-1244 by promoting the degradation of primary miR-1244 transcripts (pri-miR1244), thus increasing the expression of SERPINE1 and inducing subsequent senescence. Moreover, either SERPINE1 inhibitor or miR-1244 mimics attenuated the RBM4 depletion-induced senescence. Altogether, our study revealed a novel mechanism of RBM4 in the regulation of cancer progression through controlling senescence, providing a new avenue for targeting RBM4 in cancer therapeutics.

Synthesis, characterization, solution chemistry and anticancer activity of NiCl

In this work three Ni

Epidemiological and Therapeutic Analyses in Lung Cancer Patients Over 80 Years Old in the Hokushin Region A Retrospective Hospital Administrative Database Study.

This study was performed to validate the epidemiology, initial treatment, and clinical practice in lung cancer patients < 80 and ≥ 80 years in Hokushin region, Japan. We retrospectively surveyed data of 5481 newly diagnosed and registered lung cancer patients (4311 78.7% < 80 years 1170 21.3% ≥ 80 years ) in 22 principal hospitals in Hokushin region linked with health insurance claims data between 2016 and 2017. Stage, initial treatment, and clinical practice were compared between the 2 groups. The distributions of clinical stage IIIIIIIVunknown were 25353876541371111 in non-small cell lung cancer (NSCLC) and 37321142373 in SCLC. Initial surgery for stage I NSCLC was performed in 90.0% and 60.2% of cases in the < 80 and ≥ 80 years groups, respectively. Rates of treatment with best supportive care (BSC) for stage IV disease were significantly higher in the ≥ 80 than the < 80 years group (NSCLC58.9% vs. 18.7% SCLC 42.3% vs. 6.8%, respectively), regardless of the presenceabsence of comorbidities. Propensity score matching showed that age ≥ 80 years itself was significantly related to choice of BSC in patients with lung cancer. The ratio of initial cytotoxic chemotherapy for NSCLC was low (49.9%) but that of biomarker-based therapy including tyrosine kinase inhibitors and immune checkpoint inhibitors (50.0%) was significantly higher in the ≥ 80 than < 80 years group (70.2% vs. 29.8%, respectively). There are several differences in treatment pattern between patients < 80 and ≥ 80 years. Age ≥ 80 years may be related to BSC choice in patients with lung cancer.

Adequate Number of Lymph Nodes Sampled May Determine Appropriate Surgical Modality for Early-Stage NSCLC A Population-Based Real-World Study.

The standard surgical procedure for ≤ 2 cm non-small cell lung cancer (NSCLC), including the number of lymph nodes sampled (nLN) and surgical modality, remains controversial. This study was designed to determine the optimal cohort in which sublobectomy could be an alternative to lobectomy. Patients from 1998 to 2017 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of nLN was identified using a restrictive cubic spline graph (RCS). Kaplan-Meier analysis was used to determine cancer-specific survival (CSS). The COX proportional hazard regression model was used to identify the influence of clinical and demographic variables on survival, and propensity score matching (PSM) was used to balance differences in baseline characteristics. Finally, we used an external cohort from a single-center medical institution to verify the conclusions drawn from the SEER database. A total of 6150 patients were included. The sublobectomy subgroup included segmentectomy (308, 5.0%) and wedge resection (1611, 26.2%). The cutoff value for nLN was 7. In the nLN ≥7 subgroup of the PSM cohort, the CSS of segmentectomy and wedge resection was close to that of the lobectomy subgroup (P .12), whereas in the nLN <7 subgroup, the CSS of the lobectomy subgroup was significantly higher than that of the sublobectomy with P < .001). Surgical methods, nLN, age, sex, and differentiated grade were independent predictors of CSS. External cohort validation A total of 1106 patients from the Affiliated Jinhua Hospital of Zhejiang University School of Medicine between 2013 and 2020 were included. The grouping criteria were consistent with the SEER database. In the nLN≥7 subgroup, sublobectomy had a survival outcome similar to that of lobectomy (P .81). Sublobectomy and nLN < 7 were strongly associated with poorer CSS for early-stage NSCLC. On the premise of nLN ≥ 7, sublobectomy could provide similar survival outcomes to lobectomy for these patients.

Pulmonary artery sarcoma masquerading as pulmonary embolism an under-recognised entity.

Pulmonary artery sarcoma is a rare disease with only a handful of cases reported. It is histologically classified as leiomyosarcoma, spindle cell sarcoma, fibrous histiocytoma or undifferentiated sarcoma. The disease is mostly misdiagnosed as pulmonary thromboembolism and carries a grim prognosis with an average survival of only a few months. Misdiagnosis often results in patients being treated inappropriately and diagnosed in later stages of the disease. This delay in diagnosis can be associated with significant mortality in the setting of an already poor prognosis. Early aggressive surgery targeting complete surgical resection is the standard treatment. Chemotherapy and radiation therapy have been tried with variable outcomes. Given the aggressive nature of pulmonary artery sarcoma, regular post-surgery follow-up is indicated.

Preliminary Validation of the Injustice Experience Questionnaire in Patients With Advanced Cancer.

When diagnosed with advanced cancer, patients may perceive their situation as an injustice. The Injustice Experience Questionnaire (IEQ) is a 12-item measure of perceived unfairness originally developed for patients with chronic pain. The factor structure, reliability, and validity of the IEQ in patients with cancer have not been assessed. To examine the factor structure, internal consistency, and construct validity of the IEQ in patients with advanced cancer. Patients with advanced lung or prostate cancer (N 201) were recruited from academic and public clinics in Indianapolis, IN. Patients completed the 12-item IEQ and other measures of psychological processes and distress. IEQ instructions were modified to focus on cancer-related perceived injustice. Confirmatory factor analysis (CFA) was used to examine the dimensionality of the measure. Internal consistency reliability and construct validity were examined. CFA showed that the original IEQs 2-factor structure had an adequate fit (RMSEA 0.07, CFI 0.96, SRMR 0.05). The factors included Severityirreparability and Blameunfairness. Internal consistency was excellent (α 0.92, ω 0.94). The IEQ showed significant positive associations with physical and psychological symptoms (rs 0.20 - 0.65, Ps < 0.05). The IEQ also showed significant negative associations with quality of life and acceptance of cancer (rs-0.51 - -0.46, Ps < 0.05). Findings provide preliminary support for using the IEQ in patients with advanced cancer. Future research should assess the sensitivity of the IEQ to change in an interventional context.

Association between depressive symptoms and lung function in the United States adults without pulmonary diseases A cross-sectional study from NHANES.

Depression is a severe and common mental disorder. The association between depressive symptoms and lung function remains unclear. To determine whether depressive symptoms are associated with lung function in U.S. adults without pulmonary diseases. A cross-sectional study of National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2012 were used to estimate the relationship between depressive symptoms and lung function. Depressive symptoms were determined by a participants score on the Patient Health Questionnaire-9. Forced Expiratory Volume 1st Second (FEV1) Forced Vital Capacity (FVC) were determined by the spirometry. Weighted multivariate linear regression was used to analyze this relationship and subgroup analyses were performed. Of 8027 participants, 576 (7.18 %) participants with depression. Depression group had significant lower FEV1 and FVC than non-depression group. After adjustment for all covariates, there was a significant negative association between depressive symptoms and FVC (β -4.84, 95 % CI -9.10 to -0.57), especially in non-Hispanic White people (β -9.03, 95 % CI -14.38 to -3.69). There was no independent association between depressive symptoms and FEV1 in all participants, whereas the association was significant in non-Hispanic White people (β -4.91, 95 % CI -9.50 to -0.32). High depressive symptoms were independently associated with decline of FVC among U.S. adults without pulmonary diseases, especially in non-Hispanic White people. In addition, although it was not independently associated with FEV1 in all participants, depressive symptom score was also negatively associated with FEV1 in non-Hispanic White people.

Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort Implications for adjuvant therapy.

The landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population. We performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics. In total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p 0.02), fewer exon 20 insertions (p 0.048), fewer TP53 co-mutations (p 0.007), and were more frequently never smokers (p 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases. As (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment.

Antitumor effect of invasive Lactobacillus plantarum delivering associated antigen gene sHSP between Trichinella spiralis and Lewis lung cancer cells.

Cancer is a frequent disease that seriously harms human health, but there are no ideal therapies for it. Currently, some food-grade microorganisms such as Lactobacillus plantarum have shown better anti-tumor effects. Here, recombinant Lactobacillus plantarum lives vector vaccine NC8-sHSP was generated by using the invasive Lactobacillus plantarum NC8 expressing FnBPA to deliver the associated antigen gene sHSP between trichinella spiralis and Lewis lung cancer cells (LLC) to host cells. NC8-sHSP colonized the mouse intestine to deliver plasmids to intestinal epithelial cells and controlled the growth of LLC by inducing humoral, cellular, and mucosal immunity. The tumor inhibition rates were 62.36% and 68.37% in the prophylactic assay and 40.76% and 44.22% in the treatment assay, respectively. Recombination of Lactobacillus plantarum did not cause significant damage. In conclusion, the recombinant invasive Lactobacillus plantarum constructed in this study has better anti-Lewis lung cancer effects in mice, which will provide new ideas for the application of food-grade microorganisms in anti-tumor and the development of oral tumor vaccines.

Prediction of lung cancer metastasis by gene expression.

Tumor metastasis is the main cause of death in cancer patients. Early prediction of tumor metastasis can allow for timely intervention. At present, research on tumor metastasis mainly focuses on manual diagnosis by imaging or diagnosis by computational methods. With the deterioration of the tumor, gene expression levels in blood change greatly. It is feasible to measure the transcripts of key genes to predict whether cancer will metastasize. Therefore, in this paper, we obtained gene expression data from 226 patients from TCGA. These data included 239,322 transcripts. Background screening and LASSO analysis were used to select 31 transcripts as features. Finally, a deep neural network (DNN) was used to determine whether or not lung cancer would metastasize. We compared our methods with several other methods and found that our method achieved the best precision. In addition, in a previous study, we identified 7 genes that play a vital role in lung cancer. We added those gene transcripts into the DNN and found that the AUC and AUPR of the model were increased.

Unpleasant symptoms of immunotherapy for people with lung cancer A mixed-method study.

Immunotherapy has changed the outlook for lung cancer treatment. A closer look at the accompanying symptoms from the patients perspective is necessary to improve their tolerance to the treatment, which is also the basis for standardized symptom management. To describe the symptomatic experiences of patients receiving immunotherapy for lung cancer and explore whether symptoms reported during immunotherapy were associated with survival outcomes. Exploratory sequential mixed-method study. Patients were continuously recruited from the oncology day ward of Guangdong Provincial Peoples Hospital between October 2019 and January 2020. 59 patients with advanced lung cancer and receiving immunotherapy (median IQR age was 64 58-69 72.9 % pathological stage was IV) were included in the study. A sequential qualitative interview on symptom experiences was conducted from the perspective of lung cancer patients in immunotherapy. Summative content analysis was used to develop a standardized symptom reporting checklist. Survival outcome follow-ups of each patient were conducted 2 years after the interview. 47 symptoms were extracted from the 124 interviews of 59 patients, the common symptoms including musculoskeletal pain (52.5 %), itchy skin (45.8 %), fatigue (45.8 %), cough (44.1 %), shortness of breath (32.2 %), lack of appetite (32.2 %), and rashes (32.2 %). The timing, severity, and interference of symptoms were different among patients. The symptoms of shortness of breath, fatigue and chest pain were more common in chemo-immunotherapy, while dry mouth and blurred vision were more frequent with immunotherapy. The symptoms of musculoskeletal pain, shortness of breath, lack of appetite, drowsiness and taste change were more common for those who died two years after the interviews for those who survived, the symptoms of rash and chill were more common. We generated a symptom list related to lung cancer immunotherapy from the patients, provided a closer look at symptoms from the patients perspective, and suggested differences in the presence of symptoms between the group of treatment and survival outcome. This enables clinicians and nurses to better understand and empathize with the patients experience, so as to truly practice the essence of patient-centered care, and provide a basis for the development of standardized symptom measurement tools in the future. At least 47 unpleasant symptoms were present in immunotherapy from the perspective of lung cancer patients.

Efficacy and safety of treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy A systematic literature review and meta-analysis.

Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapserefractory) face limited therapeutic options given no approved options or consensus standard of care. This study aimed to identify and summarize clinical outcomes of all regimens evaluated in clinical trials of relapsed or refractory patients. Interventional trials enrolling advanced TC patients who failed first-line chemotherapy and reported outcomes in this group were eligible for inclusion in our systemic literature review (SLR). Between-study heterogeneity was assessed to determine the feasibility of pooling specific studies and treatments. Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR) endpoints were of interest for meta-analysis. Nineteen trials were identified in the SLR. Three trials with one or two TC patients were removed from our assessment to reduce publication bias. Response rates among studies with at least ten TC patients varied from 9 % to 38 %. Pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28 %, 24 %, and 21 %, respectively. Prolonged duration of response with pembrolizumab was observed with a pooled median of 23.8 months (95 % confidence interval CI 12, not reached). Median PFS of five months or greater was reported in patients treated with sunitinib, lenvatinib, pembrolizumab, capecitabine gemcitabine, everolimus, or S-1. Median OS of 20 months or greater was reported in trials evaluating S-1 or pembrolizumab this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Generalizability of treatment effects is challenging in the research of rare diseases and meta-analysis of clinical outcomes may help to increase precision and relevance of results to the larger TC population. Our study found limited treatment options upon relapse, demonstrating a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.

Quantitation of osimertinib, alectinib and lorlatinib in human cerebrospinal fluid by UPLC-MSMS.

Overall survival in metastatic lung cancer has been dramatically improved with the use of small molecule kinase inhibitors (SMKIs). Quantification of SMKI in cerebrospinal fluid (CSF) can be used to assess penetration of these drugs into the central nervous system. This paper describes an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS) method for quantification of the SMKIs alectinib, lorlatinib and osimertinib in human CSF. Alectinib-d8 and dasatinib-d8 were used as internal standards. Aliquots with 25 µL CSF30% albumin (91,vv) were mixed with 100 µL internal standard solution consisting of 1 ngmL dasatinib-d8 and alectinib-d8 in acetonitrile. The analytes were separated by an Acquity UPLC® HSS T3 column (2.1 ×150 mm, 1.8 µm), using gradient elution (ammonium formate pH 4.5, acetonitrile) with a flow rate of 0.400 mLmin. All calibration curves were linear for the concentration range from 2.50 to 250 ngmL. Within-run and between-run precision varied from 0.72% to 11.7%, with accuracy ranging from 95.3% to 113.2%. For all compounds, a high degree of non-specific binding to the vacutainer was observed. This issue could be countered easily by a combination of pre-coating with BSA solution (30%) in phosphate buffer pH 4.2, and immediate sample mixture with BSA solution after collection. To test the clinical applicability, CSF was collected in seven unique patients using alectinib (n 1), lorlatinib (n 2), and osimertinib (n 4). Measured CSF trough concentrations ranged between 3.37 and 116 ngmL.

Dynamic cone-beam CT reconstruction using spatial and temporal implicit neural representation learning (STINR).

ASPM activates Hedgehog and Wnt signaling to promote small cell lung cancer stemness and progression.

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the WntDVL3β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.

Risk Factors for Refractory Immune Checkpoint Inhibitor-related Pneumonitis in Patients With Lung Cancer.

Checkpoint inhibitor-related pneumonitis (CIP) is one of the most important immune checkpoint inhibitors side effects, and it is rare but fatal. Identifying patients at risk of refractory CIP before the start of CIP therapy is important for controlling CIP. We retrospectively analyzed the clinical data of 60 patients with lung cancer who developed CIP. Refractory CIP was defined as CIP with poor response to corticosteroid treatment, including CIP not relieved with corticosteroid administration or CIP recurrence during the corticosteroid tapering period. We analyzed clinical characteristics, peripheral blood biomarkers, treatment, and outcomes in nonrefractory and refractory CIP. Risk factors associated with refractory CIP were assessed. Among 60 patients with CIP, 16 (26.7%) had refractory CIP. The median onset time for patients with nonrefractory and those with refractory CIP was 16.57 (interquartile range IQR, 6.82-28.14) weeks and 7.43 (IQR, 2.71-19.1) weeks, respectively. The level of lactate dehydrogenase (LDH) was significantly higher in the refractory CIP group at baseline (255 222, 418 vs. 216 183, 252, P 0.031) and at CIP onset (321.5 216.75, 487.5 vs. 219 198. 241, P 0.019). An LDH level >320 UL at CIP onset was an independent risk factor of refractory CIP (odds ratio OR, 8.889 95% confidence interval CI 1.294-61.058 P 0.026). The incidence of refractory CIP is high among patients with CIP. An increased LDH level at CIP onset is independently associated with refractory CIP. Monitoring LDH levels during immune checkpoint inhibitors treatment is recommended.

Isolated splenic metastases from rectal carcinoma 5 years after surgery Case report.

Splenic malignancies are mostly lymphocytic tumors and splenic metastases are rarer.1 According to reports, the most common source of splenic metastases include melanoma, tumors of the breast, lung, ovary, colon, stomach, and pancreas.2,3. This paper reports a 41-year-old male patient who underwent a successful resection of low rectal cancer in our hospital 5 years ago. Three months ago, computed tomography scan revealed a tumor in the spleen, considered as an isolated metastasis. The patient underwent splenectomy and postoperative pathological examination confirmed metastatic adenocarcinoma. The patient was followed up for 3 months after surgery, there was no abdominal metastasis or recurrence. The splenic metastasis from rectal carcinoma 5 years after surgery is rare. If it is a solitary splenic metastasis, splenectomy can effectively improve the prognosis of patients. We review the literature and report this case.

Meta-analysis comparing the perioperative efficacy of single-port versus two and multi-port video-assisted thoracoscopic surgical anatomical lung resection for lung cancer.

As a new surgical procedure for non-small cell lung cancer, single-port video-assisted thoracoscopic surgery (VATS) has lately gained popularity nevertheless, it is unknown if single-port VATS offers any advantages over multi-portal. The study aims to assess the different impacts of using single-port VATS versus 2-port or multi-port VATS such as operation and drainage time, blood loss volume, number of resected lymph nodes, and hospital stay in lung cancer patients. Inclusion criteria included studies from different languages that compare single-port against 2 or multi-port VATS. The outcomes of these studies were analyzed using a random-effect model and it was used to calculate the mean difference with 95 percent confidence intervals to quantify the impact of different surgical techniques on clinical parameters. Single or Uni-portal video-assisted thoracoscopic surgery results in significantly lower drainage time after surgery compared with 2-port (P .03) and multi-port (P < .001) VATS. In contrast to the resection of lymph nodes, there was no significant difference between uni-port and 2-port (P .49) or multiport (P .29) VATS. While operation time, blood loss, complications, and hospital stay were significantly lower in uni-port compared with multi-port VATS (P .04, P .002, P < .001, respectively), but not with 2-port VATS (P .44, 0.06, P .13). There were no significant differences between uni-port and multi-port VATS regarding conversion rate, mortality, and staging. Single or Uni-portal video-assisted thoracoscopic surgery has high efficacy and lower side effects compared with multi-port regarding the perioperative outcomes. Two-port VATS has similar results with uni-port in several parameters.

Simultaneous treatment of two lung cancer lesions with stereotactic MR-guided adaptive radiation therapy A case report.

Lung cancer is 1 of the most prevalent cancers globally. Definitive stereotactic ablative radiotherapy (SABR) is suggested for those who are unfit for or refuse surgical intervention. Here we present a patient with 2 lung cancer lesions who received SABR simultaneously with magnetic resonance Linear accelerator (Linac)-magnetic resonance (MR). A 46-years-old man had history of left lower lung cancer post lobectomy in 2018. Two recurrent tumors were found 2 years following, then became enlarged 4 months later. The recurrent tumors were found by computed tomography. SABR was indicated due to inoperability and small size. Simulation was done both by computed tomography and MR scan with ViewRay MRIdian Linac, with the prescription dose being 50 gray in 4 fractions performed every other day within 2 weeks. The 2 lesions were irradiated at the same time with a single isocenter with mean treatment time was 78 minutes. No acute side effect was noted. Follow-up chest computed tomography scan 14 months after SABR showed mild consolidation and pneumonitis over the upper irradiated site favoring radiation-related reasons, while pneumonitis was resolved over the lower irradiated site. Positron emission tomography showed no definite evidence of FDG-avid recurrence. The patient has survived over 18 months following SABR and more than 4 years from the first diagnosis of lung cancer without significant adverse effects. Simultaneous SABR for multiple lung lesions is quite challenging because tumor motion by breathing can increase the risk of missing the target. With help by MR-Linac, simultaneous SABR to multiple lung lesions can be performed safely with efficacy.

Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine A Pilot Study in Healthy Volunteers.

Multi-scale dense selective network based on border modeling for lung nodule segmentation.

Accurate quantification of pulmonary nodules helps physicians to accurately diagnose and treat lung cancer. We try to improve the segmentation efficiency of irregular nodules while maintaining the segmentation accuracy of simple types of nodules. In this paper, we obtain the unique edge part of pulmonary nodules and process it as a single branch stream, i.e., border stream, to explicitly model the nodule edge information. We propose a multi-scale dense selective network based on border modeling (BorDenNet). Its overall framework consists of a dual-branch encoder-decoder, which achieves parallel processing of classical image stream and border stream. We design a dense attention module to facilitate a strongly coupled status of feature images to focus on key regions of pulmonary nodules. Then, during the process of model decoding, the multi-scale selective attention module is proposed to establish long-range correlation relationships between different scale features, which further achieves finer feature discrimination and spatial recovery. We introduce border context enhancement module to mutually fuse and enhance the edge-related voxel features contained in the image stream and border stream and finally achieve the accurate segmentation of pulmonary nodules. We evaluate the BorDenNet rigorously on the lung public dataset LIDC-IDRI. For the segmentation of the target nodules, the average Dice score is 92.78Formula see text, the average sensitivity is 91.37Formula see text, and the average Hausdorff distance is 3.06 mm. We further test on a private dataset from Shanxi Provincial Peoples Hospital, which verifies the excellent generalization of BorDenNet. Our BorDenNet relatively improves the segmentation efficiency for multi-type nodules such as adherent pulmonary nodules and ground-glass pulmonary nodules. Accurate segmentation of irregular pulmonary nodules can obtain important clinical parameters, which can be used as a guide for clinicians and improve clinical efficiency.

Radiomic and quantitative-semantic models of low-dose computed tomography for predicting the poorly differentiated invasive non-mucinous pulmonary adenocarcinoma.

Poorly differentiated invasive non-mucinous pulmonary adenocarcinoma (IPA), based on the novel grading system, was related to poor prognosis, with a high risk of lymph node metastasis and local recurrence. This study aimed to build the radiomic and quantitative-semantic models of low-dose computed tomography (LDCT) to preoperatively predict the poorly differentiated IPA in nodules with solid component, and compare their diagnostic performance with radiologists. A total of 396 nodules from 388 eligible patients, who underwent LDCT scan within 2 weeks before surgery and were pathologically diagnosed with IPA, were retrospectively enrolled between July 2018 and December 2021. Nodules were divided into two independent cohorts according to scanners primary cohort (195 wellmoderate differentiated and 64 poorly differentiated) and validation cohort (104 wellmoderate differentiated and 33 poorly differentiated). The radiomic and quantitative-semantic models were built using multivariable logistic regression. The diagnostic performance of the models and radiologists was assessed by area under curve (AUC) of receiver operating characteristic (ROC) curve, accuracy, sensitivity, and specificity. No significant differences of AUCs were found between the radiomic and quantitative-semantic model in primary and validation cohorts (0.921 vs. 0.923, P 0.846 and 0.938 vs. 0.911, P 0.161). Both the models outperformed three radiologists in the validation cohort (all P < 0.05). The radiomic and quantitative-semantic models of LDCT, which could identify the poorly differentiated IPA with excellent diagnostic performance, might provide guidance for therapeutic decision making, such as choosing appropriate surgical method or adjuvant chemotherapy.

Reproducibility of CT radiomic features in lung neuroendocrine tumours (NETs) patients analysis in a heterogeneous population.

The aim is to find a correlation between texture features extracted from neuroendocrine (NET) lung cancer subtypes, both Ki-67 index and the presence of lymph-nodal mediastinal metastases detected while using different computer tomography (CT) scanners. Sixty patients with a confirmed pulmonary NET histological diagnosis, a known Ki-67 status and metastases, were included. After subdivision of primary lesions in baseline acquisition and venous phase, 107 radiomic features of first and higher orders were extracted. Spearmans correlation matrix with Wards hierarchical clustering was applied to confirm the absence of bias due to the database heterogeneity. Nonparametric tests were conducted to identify statistically significant features in the distinction between patient groups (Ki-67 < 3-Group 1 3 ≤ Ki-67 ≤ 20-Group 2 and Ki-67 > 20-Group 3, and presence of metastases). No bias arising from sample heterogeneity was found. Regarding Ki-67 groups statistical tests, seven statistically significant features (p value < 0.05) were found in post-contrast enhanced CT three in baseline acquisitions. In metastasis classes distinction, three features (first-order class) were statistically significant in post-contrast acquisitions and 15 features (second-order class) in baseline acquisitions, including the three features distinguishing between Ki-67 groups in baseline images (MCC, ClusterProminence and Strength). Some radiomic features can be used as a valid and reproducible tool for predicting Ki-67 class and hence the subtype of lung NET in baseline and post-contrast enhanced CT images. In particular, in baseline examination three features can establish both tumour class and aggressiveness.

Development and Evaluation of Brief Web-Based Education for Primary Care Providers to Address Inequities in Lung Cancer Screening and Smoking Cessation Treatment.

Annual lung cancer screening (LCS) is recommended for individuals at high risk for lung cancer. However, primary care provider-initiated discussions about LCS and referrals for screening are low overall, particularly among Black or African Americans and other minoritized racial and ethnic groups. Disparities also exist in receiving provider advice to quit smoking. Effective methods are needed to improve provider knowledge about LCS and tobacco-related disparities, and to provide resources to achieve equity in LCS rates. We report the feasibility and impact of pairing a self-directed Lung Cancer Health Disparities (HD) Web-based course with the National Training Network Lung Cancer Screening (LuCa) course on primary care providers knowledge about LCS and the health disparities associated with LCS. In a quasi-experimental study, primary care providers (N 91) recruited from the MedStar Health System were assigned to complete the LuCa course only vs. the LuCa HD courses. We measured pre-post-LCS-related knowledge and opinions about the courses. The majority (60.4%) of providers were resident physicians. There was no significant difference between groups on post-test knowledge (p > 0.05). However, within groups, there was an improvement in knowledge from pre- to post-test (LuCa only (p 0.03) LuCa HD (p < 0.001)). The majority of providers (81%) indicated they planned to improve their screening and preventive practices after having reviewed the educational modules. These findings provide preliminary evidence that this e-learning course can be used to educate providers on LCS, smoking cessation, and related disparities impacting patients.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer a Prospective Observational Study.

Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC There was a significant association between the AUC Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs therefore, monitoring these may be beneficial for osimertinib AE management.

The impact of the advanced lung cancer inflammation index on the outcomes of patients with metastatic colorectal cancer who receive chemotherapy.

Advanced lung cancer inflammation index (ALI) is reported to be a prognosticator in various cancer patients with chemotherapy. However, the clinical impact of the ALI on treatment strategies in metastatic colorectal cancer (mCRC) patients remains unclear. A total of 356 patients, who received first-line chemotherapy for mCRC between April 2005 and November 2019 in a single institution, were retrospectively enrolled. The association of pretreatment ALI (calculated as follows BMI × albumin valueneutrophil-to-lymphocyte ratio) status with clinicopathological factors and patient survival outcome was analyzed, using subgroup analysis. The ALI-low cases were significantly associated with female sex, more synchronous metastasis, multiple metastatic sites, less primary tumor resection, less liver resection after chemotherapy, and poor overall survival (OS). A multivariate Cox proportional hazards analysis clarified that the ALI-low status was independently associated with poor OS (HR 1.78, 95% CI 1.27-2.48, P 0.001), in addition to right side tumor, multiple metastatic sites, and the non-performance of liver resection after chemotherapy. A subgroup analysis revealed that primary tumor resection and the resection of liver metastases after chemotherapy could not improve the prognosis of ALI-low cases in comparison with ALI-high cases, and the type of first-line chemotherapy did not significantly affect the association between the prognosis and the ALI status. ALI comprehensively evaluates the prognostic host status and is a reliable prognosticator for the mCRC patients with chemotherapy. Calculating pretreatment ALI may serve as a cost-effective and easily available tool for constructing treatment strategies.

Augmenting Granzyme B-Expressing NK Cells by Invariant NKT Ligand-Loaded APCs in Patients with Postoperative Early Stage Non-Small Cell Lung Cancer Results of a Randomized Phase II Study.

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APCGal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APCGal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APCGal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients 31%). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APCGal therapy.

Circ-N4BP2L2 enhances mitochondrial function in non-small cell lung cancer cells through regulating the miR-135a-5pARL5B axis.

Non-small cell lung cancer (NSCLC) is the main histological subtype of lung cancer with a high incidence and mortality. Circular RNAs (circRNAs) exert vital functions in various cancers by acting as a sponge of miRNAs to abolish their inhibitory effect on target genes. This study aims to explore the biological function of circRNA NEDD4 binding protein 2 like 2 (circ-N4BP2L2) in NSCLC. We found that circ-N4BP2L2 was upregulated in NSCLC tissues and cells by using RT-qPCR. A549 cells were transfected with pcDNA-circN4BP2L2 or sh-circN4BP2L2 to obtain circN4BP2L2-overexpressed or -silenced cells, and then cell proliferation, invasion and apoptosis were determined. The results showed that knockdown of circ-N4BP2L2 repressed cell proliferation, invasion as well as mitochondrial function, and promoted cell apoptosis while overexpression of circ-N4BP2L2 resulted in the opposite results. Mechanistically, the targeting correlations between miR-135a-5p and circ-N4BP2L2 or ADP-ribosylation factorlike 5B (ARL5B) were confirmed by using dual luciferase reporter, RNA pull-down and RNA immunoprecipitation assays. In addition, we found that circ-N4BP2L2 could promote the expression of ARL5B by serving as a sponge of miR-135a-5p. Moreover, rescue assays revealed that silencing miR-135a-5p or overexpressing ARL5B was able to abate the effects of circ-N4BP2L2 knockdown on malignant phenotypes and mitochondrial function of A549 cells. Finally, tumorigenicity assay demonstrated that circ-N4BP2L2 facilitated NSCLC tumor growth in vivo. Taken together, circ-N4BP2L2 enhanced NSCLC progression via the miR-135a-5pARL5B axis, which may provide a novel therapeutic target of NSCLC.

Triptonide inhibits growth and metastasis in HCC by suppressing EGFRPI3KAKT signaling.

Liver cancer represents one of the deadliest cancers, with a rising incidence worldwide. Triptonide is found in the traditional Chinese medicinal plant Tripterygium wilfordii Hook. This study aimed to examine the anticancer properties of triptonide in human hepatocellular carcinoma (HCC). HCC cells were administered with triptonide at various levels, and CCK-8 and colony formation assays were carried out for detecting HCC cell proliferation. Then, cell apoptosis and cell cycle distribution were evaluated by flow cytometry. Tumor growth was monitored noninvasively by ultrasound imaging. Cell migration and invasion were quantitated by wound healing and Transwell assays. A metastasis model was established via tail vein injection of HCC cells in nude mice. Immunoblot was performed to quantitate the expression of proteins involved in the EGFRPI3KAKT signaling and its downstream effectors. Triptonide repressed cell proliferation and induced cell cycle arrest and apoptosis in cultured HCC cells, and suppressed tumor growth in vivo. In addition, triptonide inhibited EMT, migration and invasion in cultured HCC cells, and lung metastasis in nude mice. Mechanistically, triptonide acted by inhibiting the EGFRPI3KAKT signaling and downregulated its downstream effectors, e.g., the cell cycle-associated protein cyclin D1, the apoptosis-related protein Bcl-2, the EMT marker E-cadherin, and the invasion-related protein MMP9. Triptonide suppresses proliferation, EMT, migration and invasion, and promotes apoptosis and cell cycle arrest by repressing the EGFRPI3KAKT signaling. Therefore, triptonide might be considered for liver cancer treatment.

Zerumbone combined with gefitinib alleviates lung cancer cell growth through the AKTSTAT3SLC7A11 axis.

Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human pulmonary alveolar epithelial cells (HPAEpiC), A549, and H460 cell lines were used to detect the efficacy of zerumbone. BALBc nude mice were randomly divided into five groups, including model, gefitinib (Gef, 10 mgkg), low dose zerumbone (L-Zer, 20 mgkg), high dose zerumbone (H-Zer, 40 mgkg), and H-Zer Gef groups. , and the tumor growth in each group was monitored. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect cell apoptosis. Immunohistochemistry (IHC), immunofluorescence, and western blot were used to analyze the protein expressions in tumor tissues. Glutathione (GSH) and malondialdehyde (MAD) were detected by special kits. Zerumbone inhibited the proliferation of lung cancer cells in vitro. Tumor volume and weight were reduced after Gef or zerumbone treatment. Gefitinib and zerumbone treatment significantly promoted the apoptosis of tumor cells. The expression of Bcl-2, Bax, and P53 proteins confirmed the cell apoptosis. IHC results indicated that zerumbone and gefitinib treatment decreased tumor angiogenesis. Consistent with this result, the expression of EGFR, VEGFR2, and Ki-67 proteins decreased, while the expression of angiostatin and endostatin proteins increased. Interestingly, zerumbone treatment increased the level of MDA while decreasing GSH. Next, the levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) decreased after zerumbone and gefitinib treatment. Our study suggested that zerumbone combined with gefitinib could effectively inhibit lung cancer for multi-model therapies, including the inhibition of tumor growth, angiogenesis, induce cell apoptosis, and ferroptosis.

Preparation and evaluation of paclitaxel-loaded reactive oxygen species and glutathione redox-responsive poly(lactic-co-glycolic acid) nanoparticles for controlled release in tumor cells.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer part II.

Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung carcinoma part I.

Lung cancer is the second leading cause of cancer-related mortality globally, and non-small-cell lung cancer accounts for most lung cancer cases. Nanotechnology-based drug-delivery systems have exhibited immense potential in lung cancer therapy due to their fascinating physicochemical characteristics,

Overweight and Obesity are Associated with Poorer Survival Among Patients with Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemotherapy.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced-stage disease and therefore have poor overall survival. It remains unclear whether nutritional status affects response rate and overall survival in NSCLC patients. This study aimed to evaluate the association of nutritional status with treatment response and overall survival in patients with advanced stage of NSCLC. Patients aged ≥18 years with stage II-IV NSCLC (January-June 2018) in a national cancer center in Indonesia were enrolled in this study. The patients were followed up for 2 years since NSCLC diagnosis was established. Clinical data including age, sex, histology of cancer, disease stage, cachexia, and weight status before chemotherapy were reviewed and analyzed. Logistic regression and Cox regression analyses were performed. A total of 174 patients (71% males, mean age 58±9.4 years) was included. Complete response was found in <1% patients, partial response 41%, stable disease 33%, and progressive disease 25%. Median survival was 12 months (95% CI 11-13 months). Mortality rate was 5.7 per 100 person-months. Poor survival was associated with being males (HR 1.77, 95% CI 1.15-2.72, P 0.009), and overweight or obesity (HR 1.67, 95% CI 1.04-2.69, P 0.034). These associations were independent of sex, age, staging, histopathology, performance status and D-dimer level at baseline. Cachexia and BMI at baseline were not associated with treatment response. Males and having overweight or obesity are independently associated with lower survival in patients with advanced stage of NSCLC undergoing platinum-based chemotherapy.

Deliberation on Deferred Cytoreductive Nephrectomy and Postoperative Treatment for Advanced Renal Cell Carcinoma A Case Report.

In a rare case, free from systemic therapy, deferred cytoreductive nephrectomy was implemented in treating an advanced renal cell carcinoma with liver, lung, and splenic colon metastases. A 59-year-old man diagnosed with advanced renal cell carcinoma underwent deferred cytoreductive nephrectomy due to a partial response to systemic treatment after a period of 1 year. After the surgery, no additional treatment was implemented. Furthermore, after 10 months, the patient had no recurrence of renal cell carcinoma. Through a review of this case and deferred cases in the current literature, we could emphasize the importance of image evaluation and pathological findings as an indication for surgery and subsequent treatment options. However, there is room for debate with regards to the indications for deferred cytoreductive nephrectomy as well as a therapeutic strategy after the surgery. This report discusses the significance of deferred cytoreductive nephrectomy in terms of prognosis and quality-of-life improvement in advanced renal cancer.

Observational study of health utilities in adult primary ciliary dyskinesia patients preliminary data on associations with molecular diagnosis, clinical phenotype and HRQOL measures.

Primary ciliary dyskinesia (PCD) is a congenital disorder characterized by chronic respiratory morbidity. To date, there is no information on PCD-specific preference-based quality of life measures such as health utilities (HU). We cross-sectionally assessed HU in adult PCD patients and explored relationships with genotype, phenotype and quality of life (QOL)-PCD scales. Diagnostic testing was performed according to international guidelines, while participants completed the visual analog scale (VAS), time trade off (TTO), standard gamble (SG), and EuroQol 5 dimensions (EQ5D) HU instruments, as well as the QOL-PCD questionnaire. Hierarchical regression was used to identify the QOL-PCD scales that are most predictive of HU. Among 31 patients, median HU are 0.75 (VAS), 0.86 (EQ5D), 0.91 (TTO) and 0.99 (SG). The underlying genotype is not associated with HU measures. VAS and EQ5D are associated with lung function, while TTO and SG values are not sensitive to any of the examined factors. Among the QOL-PCD scales, physical functioning and lower respiratory symptoms explained much of VAS (R Our study demonstrates that HU elicitation in PCD is feasible using both direct and indirect methods. Overall, HU scores are relatively high among adult patients, with higher scores observed in SG and TTO, followed by EQ5D and VAS. VAS and EQ5D HU values are sensitive to lung function as well as to QOL-PCD physical functioning and lower respiratory symptom scores.

Higher radiation doses after partial laryngectomy may raise the incidence of pneumonia A retrospective cohort study.

Currently, studies have shown that a high dose of radiotherapy to the throat have various harmful and adverse effects on the patients laryngeal function, resulting in the development of pneumonia. This study aimed to explore how radiotherapy dose affected the probability of pneumonia following laryngeal cancer surgery. A retrospective analysis was done on patients diagnosed with laryngeal cancer between 2010 and 2020 and were treated surgically and with postoperative radiotherapy in the same institution. This study included 108 patients in total, 51 of who were in the low-dose group and 57 of whom were in the high-dose group. Age, gender, the location of laryngeal cancer, the presence or absence of lymph node metastasis, and other demographic and clinical characteristics were collected, and the prevalence of postoperative pneumonia was compared between the two groups. The total prevalence of postoperative pneumonia was 59.3%, but there was a significant difference between the two groups(high-dose group 71.9% VS low-dose group 45.1% p0.005). A total of 9.3% (10108) of the patients had readmission due to severe pneumonia, and the rate of readmission due to pneumonia was significantly different between the two groups (high-dose group 15.8% VS low-dose group 2.0%, p0.032). Additionally, the high-dose groups prevalence of Dysphagia was significantly higher than the low-dose groups. According to multivariate logistic modeling, high-dose radiation was a risk factor for pneumonia (OR4.224, 95%CI 1.603-11.131, p0.004). Pneumonia risk could increase with radiotherapy doses > 50 Gy in the treatment of laryngeal cancer. Therefore, we recommend that when the radiation dose surpasses 50Gy, doctors should pay particular attention to the lung health of patients with laryngeal cancer.

Immune Checkpoint Inhibitor Myocarditis Treatment Strategies and Future Directions.

Figure see text

Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor-Induced Myocarditis.

Myocarditis is a dreaded and unpredictable complication of immune checkpoint inhibitors (ICI). We sought to determine whether routinely measured biomarkers could be helpful in monitoring for ICI myocarditis. The authors examined biomarker trends of patients on ICI and their association with the incidence of ICI myocarditis and outcomes. We conducted an observational cohort study of adults who received at least one dose of ICI at Michigan Medicine between June 2014 and December 2021 and underwent systematic serial testing for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatine phosphokinase (CPK), and lactate dehydrogenase during ICI therapy. Among 2,606 patients (mean age 64 ± 13 years 60.7% men), 27 (1.0%) were diagnosed with ICI myocarditis. At diagnosis, patients with myocarditis had an elevated high-sensitivity troponin T (100%), ALT (88.9%), AST (85.2%), CPK (88.9%), and lactate dehydrogenase (92.6%). Findings were confirmed in an independent cohort of 30 patients with biopsy-confirmed ICI myocarditis. A total of 95% of patients with ICI myocarditis had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated (per 100% increase) with the development of myocarditis (HR 1.83 95% CI 1.59-2.10) and all-cause mortality (HR 1.10 95% CI 1.01-1.20) in multivariable analysis. Elevations in CPK had a sensitivity of 99% and specificity of 23% for identifying myocarditis. ICI myocarditis is associated with changes in AST, ALT, and CPK. An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis.

Cancer Immunotherapy Beyond Checkpoint Blockade

Avoidance of immune destruction is recognized as one of the hallmarks of cancer development. Although first predicted as a potential antitumor treatment modality more than 50 years ago, the widespread clinical use of cancer immunotherapies has only recently become a reality. Cancer immunotherapy works by reactivation of a stalled pre-existing immune response or by eliciting a de novo immune response, and its toolkit comprises antibodies, vaccines, cytokines, and cell-based therapies. The treatment paradigm in some malignancies has completely changed over the past 10 to 15 years. Massive efforts in preclinical development have led to a surge of clinical trials testing innovative therapeutic approaches as monotherapy and, increasingly, in combination. Here we provide an overview of approved and emerging antitumor immune therapies, focusing on the rich landscape of therapeutic approaches beyond those that block the canonical PD-1PD-L1 and CTLA-4 axes and placing them in the context of the latest understanding of tumor immunology.

The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity.

• ICIs used in cancer therapy can cause serious cardiac immune-related side effects. • Single-cell multi-omics are powerful tools in understanding cell subsetsphenotypes. • Multi-omics technology can elucidate disease mechanisms in ICI-induced myocarditis. Figure see text

Impact of image filtering and assessment of volume-confounding effects on CT radiomic features and derived survival models in non-small cell lung cancer.

No evidence supports the choice of specific imaging filtering methodologies in radiomics. As the volume of the primary tumor is a well-recognized prognosticator, our purpose is to assess how filtering may impact the featurevolume dependency in computed tomography (CT) images of non-small cell lung cancer (NSCLC), and if such impact translates into differences in the performance of survival modeling. The role of lesion volume in model performances was also considered and discussed. Four-hundred seventeen CT images NSCLC patients were retrieved from the NSCLC-Radiomics public repository. Pre-processing and features extraction were implemented using Pyradiomics v3.0.1. Features showing high correlation with volume across original and filtered images were excluded. Cox proportional hazards (PH) with least absolute shrinkage and selection operator (LASSO) regularization and CatBoost models were built with and without volume, and their concordance (C-) indices were compared using Wilcoxon signed-ranked test. The Mann Whitney U test was used to assess model performances after stratification into two groups based on low- and high-volume lesions. Radiomic models significantly outperformed models built on only clinical variables and volume. However, the exclusioninclusion of volume did not generally alter the performances of radiomic models. Overall, performances were not substantially affected by the choice of either imaging filter (overall C-index 0.539-0.590 for Cox PH and 0.589-0.612 for CatBoost). The separation of patients with high-volume lesions resulted in significantly better performances in 210 and 710 cases for Cox PH and CatBoost models, respectively. Both low- and high-volume models performed significantly better with the inclusion of radiomic features (P<0.0001), but the improvement was largest in the high-volume group (10.2% against 8.7% improvement for CatBoost models and 10.0% against 5.4% in Cox PH models). Radiomic features complement well-known prognostic factors such as volume, but their volume-dependency is high and should be managed with vigilance. The informative content of radiomic features may be diminished in small lesion volumes, which could limit the applicability of radiomics in early-stage NSCLC, where tumors tend to be small. Our results also suggest an advantage of CatBoost models over the Cox PH models.

The clinico-pathological characteristics of surgically treated young women with NSCLC.

Non-small cell lung cancer diagnosed in young patients is rare. Younger patients with lung cancer are mostly female and have a more advanced stage at initial diagnosis. To our knowledge, no studies have compared single-surgical treatment in different age groups among women. Our study aimed to elucidate the clinicopathological characteristics and the best strategies for surgically treating young women with non-small-cell lung cancer. The data were collected retrospectively from the Polish Lung Cancer Study Group database. Women who were surgically treated for non-small-cell lung cancer between 2007 and 2020 were included in the study. The participants (n11,460) were divided into two subgroups aged ≤55 and >55 years. Statistically significant differences were found for grades IB, IIA, IIIA, and IIIB (22.8% Younger women treated surgically were characterized by a lower percentage of comorbidities, were treated in a more advanced stage of the disease and had a lower percentage of postoperative complications, which, however, did not affect the hospitalization time. Despite the more advanced stage of the disease, survival in selected stages was much better than in the group of older women.

Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.

Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides. We evaluated the clinical impact of metabolic reprogramming. We performed comparative analysis of publicly available data on non-squamous NSCLC, to identify concensus altered metabolic pathways. We investigated whether alterations of metabolic genes controlling those consensus metabolic pathways impacted clinical outcome. Using the clinically annotated lung adenocarcinoma (LUAD) cohort from The Cancer Genome Atlas, we surveyed the distribution and frequency of function-altering mutations in metabolic genes and their impact on overall survival (OS). We identified 42 metabolic genes of clinical significance, the majority of which (37 of 42) clustered across three metabolic superpathways (carbohydrates, amino acids, and nucleotides) and most functions (40 of 42) were associated with shorter OS. Multivariate analyses showed that dysfunction of carbohydrate metabolism had the most profound impact on OS hazard ratio (HR) 5.208 95% confidence interval (CI) 3.272 to 8.291, false discovery rate (FDR)-P≤0.0001, followed by amino acid metabolism (HR 3.346 95% CI 2.129 to 5.258), FDR-P≤0.0001 and nucleotide metabolism (HR 2.578 95% CI 1.598 to 4.159), FDR-P0.0001. The deleterious effect of metabolic reprogramming on non-squamous NSCLC was observed independently of disease stage and across treatments groups. By providing a detailed landscape of metabolic alterations in non-squamous NSCLC, our findings offer new insights in the biology of the disease and metabolic adaptation mechanisms of clinical significance.

Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas.

Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts. Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays all n676, adenocarcinomas (AC) n401, squamous cell carcinomas (SCC) n213, other NSCLC n62. ROS1-rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n21). Using FISH, 2630 (0.3% all NSCLC 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24665 (3.6% all NSCLC 5.1% non-squamous NSCLC) cases with clone D4D6, in 18639 (2.8% all NSCLC 3.9% non-squamous NSCLC) cases with clone SP384, and in 1593 (0.2% all NSCLC 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA-sequencing data. Other cases with high proteinRNA-expression or ambiguous FISH were negative in the NanoString-assay. The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics.

Immunotherapy with radiotherapy fails to improve prognosis of patients with stage IV non-small cell lung cancer a retrospective cohort analysis of the THUNDER-2 study.

Radiotherapy (RT) may enhance the systemic antitumor reaction to immunotherapy (IT). Currently, the effect of RT in stage IV non-small cell lung cancer (NSCLC) patients treated with IT is uncertain. This study aimed to confirm the role of RT in these patients. We enrolled 120 stage IV NSCLC patients who had been treated with IT and had received external beam radiation therapy (EBRT) or radioactive particle implantation (RPI) at 3 oncology centers in Shandong province between 2019 and 2021. We assessed relevant clinical factors and regular follow-up was conducted via electronic medical records and telephone. The primary endpoint was overall survival (OS). Different combination models in various populations were compared by generating Kaplan-Meier curves and Cox regression analysis. The OS for the overall population was 5 months (range, 0-31 months) and the overall survival rate was 47.5%. Patients receiving IT with RPI had the least favorable prognostic trend (median survival 2 months) compared to those receiving IT without RT (median survival 9 months) and IT with EBRT (median survival 10 months), but this difference was not significant (P0.148). In subgroup analysis, patients treated with IT with RPI appeared to have a worse prognosis in some specific cohorts, such as males hazard ratio (HR) 2.433, P0.031, non-squamous carcinoma histologies (HR 2.680, P0.034), patients with oligometastases (HR 7.967, P0.024), patients with liver metastases (HR 10.808, P0.011) or brain metastases (HR 20.087, P0.005), and those with Eastern Cooperative Oncology Group (ECOG) performance score ≥2 (HR 2.769, P0.043). Multivariate Cox analysis of total population revealed that ECOG score and IT stage were the independent prognostic factors. IT combined with EBRT did not have a significant survival benefit in all subgroups. Concurrent IT with RT and first-line and second-line IT combined with RT trended toward improved long-term prognosis. While the robustness of the present conclusions is limited by relatively small sample size and retrospective nature of this research, the addition of EBRT or RPI to IT did not significantly improve patients OS in stage IV NSCLC. Early combination IT after RT may benefit patients with long-term survival.

Three non-small cell lung cancer patients who developed pulmonary thromboses during osimertinib treatment and could safely resume concomitant anticoagulation treatment a report of three cases.

Previous phase III study has demonstrated that osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine-kinase inhibitor (TKI), exhibits superior antitumor effects compared to first-generation EGFR-TKIs and successfully prolonged overall survival (OS) in patients with Three male patients, aged 66-74 years, with NSCLC harboring We report the cases of three NSCLC patients who developed VTE during osimertinib. Osimertinib may cause VTE and should be used cautiously. In such cases, osimertinib treatment may be continued with direct oral anticoagulation therapy.

A multidisciplinary approach to the work up and management of pulmonary carcinoid tumors and DIPNECH a narrative review.

Low and intermediate grade neuroendocrine tumors of the lung are uncommon malignancies representing 2% of all lung cancers. These are termed typical and atypical pulmonary carcinoid tumors. These can arise in the setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The presentation, workup, management and outcomes of patients with these tumors can overlap with more common lung cancers but differ in that many of these patients have a prolonged clinical course. The objective of this narrative review is to summarize the literature and provide evidence and expert-based algorithms for work up and treatment of pulmonary carcinoids and DIPNECH. A search of PubMed and Web of Science databases ending April 15, 2022, with the following keywords lung carcinoid, DIPNECH, lung neuroendocrine, and bronchopulmonary carcinoid. Pulmonary carcinoid tumors benefit from a multidisciplinary approach. Pre-treatment imaging with contrast-enhanced computed tomography, and DOTATATE positron emission tomography is required. Surgical resection is the gold standard for curative intent, and possibly including sublobar resections. Patients can recur or develop new primaries thus emphasizing the importance of surveillance national guidelines recommend at least a 10-year follow up. A growing body of literature support the use of endobronchial therapy, with long responses documented. Systemic therapy consists of everolimus, somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Diffuse idiopathic pulmonary neuroendocrine tumor cell hyperplasia is rare, but series suggest somatostatin analogs may confer clinical benefit. Pulmonary carcinoid tumors and DIPNECH are rare. Despite lack of regulatory approvals for advanced disease, multiple options are available but should be sequenced according to the clinical status and disease biology. Each patient should be discussed in a multidisciplinary setting and clinical trials should be considered if available.

Erratum to efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients a retrospective analysis.

This corrects the article DOI 10.21037tlcr-22-545..

Efficacy and safety of alectinib in

Alectinib is a second generation of Patients with Twenty patients progressed after first-line treatment (n59) with alectinib, and 21 patients progressed following second-line treatment (n36) with alectinib. The median PFS of first-line treatment patients was not achieved, and the median PFS of patients undergoing second-line treatment was 15.0 months 95% confidence interval (CI) 0.00-32.23. The most common adverse reactions were liver dysfunction (37.50%), anemia (37.50%), and constipation (20.83%). The incidence of grade III and above adverse reactions was 6.25%. Univariate analysis showed that neutrophil-to-lymphocyte ratio NLR hazard ratio (HR) 0.424, P0.005 carcinoembryonic antigen (CEA HR 0.482, P0.029), lactate dehydrogenase (LDH HR 0.327, P<0.001), carbohydrate antigen (CA)199 (HR 0.313, P0.002), and circulating cell free DNA (cfDNA HR 0.229, P0.008) concentration levels were associated with PFS, and multivariate analysis showed that NLR (HR 3.058, P0.034) was independent prognostic factor. After three months of treatment, CEA, CA199, NLR, and LDH, could further predict the prognosis of alectinib treatment. The efficacy and safety of alectinib as a first-line or second-line treatment for

SP142 evaluation contributes to the prediction of immune checkpoint inhibitor efficacy in non-small cell lung cancer with high PD-L1 expression assessed by 22C3.

It remains unclear whether assessing programmed death-ligand 1 (PD-L1) expression by SP142 plus 22C3 adds value for predicting the response to immunotherapy in non-small cell lung cancer (NSCLC). This retrospective multicenter study included patients with advanced NSCLC treated with immune-checkpoint inhibitors. We constructed tissue microarrays (TMAs) and performed immunohistochemical staining with 22C3 and SP142 assays. We denoted the PD-L1 tumor proportion score (TPS) obtained from clinical medical records based on 22C3 staining as 22C3 (C) and that obtained with 22C3 staining using our TMA as 22C3 (TMA). SP142 staining was evaluated in both tumor cells and immune cells. We assessed the concordance between each PD-L1 assessment method and analyzed the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) based on the PD-L1 expression level determined using the 22C3 and SP142 assays. In total, 288 patients were included. Among those with 22C3 (TMA) ≥50%, 60% of patients showed SP142 TC3 or IC3 among patients with 22C3 (C) <1%, 9% and 18% exhibited 22C3 (TMA) ≥1% and SP142 TC123 or IC123, respectively. Among patients with 22C3 (C) ≥50% treated with immune-checkpoint inhibitor monotherapy, the SP142 TC123 or IC123 group showed significantly better ORR, PFS and OS than the SP142 TC0 and IC0 group (54% SP142 evaluation contributes to the prediction of immune-checkpoint inhibitor efficacy in NSCLC with high PD-L1 expression assessed by 22C3.

Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer a systematic review.

Operable stage I-III non-small cell lung cancer (NSCLC) has a high risk of recurrence, mainly due to remnant clones of the disease defined as minimal residual disease (MRD). Adjuvant chemotherapy has a limited efficacy in reducing the risk of relapse, and prognostic as well as predictive biomarkers in this context are currently missing. We performed a systematic review to evaluate the state of the art about the role of circulating tumor DNA detection through liquid biopsy for the assessment of MRD in resected early-stage NSCLC patients. Among the 650 studies identified, 13 were eligible and included. Although highly heterogeneous, all the studies demonstrated a poor prognosis in patients with post-operative MRD, with a detection rate ranging from 6% to 45%. MRD detection preceded radiographicclinical recurrence by a mean of 5.5 months. MRD positive patients were most likely to benefit from adjuvant treatment in terms of recurrence-free survival (RFS). Consistently, adjuvant therapy did not minimize the risk of relapse in the MRD negative group. Liquid biopsy has a relevant role in assessing post-surgical MRD in resected NSCLC. Since currently there are no criteria other than stage and risk factors for the choice of adjuvant treatment in this setting, post-operative assessment of MRD through liquid biopsy might be a promising approach to guide the decision.

PD-1PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer-an IMMUNOTARGET case series.

Prior IMMUNOTARGET registry data had suggested that responses to immune anti PD(L)1 monotherapy in gene-arranged non-small cell lung cancer (NSCLC) were rare or absent, depending on the specific oncogene. IMMUNOTARGET sites reporting prior registry data or new individual cases of gene rearranged NSCLC seeming to benefit from immune monotherapy were explored in detail looking to both validate their diagnosis of a functional gene rearrangement and to look for features potentially differentiating them from other such cases associated with low response rates. Five cases of NSCLC with a gene rearrangement with reported responses or prolonged stabilization from immune monotherapy were identified in total. All had little or no prior smoking history and had programmed death-ligand 1 (PD-L1) values ranging from zero to 100%. A confirmed rearrangement partner was reported in only 2 of the cases (CD74-ROS1 and KIF5B-RET), however in one of the other three cases analplastic lymophoma kinase (ALK), significant benefit from a relevant prior targeted therapy was noted, also consistent with the rearrangement status being correctly assigned. Not all driver oncogene subtypes of NSCLC are equally responsive to immune monotherapy, however even among patients with well-validated gene rearranged NSCLC which has traditionally been considered immune hyporesponsive, objective responses can occur. Additional explorations of the features associated with and underlying the immune hypo-responsiveness of most, but not all, cases of gene-rearranged NSCLC are required.

Alectinib as first-line treatment for advanced ALK-positive non-small cell lung cancer in the real-world setting preliminary analysis in a Chinese cohort.

Tyrosine kinase inhibitors (TKIs) have been a major advance in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) which have been substantiated in clinical trials. However, real-world data on first-line alectinib in a Chinese patient population are limited. We enrolled patients diagnosed with advanced ALK-positive NSCLC treated with first-line alectinib at 8 centers in China, including cases with symptomatic or active CNS metastases. Continuation of alectinib was permitted after local or gradual progression at the treating clinicians discretion. Time-to-treatment failure (TTF) was defined as the period from the start of alectinib to discontinuation for any cause including disease progression, death, adverse events and patients preference. We defined longer EML4-ALK variants as containing EML4 fusions to at least exon 13 and shorter variants had EML4 fusions up to exon 6. Of the 110 patients included, 26.4% had Eastern Cooperative Oncology Group Performance Status (ECOG) ≥2 points. The objective response rate (ORR) was 88.5% 95% confidence interval (CI) 79.9-94.3% and median tumor shrinkage rate was 60% (range, 0-100%) in patients with target lesions. For patients with measurable central nervous system (CNS) metastases, the CNS-ORR was 92.9% (95% CI 66.1-99.8%), additionally, 80% (810) of patients experienced significant improvement in CNS-related symptoms following alectinib treatment. With a median follow-up of 18.3 months, the estimated 2-year progression-free survival (PFS) rate and 2-year treatment failure-free rate were 81.1% (95% CI 71.5-87.7%) and 81.0% (95% CI 70.6-88.0%) respectively. Grade 3-4 adverse events occurred in 6.4% and only 2 patients (1.8%) permanently discontinued alectinib due to adverse events. Multivariate analysis indicated that patients with metastases in ≥3 distant organs and a tumor reduction rate ≤50% demonstrated more unfavorable mPFS than their counterparts. Furthermore, patients carrying longer variants showed superior mPFS to those with shorter variants (not reached Alectinib showed substantial efficacy and an excellent safety profile in a real-world setting of Chinese patients. Clinical outcomes and long-term survival still require longer follow-up. Tumors with shorter EML4 fusion variants, more extensive metastases and less reduction in tumor lesions may require more aggressive strategies.

Effectiveness and safety of opioids for dyspnea in patients with lung cancer secondary analysis of multicenter prospective observational study.

Patients with lung cancer are more likely to have comorbidities e.g., interstitial lung disease (ILD), chronic obstructive pulmonary disease) and metastases that may affect dyspnea and the effectiveness and safety of opioids for dyspnea than other cancer types. Therefore, this study examined the effectiveness and safety of opioids for dyspnea, among the patients with lung cancer. The present study is a secondary analysis of a multicenter prospective observational study examining the effectiveness and safety of opioids for dyspnea in patients with cancer in Japan. For this secondary analysis, patients with lung cancer with a documented dyspnea Numerical Rating Scale (NRS) at baseline were included. The primary outcome was dyspnea NRS, and Integrated Palliative care Outcome ScaleSupport Team Assessment Schedule (IPOSSTAS) scores change between baseline and 24 hours after baseline. As secondary outcomes, we investigated the predictors of opioid effectiveness for dyspnea improvement and adverse events (nausea, somnolence, and delirium). This study analyzed 124 patients with lung cancer with known dyspnea NRS at baseline. The median age was 74, and the Eastern Cooperative Oncology Group performance status of 107 patients were 3-4. Both NRS and IPOSSTAS score of dyspnea significantly improved 24 hours after opioid initiation -1.64, 95% confidence interval (CI) -2.12 to -1.17, P<0.001 -1.03 95% CI -1.21 to -0.85, P<0.001 respectively. Moreover, the improvement of NRS score was greater than the minimal clinically important difference of 1 point. In the multivariate logistic regression analysis, ILD was significantly associated with a better improvement (hazard ratio (HR) 3.39, 95% CI 1.34-11.09, P0.043. Somnolence was the most common grade 3-4 adverse event (n16), followed by delirium (n9). Opioids were effective and safe for treating dyspnea in patients with lung cancer. Furthermore, lung cancer patients with ILD may benefit more from opioids.

Erratum to clinical features and prognosis of resectable pulmonary primary invasive mucinous adenocarcinoma.

This corrects the article DOI 10.21037tlcr-22-190..

DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy and immunotherapy plus platinum-based chemotherapy in advanced non-small cell lung cancer a retrospective Chinese cohort study.

Platinum-based chemotherapy (PC) and immunotherapy plus platinum-based chemotherapy (IPC) remain the first-line treatment for advanced NSCLC. But only a minority patients benefit from PC, and existing biomarkers, such as PD-L1, have been shown to be defective in predicting the efficacy of IPC. Highlighting the need to identify novel biomarkers for the efficacy of PC and IPC. DNA damage repair (DDR) mutations are known to predict response to PC in solid tumors. However, the predictive value of DDR in PC and IPC of NSCLC remains unclear. Patients diagnosed with advanced or metastatic NSCLC were retrospectively included if they underwent next generation sequencing prior to starting treatment. Primary endpoints were to explore whether DDR mutations (DDRmut) are associated with clinical outcomes of PC and IPC. Secondary end point were to explore the association between DDRmut and the choice to add immunotherapy to chemotherapy, and the impact of different DDR pathways on efficacy in PC and IPC. DDRmut showed a strong association with tumor mutation burden-high (TMB-H) versus DDR wild-type (DDRwt) and higher rates of PD-L1 TPS ≥50% positivity. In 63 patients treated with PC, ORRs were 15.38% and 2.86% for DDRmut and DDRwt subgroup (P0.1536), and DCRs were 88.46% and 45.72% (P0.00097) at 6 months after PC. The DDRmut patients had significantly improved median PFS (mPFS) and median overall survival (mOS) than DDRwt group (mPFS 7.6 There is potential for DDR to serve as a positive predictor of PC and IPC in advanced NSCLC patients.

Preoperative immunochemotherapy for locally advanced non-small cell lung cancer an analysis of the clinical outcomes, optimal number of cycles, and peripheral immune markers.

This retrospective study aimed to evaluate the real-world efficacy of neoadjuvant immunochemotherapy in locally advanced stage III non-small cell lung cancer (NSCLC), with a particular focus on analyzing the optimal treatment cycle and peripheral immune markers. Eligible patients with biopsy-confirmed stage III NSCLC who underwent neoadjuvant immunochemotherapy between January 1 A total of 115 patients were identified, among whom 61, 51, and three cases were classified as clinical stage IIIA, IIIB, and IIIC at presentation, respectively. The objective response rate was 61.7% (71115) after immunochemotherapy. The most frequent surgical procedure was lobectomy, performed in 91 (79.1%) cases, and all patients had microscopic-free margins. Major pathological response (MPR) was observed in 64 (55.7%) patients, among whom 44 (38.3%) achieved a complete pathological response pathological-confirmed lymph node downstage (cN2-3 to ypN0-1) was described in 73.6% (6791) of patients with cN2-3 diseases. The median disease-free survival (DFS) of all enrolled patients was 23.6 95% confidence interval (CI) 15.9-31.3 months, while for patients with residual tumors of more than 10%, the median DFS was 18.1 (95% CI 12.5-23.8) months. The post-hoc multivariable analysis showed that three odds ratio (OR), 4.78 95% CI 1.17-19.55 and four (OR 6.50 95% CI 1.12-37.54) cycles of neoadjuvant immunochemotherapy were prone to higher MPR rates compared to two cycles in patients that were classified as completepartial response (CRPR). However, adding over five cycles was not associated with a higher MPR rate (OR, 0.91 95% CI 0.15-5.47). The pretreatment lymphocyte count level (1.89±0.68 The present study confirmed a favorable real-world tumor downstage efficacy of neoadjuvant immunochemotherapy in locally advanced NSCLC. Even though CRPR was achieved, it is still beneficial when extended into 3-4 cycles of neoadjuvant immunochemotherapy.

The epidemic of malignant mesothelioma in China a prediction of incidence during 2016-2030.

Malignant mesothelioma is an invasive cancer with a poor prognosis. The crude incidence rate of malignant mesothelioma in China increased throughout 2000 to 2013, which attracted attention. In order to predict the incidence trend of malignant mesothelioma in China, a Bayesian age-period-cohort (APC) prediction model was constructed using publicly available data from the National Cancer Registration Network. Based on the annual reports of the national cancer registration from 2005 to 2015, the incidence trend of malignant mesothelioma from 2016 to 2030 in China was forecast using the APC Modeling and Prediction package from the Institute of Biomedical Engineering, London. The crude incidence rates of malignant mesothelioma decreased from 2.2 per one million person-years in 2005 to 1.6 per one million person-years in 2015. The incidence rates remained stable over the 11-year time period after age standardization. Aging was found to have a dominant effect on the trends. The Bayesian APC model showed that the crude incidence rates would increase from 1.4 per one million person-years in 2016 to 1.9 per one million person-years in 2030, and the estimated number of new incident cases would increase to 2,775 in 2030. The age-standardized incidence rate (ASR) remained steady. In the future decade, the incidence of malignant mesothelioma may increase, but the ASR will remain stable. Considering its high degree of malignancy, malignant mesothelioma still needs to be taken seriously.

Adjuvant chemotherapy for completely resected IIA-IIIA non-small cell lung cancer compliance to guidelines, safety and efficacy in real-life practice.

Since randomised clinical trials demonstrated a survival benefit of adjuvant chemotherapy (AC) following curative-intent lung surgery, AC has been implemented as a standard therapeutic strategy for patients with a completely resected IIA-IIIA non-small cell lung cancer (NSCLC). Regarding the moderate benefit of AC and the lack of literature on AC use in real-life practice, we aimed to evaluate compliance to guidelines, AC safety and efficacy in a less selected population. Between January 2009 and December 2014, we retrospectively analysed 210 patients with theoretical indication of AC following curative-intent lung surgery for a completely resected IIA-IIIA NSCLC. The primary objective of this retrospective study was to evaluate compliance to AC guidelines. Secondary objectives included safety and efficacy of AC in real-life practice. Among 210 patients with a theoretical indication of AC, chemotherapy administration was validated in multidisciplinary team (MDT) for 62.4% of them and 117 patients (55.7%) finally received AC. Patients clinical conditions were the main reasons advanced in MDT for no respect to AC guidelines. Most of the patients received cisplatin-vinorelbine (86.3%) and AC was initiated within 8 weeks following lung surgery for 73.5% of patients. One-half of patients who received AC experienced side effects leading to either dose-intensity modification or treatment interruption. In real-life practice, AC was found to provide a survival benefit over surgery alone. Factors related to daily-life practice such as delayed AC initiation or incomplete AC planned dose received were not associated with an inferior survival. Although AC use might differ from guidelines in real-life practice, this retrospective study highlights that AC can be used safely and remains efficient among a less selected population. In the context of immunotherapy and targeted therapies development in peri-operative treatment strategies, the place of AC has to be precised in the future.

Does Preoperative Hookwire Localization Influence Postoperative Acute and Chronic Pain After Video-Assisted Thoracoscopic Surgery A Prospective Cohort Study.

This study aimed to investigate whether preoperative computerized tomography-guided hookwire localization-associated pain could affect acute and chronic postsurgical pain (CPSP) in patients undergoing video-assisted thoracoscopic surgery (VATS). We enrolled 161 adult patients who underwent elective VATS sixty-nine patients experienced hookwire localization (Group A) and 69 did not (Group B). Group A was further subdivided into the multiple localization group (n35, Group A The incidence and severity of acute postoperative pain were similar between Group A and Group B (p > 0.05). The incidence (56.5% vs 30.4%, p 0.002) and the NRS scores (2.0 2.0-3.0 vs 1.0 1.0-2.0, p 0.011) for CPSP were significantly higher in Group A than in Group B at 3 months postoperatively. On subgroup analysis, compared with Group A The preoperative pain stress of hookwire localization increased the incidence and intensity of CPSP rather than acute pain at 3 months postoperatively, especially in patients with multiple hookwires.

Tiragolumab (Anti-TIGIT) in SCLC Skyscraper-02, a Towering Inferno.

Small cell lung cancer (SCLC) is characterized by rapid progression and poor prognosis. Although the phase II CITYSCAPE-02 trial found objective response rate (ORR) and progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients improved when tiragolumab was added to atezolizumab and chemotherapy, the phase III SKYSCRAPER-02 failed to find PFS or OS benefit in patients with SCLC. Atezolizumab was the first immunotherapy to show survival benefit in extensive SCLC based on the phase III IMpower133 study. Given that immunotherapy has become the standard of care for SCLC patients, further research is needed into ways to augment the immune system to better treat these patients.

Demographic, Clinical, and Behavioral Factors Associated With Electronic Nicotine Delivery Systems Use in a Large Cohort in the United States.

Our primary purpose is to understand comorbidities and health outcomes associated with electronic nicotine delivery systems (ENDS) use. Study participants were Kaiser Permanente (KP) members from eight US regions who joined the Kaiser Permanente Research Bank (KPRB) from September 2015 through December 2019 and completed a questionnaire assessing demographic and behavioral factors, including ENDS and traditional cigarette use. Medical history and health outcomes were obtained from electronic health records. We used multinomial logistic regression to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of current and former ENDS use according to member characteristics, behavioral factors, and clinical history. We used Cox regression to estimate hazard ratios (HRs) and 95% CIs comparing risk of health outcomes according to ENDS use. Of 119 593 participants, 1594 (1%) reported current ENDS use and 5603 (5%) reported past ENDS use. ENDS users were more likely to be younger, male, gay or lesbian, and American Indian Alaskan Native or Asian. After adjustment for confounding, current ENDS use was associated with current traditional cigarette use (OR 39.55 CI33.44-46.77), current marijuana use (OR 6.72 CI5.61-8.05), history of lung cancer (OR 2.64 CI1.42-4.92), non-stroke cerebral vascular disease (OR 1.55 CI1.21-1.99), and chronic obstructive pulmonary disease (OR 2.16 CI1.77-2.63). Current ENDS use was also associated with increased risk of emergency room (ER) visits (HR 1.17 CI 1.05-1.30) and death (HR 1.84 CI1.02-3.32). Concurrent traditional cigarette use, marijuana use, and comorbidities were prevalent among those who used ENDS, and current ENDS use was associated with an increased risk of ER visits and death. Additional research focused on health risks associated with concurrent ENDS and traditional cigarette use in those with underlying comorbidities is needed.

Malignant melanoma (MM) is an aggressive malignant tumor, which mostly occurs on the skin, uvea, etc. The mucosal MM accounts for a small proportion of all MM and can occur in the digestive tract. Primary MM of the digestive tract is rare and can be found in the middle and lower third of the esophagus and the rectum containing melanocytes. Primary rectal MM often occurs in middle-aged and elderly women, with rapid progress and strong invasion. We report a case of a 61-year-old man diagnosed with primary malignant melanoma of the rectum with liver metastases mimicking rectum cancer.

Congenital cardiac liver cirrhosis with combined hepatocellular-cholangiocarcinoma-a case report.

Cardiac liver cirrhosis secondary to Fontan procedure has been associated with hepatocellular carcinoma at a younger age. However, Fontan associated liver disease and combined hepatocellular-cholangiocarcinoma has not been previously reported. Combined hepatocellular-cholangiocarcinoma is a rare cancer that accounts for 2-5% of primary liver tumors and poses significant diagnostic and treatment challenges. This case highlights these needs and potential screening and treatment considerations. Herein we describe a case of combined hepatocellular-cholangiocarcinoma in a patient with autism, congenital heart disease, and Fontan procedure. The patient is a 27-year-old male who presented with a liver mass detected on MRI performed in the context of a rising alpha-fetoprotein during a screening visit. Biopsy of the mass revealed a combined hepatocellular-cholangiocarcinoma which was staged as localized. Due to the COVID-19 pandemic and subsequent halt of all elective surgeries, the patient received local therapy with chemoembolization followed by pembrolizumab. The disease progressed though, and therapy was changed to gemcitabine plus cisplatin. Patient received 2 cycles of therapy, after which he and his family decided to transfer medical care to Memorial Sloan Kettering. Next generation sequencing of the tumor revealed This challenging case raises awareness towards screening and monitoring all patients with Fontan procedure for Fontan associated liver disease and liver cancers, including combined hepatocellular-cholangiocarcinoma. To the best of our knowledge, this is the first description of combined hepatocellular-cholangiocarcinoma occurring in the context of cardiac cirrhosis. The management difficulties that led to altering the goals of care, is another reminder of the dynamic nature of the care oncologists would provide.

Clinical best practices in optimal monitoring, early diagnosis, and effective management of antibody-drug conjugate-induced interstitial lung disease or pneumonitis a multidisciplinary team approach in Singapore.

Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT). A thorough literature search was conducted using PubMed to identify relevant articles related to ADCs published between 1 January 2010 and 31 November 2022. Based on the review of the literature combined with expert opinions, this review article offers an overview of incidences of ILDs associated with the use of newer anticancer therapies, specifically ADCs, and discusses local-regional best practices in optimal monitoring, early diagnosis, and management of DILD involving an MDT. Multidisciplinary input and consensus are crucial in the accurate diagnosis of DILD. The core group of essential attendees in the MDT are oncologists, pulmonologists, thoracic radiologists, and pathologists. This allows for the integration of expertise from different specialists to achieve a best fit diagnosis and management.

C-PLAN index as a prognostic factor for patients with previously untreated advanced non-small cell lung cancer who received combination immunotherapy A multicenter retrospective study.

Combination immunotherapy (immune checkpoint inhibitors and cytotoxic anticancer agents) is widely used as first-line treatment for advanced non-small cell lung cancer (NSCLC). However, the therapeutic effect of combination immunotherapy has not been fully investigated. C-reactive protein, performance status, lactate dehydrogenase, albumin, and derived neutrophil-to-lymphocyte ratio (C-PLAN) are useful biomarkers for predicting the prognosis of NSCLC however, there are no reports examining the C-PLAN index, which combines these five factors in a single prognostic factor. We retrospectively collected data from 178 patients with previously untreated advanced NSCLC who received combination immunotherapy at multicenter institutions in Nagano Prefecture between December 2018 and April 2022. We investigated the utility of the C-PLAN index as a prognostic factor using Cox regression analysis and correlated it with survival. The good and poor C-PLAN index groups included 85 and 93 patients, respectively. The good C-PLAN index group had a longer median progression-free survival (PFS) (10.7 vs. 6.0 months p 0.022) and overall survival (OS) (25.3 vs. 16.5 months p 0.003) than the poor C-PLAN index group. The C-PLAN index was an independent favorable prognostic factor that correlated with PFS and OS in multivariate analysis. The good C-PLAN index group had a higher proportion of never-smokers (16.5 vs. 4.3% p 0.007) and stage III diseasepostoperative recurrence (32.9 vs. 15.1% p 0.005) than the poor C-PLAN index group. The C-PLAN index is a useful prognostic factor for patients with previously untreated advanced NSCLC undergoing combination immunotherapy.

Solitary extramedullary plasmacytoma of the left main bronchus A case report and literature review.

Tracheal tumors are rare, accounting for 0.1% of all malignancies. Squamous cell carcinoma and adenoid cystic carcinoma are the two most prevalent tracheal cancers. Less than 20 cases of extramedullary plasmacytoma in the trachea and main bronchus have ever been documented in the literature, making it extremely uncommon. Although the origin of these lesions is unclear, viral pathogenesis and persistent inflammation are thought to be the main causes. Clinically, these individuals exhibit vague symptoms such as stridor, a persistent cough, dyspnea, or wheezing, making a correct diagnosis difficult.

Extracellular vesicle-encapsulated CC16 as novel nanotherapeutics for treatment of acute lung injury.

Acute lung injury (ALI) is still associated with high mortality. Growing evidence suggests that Club Cell Protein 16 (CC16) plays a protective role against ALI. However, the doses of recombinant CC16 (rCC16) used in preclinical studies are supraphysiological for clinical applications. Extracellular vesicles (EVs) are nanovesicles endogenously generated by mammalian cells. Our study demonstrated that CC16 is released via small EVs and EV-encapsulated CC16 (sEV-CC16) and has anti-inflammatory activities, which protect mice from lipopolysaccharide (LPS) or bacteria-induced ALI. Additionally, sEV-CC16 can activate the DNA damage repair signaling pathways. Consistent with this activity, we observed more severe DNA damage in lungs from Cc16 knockout (KO) than wild-type (WT) mice. Mechanistically, we elucidated that CC16 suppresses nuclear factor κB (NF-κB) signaling activation by binding to heat shock protein 60 (HSP60). We concluded that sEV-CC16 could be a potential therapeutic agent for ALI by inhibiting the inflammatory and DNA damage responses by reducing NF-κB signaling.

Lactobacillus rhamnosus GG ameliorates radiation-induced lung fibrosis via lncRNASNHG17PTBP1NICD axis modulation.

Radiation-induced pulmonary fibrosis (RIPF) is a major side effect experienced for patients with thoracic cancers after radiotherapy. RIPF is poor prognosis and limited therapeutic options available in clinic. Lactobacillus rhamnosus GG (LGG) is advantaged and widely used for health promotion. However. Whether LGG is applicable for prevention of RIPF and relative underlying mechanism is poorly understood. Here, we reported a unique comprehensive analysis of the impact of LGG and its derived lncRNA SNHG17 on radiation-induced epithelial-mesenchymal transition (EMT) in vitro and RIPF in vivo. As revealed by high-throughput sequencing, SNHG17 expression was decreased by LGG treatment in A549 cells post radiation and markedly attenuated the radiation-induced EMT progression (p < 0.01). SNHG17 overexpression correlated with poor overall survival in patients with lung cancer. Mechanistically, SNHG17 can stabilize PTBP1 expression through binding to its 3UTR, whereas the activated PTBP1 can bind with the NICD part of Notch1 to upregulate Notch1 expression and aggravated EMT and lung fibrosis post radiation. However, SNHG17 knockdown inhibited PTBP1 and Notch1 expression and produced the opposite results. Notably, A549 cells treated with LGG also promoted cell apoptosis and increased cell G2M arrest post radiation. Mice of RIPF treated with LGG decreased SNHG17 expression and attenuated lung fibrosis. Altogether, these data reveal that modulation of radiation-induced EMT and lung fibrosis by treatment with LGG associates with a decrease in SNHG17 expression and the inhibition of SNHG17PTBP1Nothch1 axis. Collectively, our results indicate that LGG exerts protective effects in RIPF and SNHG17 holds a potential marker of RIPF recovery in patients with thoracic cancers.

Overcoming multidrug-resistant lung cancer by mitochondrial-associated ATP inhibition using nanodrugs.

Despite the development of therapeutic modalities to treat cancer, multidrug resistance (MDR) and incomplete destruction of deeply embedded lung tumors remain long-standing problems responsible for tumor recurrence and low survival rates. Therefore, developing therapeutic approaches to treat MDR tumors is necessary. In this study, nanodrugs with enhanced intracellular drug internalization were identified by the covalent bonding of carbon nanotubes of a specific nano size and doxorubicin (DOX). In addition, carbon nanotube conjugated DOX (CNT-DOX) sustained in the intracellular environment in multidrug-resistant tumor cells for a long time causes mitochondrial damage, suppresses ATP production, and results in the effective therapeutic effect of drug-resistant tumors. This study identified that H69AR lung cancer cells, an adriamycin (DOX) drug-resistant tumor cell line, did not activate drug resistance function on designed nano-anticancer drugs with a specific nano size. In summary, this study identified that the specific size of the nanodrug in combination with DOX overcame multidrug-resistant tumors by inducing selective accumulation in tumor cells and inhibiting ATP by mitochondrial damage.

Using the Framework for Reporting Adaptations and Modifications-Expanded (FRAME) to study adaptations in lung cancer screening delivery in the Veterans Health Administration a cohort study.

Lung cancer screening is a complex clinical process that includes identification of eligible individuals, shared decision-making, tobacco cessation, and management of screening results. Adaptations to the delivery process for lung cancer screening in situ are understudied and underreported, with the potential loss of important considerations for improved implementation. The Framework for Reporting Adaptations and Modifications-Expanded (FRAME) allows for a systematic enumeration of adaptations to implementation of evidence-based practices. We applied FRAME to study adaptations in lung cancer screening delivery processes implemented by lung cancer screening programs in a Veterans Health Administration (VHA) Enterprise-Wide Initiative. We prospectively conducted semi-structured interviews at baseline and 1-year intervals with lung cancer screening program navigators at 10 Veterans Affairs Medical Centers (VAMCs) between 2019 and 2021. Using this data, we developed baseline (1st) process maps for each program. In subsequent years (year 1 and year 2), each program navigator reviewed the process maps. Adaptations in screening processes were identified, documented, and mapped to FRAME categories. We conducted a total of 16 interviews across 10 VHA lung cancer screening programs (n6 in year 1, n10 in year 2) to collect adaptations. In year 1 (2020), six programs were operational and eligible. Of these, three reported adaptations to their screening process that were planned or in response to COVID-19. In year 2 (2021), all 10 programs were operational and eligible. Programs reported 14 adaptations in year 2. These adaptations were planned and unplanned and often triggered by increased workload 57% of year 2 adaptations were related to the identification and eligibility of Veterans and 43% were related to follow-up with Veterans for screening results. Throughout the 2 years, adaptations related to data management and patient tracking occurred in 60% of programs to improve the data collection and tracking of Veterans in the screening process. Using FRAME, we found that adaptations occurred primarily in the areas of patient identification and communication of results due to increased workload. These findings highlight navigator time and resource considerations for sustainability and scalability of existing and future lung cancer screening programs as well as potential areas for future intervention.

Pulmonary sequestration in adult patients a single-center retrospective study.

Pulmonary sequestration (PS) is a rare congenital lower airway malformation. This study presents the clinical and imaging features and surgical outcomes of PS in adults, and compare the safety and feasibility of minimally invasive surgery versus open thoracotomy for PS. Adult patients with PS treated at our center from July 2011 to September 2021 were included. Information regarding the patient demographics, clinical and CT features, arterial supply and venous drainage, and surgical outcomes were collected. Ninety seven patients were included. The most common CT findings were mass lesions (50.5%) and cystic lesions (20.6%). The vast majority of the lesions (96 out of 97) were located close to the spine in the lower lobes (left vs. right 3.6 vs. 1). Arterial supply was mainly provided by the thoracic aorta (87.4%) and abdominal aorta (10.5%). Intralobar and extralobar PS accounted for 90.7% and 9.3% of the patients, respectively. Three (4.5%) patients who underwent minimally invasive surgery were converted to open thoracotomy due to dense adhesions. Though no significant differences regarding operative time (P 0.133), the minimally invasive surgery group was significantly better than the open thoracotomy group regarding intraoperative blood loss (P 0.001), drainage volume (P 0.004), postoperative hospital days (P 0.017) and duration of chest drainage (P 0.001). There were no cases of perioperative mortality. Only four (4.1%) patients developed postoperative complications, and no significant difference existed between the two groups. Our study revealed PS can present with a variety of different clinical and radiologic manifestations. Clinicians should consider the possibility of PS when diagnosing a lesion in the lower lobes close to the spine. Moreover, minimally invasive surgery is a safe and effective treatment modality for the treatment of PS in an experienced center.

A noval prognostic signature of the N7-methylguanosine (m7G)-related miRNA in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is characterized by high morbidity and mortality rates and poor prognosis. N7-methylguanosine play an increasingly vital role in lung adenocarcinoma. However, the prognostic value of N7-methylguanosine related-miRNAs in lung adenocarcinoma remains unclear. In the study, the mRNA and miRNA expression profiles and corresponding clinical informations were downloaded from the public database. The prognostic signature was built using least absolute shrinkage and selection operator Cox analysis. The Kaplan-Meier method was used to compare survival outcomes between the high- and low-risk groups. Signatures for the development of lung adenocarcinoma were tested using univariate and multivariate Cox regression models. Single-sample gene set enrichment analysis was used to determine the immune cell infiltration score. First, we predicted METTL1 and WDR4 chemosensitivities based on a public pharmacogenomics database. The area under the receiver operating characteristic curve showed that the performance of signature in 1-,3-, and 5-year survival predictions were 0.68, 0.65, and 0.683, respectively. We established a novel prognostic signature consisting of 9 N7-Methylguanosine related miRNAs using least absolute shrinkage and selection operator Cox analysis. Patients in the high-risk group had shorter survival times than those in the low-risk group did. The calibration curves at 1, 3, and 5-year also illustrate the high predictive power of the structure. Signature was corrected using the Toumor stage. The expression levels of METTL1 and WDR4 significantly correlated with the sensitivity of cancer cells to antitumor drugs. A novel signature constructed using 9 N7-methylguanosine related-miRNAs can be used for prognostic prediction.

Identification of potential biomarkers for papillary thyroid carcinoma by comprehensive bioinformatics analysis.

To perform bioinformatics analysis on the papillary thyroid carcinoma (PTC) gene chip dataset to explore new biological markers for PTC. The gene expression profiles of GSE3467 and GSE6004 chip data were collected by GEO2R, and the differentially expressed genes (DEGs) were selected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein-protein interaction (PPI) relationship analysis was achieved using STRING, and the hub genes were obtained using the Cytoscape software. GEPIA was used to validate the expressions of the hub genes in the normal and tumor tissues and to conduct survival analyses. Pertinent genetic pathology results were fetched using the HPA database. Finally, the key genes were clinically verified by reverse transcription-polymerase chain reaction. 97 genes were jointly up-regulated and 107 genes were jointly down-regulated in GSE3467 and GSE6004. GO function enrichment analysis revealed that the DEGs were involved in the regulation of calcium ion transport into cytosol, integrin binding, and cell adhesion molecule binding. KEGG pathway enrichment analysis indicated that the DEGs were chiefly associated with thyroid cancer and non-small cell lung cancer. According to the PPI network, 30 key target genes were identified. Only the expressions of ANK2, TLE1, and TCF4 matched between the normal and tumor tissues, and were associated with disease prognosis. When compared with the normal thyroid tissues, the protein and mRNA expressions of ANK2, TLE1, and TCF4 were down-regulated in PTC. Significant differences exist in overall gene expression between the thyroid tissues of patients with PTC and those of healthy people. Furthermore, the differential genes ANK2, TLE1, and TCF4 are expected to be reliable molecular markers for the mechanism study and diagnosis of PTC.

Impact of Prior Cancer History on Outcomes of Resected Lung Cancer.

Previous studies concerning the impact of prior cancer on newly diagnosed lung cancer are mainly based on databases and obtained mixed results. Utilizing a large study population, we aimed to reveal this impact. Lung cancer patients from January 2008 to April 2021 were enrolled. The Kaplan-Meier method was used to perform survival analyses. To investigate the impact of prior cancer, a Cox proportional hazards model was conducted. To minimize the influence of the heterogeneity of prior cancer, stratified analyses were carried out. In total, 17,423 lung cancer patients were reviewed, among which we identified 1469 (8.4%) patients with a history of prior cancer. Cox regression analysis revealed that prior cancer was an independent poor prognostic factor on overall survival (HR 1.430, 95% CI 1.147-1.784, p 0.001) but did not affect lung cancer-specific survival (HR 1.120, 95% CI 0.876-1.434, p 0.366). Interestingly, in further stratified analyses, we found that prior cancer history affected overall survival only in pTNM stage 0I patients (HR 1.670, 95% CI 1.247-2.237, p 0.001), but not in pTNM stage IIIIIIV patients (HR 1.237, 95% CI 0.877-1.743, p 0.226). Similarly, prior cancer was an independent poor prognostic factor on overall survival only for pN0 patients. Subsequently, subgroup analyses indicated that the impact of prior cancer varied in pTNM stage 0I patients according to the type of prior cancer and the interval time. Considering that prior cancer affects overall survival in patients with clinically curable lung cancer, clinicians should pay attention to this effect and improve the management of these patients to achieve a better prognosis.

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPRCas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPRCas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRAS

A novel pH sensitive theranostic PLGA nanoparticle for boron neutron capture therapy in mesothelioma treatment.

This study aims to develop poly lactic-co-glycolic acid (PLGA) nanoparticles with an innovative imaging-guided approach based on Boron Neutron Capture Therapy for the treatment of mesothelioma. The herein-reported results demonstrate that PLGA nanoparticles incorporating oligo-histidine chains and the dual GdB theranostic agent AT101 can successfully be exploited to deliver a therapeutic dose of boron to mesothelioma cells, significantly higher than in healthy mesothelial cells as assessed by ICP-MS and MRI. The selective release is pH responsive taking advantage of the slightly acidic pH of the tumour extracellular environment and triggered by the protonation of imidazole groups of histidine. After irradiation with thermal neutrons, tumoral and healthy cells survival and clonogenic ability were evaluated. Obtained results appear very promising, providing patients affected by this rare disease with an improved therapeutic option, exploiting PLGA nanoparticles.

GWAS Explorer an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55-74 at enrollment in 1993-2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology.

Pericentromeric satellite lncRNAs are induced in cancer-associated fibroblasts and regulate their functions in lung tumorigenesis.

The abnormal tumor microenvironment (TME) often dictates the therapeutic response of cancer to chemo- and immuno-therapy. Aberrant expression of pericentromeric satellite repeats has been reported for epithelial cancers, including lung cancer. However, the transcription of tandemly repetitive elements in stromal cells of the TME has been unappreciated, limiting the optimal use of satellite transcripts as biomarkers or anti-cancer targets. We found that transcription of pericentromeric satellite DNA (satDNA) in mouse and human lung adenocarcinoma was observed in cancer-associated fibroblasts (CAFs). In vivo, lung fibroblasts expressed pericentromeric satellite repeats HS2HS3 specifically in tumors. In vitro, transcription of satDNA was induced in lung fibroblasts in response to TGFβ, IL1α, matrix stiffness, direct contact with tumor cells and treatment with chemotherapeutic drugs. Single-cell transcriptome analysis of human lung adenocarcinoma confirmed that CAFs were the cell type with the highest number of satellite transcripts. Human HS2HS3 pericentromeric transcripts were detected in the nucleus, cytoplasm, extracellularly and co-localized with extracellular vesicles in situ in human biopsies and activated fibroblasts in vitro. The transcripts were transmitted into recipient cells and entered their nuclei. Knock-down of satellite transcripts in human lung fibroblasts attenuated cellular senescence and blocked the formation of an inflammatory CAFs phenotype which resulted in the inhibition of their pro-tumorigenic functions. In sum, our data suggest that satellite long non-coding (lnc) RNAs are induced in CAFs, regulate expression of inflammatory genes and can be secreted from the cells, which potentially might present a new element of cell-cell communication in the TME.

Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases A Single-Center Experience.

Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine-total body irradiation (TBI) with fludarabine among patients with hematologic diseases. This retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mgkgd × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years. The donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P .06, and 5-year OS rate 53% vs 39%, P .13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P .003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P .001) in both groups. A high disease risk index was possibly associated with inferior OS (P .07) in both groups. The FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non-small-Cell Lung Cancer Patients.

Platinum doublet chemotherapy is the standard of care in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC. We retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy. Of the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months 95% confidence interval CI 5.0-8.5 vs. 4.2 months 95% CI 3.3-5.0, hazard ratio HR 0.64, 95% CI 0.46-0.89, P .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 95% CI 22.6-30.8 vs. 13.4 months 95% CI 10.4-16.4, HR, 0.49 95% CI 0.31-0.75, P .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively). The combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.

Increased odds of mortality from non-malignant respiratory disease and lung cancer are highest among US coal miners born after 1939.

Coal miners suffer increased mortality from non-malignant respiratory diseases (NMRD), including pneumoconioses and chronic obstructive pulmonary disease, compared with the US population. We characterised mortality trends from NMRD, lung cancer and ischaemic heart disease (IHD) using data from the Federal Black Lung Program, National Coal Workers Health Surveillance Program and the National Death Index. We compared mortality ORs (MORs) for NMRD, lung cancer and IHD in former US coal miners to US white males. MORs were computed for the study period 1979-2017 by birth cohort (<1920, 1920-1929, 1930-1939, ≥1940), with a subanalysis restricted to Central Appalachia. The study population totalled 235 550 deceased miners, aged >45 years. Odds of death from NMRD and lung cancer across all miner birth cohorts averaged twice those of US males. In Central Appalachia, MORs significantly increased across birth cohorts. There was an eightfold increase in odds of death from NMRD among miners born after 1940 (MOR US coal miners have excess mortality from NMRD and lung cancer compared with total US and Appalachian populations. Mortality is highest in the most recent birth cohorts, perhaps reflecting increased rates of severe pneumoconiosis.

Malignant mesothelioma among US Medicare beneficiaries incidence, prevalence and therapy, 2016-2019.

Mesothelioma is a rare, aggressive cancer caused by exposure to asbestos fibres. Mesothelioma patients who receive trimodal therapy (chemotherapy, surgical resection and radiation) survive longer than those who receive two or fewer therapy modalities. This study analyses the 2016-2019 Medicare claims data to estimate the burden of malignant mesothelioma and describe therapy patterns (when available) among continuously enrolled fee-for-service (FFS Medicare parts A and B) beneficiaries. We analysed claims and enrolment information from 42 529 117 FFS Medicare beneficiaries using three mesothelioma case definitions (broad, intermediate and narrow) with varying levels of diagnostic requirements. Results are presented as ranges of values for the three definitions. Among FFS beneficiaries, 8213-19 036 beneficiaries with mesothelioma were identified depending on the case definition. The annual prevalence per 100 000 beneficiaries ranged from 8.8 in 2016 (narrow) to 31.3 in 2019 (broad) and annual incidence per 100 000 beneficiaries ranged from 4.5 in 2019 (narrow) to 12.6 in 2017 (broad). Depending on the mesothelioma case definition, 41.8%-81.5% had available therapy claim information indicating that 7.6%-11.3% received chemotherapy alone, 1.3%-1.5% received radiation alone, and 14.3%-27.0% underwent surgery only, with 4.6%-10.5% receiving all three therapy modalities. Mesothelioma was a prevalent disease among FFS Medicare beneficiaries during 2016-2019, and a limited proportion of beneficiaries received all three therapy modalities. Medicare data build on findings from cancer registry data to enhance our understanding of the mesothelioma burden and therapy patterns.

Metabolic flux augmentation via glucose transport activation may be desirable in Glucose transporter 1 (Glut1) deficiency (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly express Glut1 relative to other glucose transporters, we screened 11,613 compounds for effects on the accumulation of an extracellularly-applied fluorescent glucose analog. 5 drugs currently prescribed for unrelated indications or preclinically-characterized robustly enhanced intracellular fluorescence. Additionally identified were 37 novel activating and 9 inhibitory compounds lacking previous biological characterization. Because few glucose-related mechanistic or pharmacological studies were available for these compounds, we developed a method to quantify G1D mouse behavior to infer potential therapeutic value. To this end, we designed a 5-track apparatus to record and evaluate spontaneous locomotion videos. We applied this to a G1D mouse model that replicates the ataxia and other manifestations cardinal to the human disorder. Because the first two drugs that we examined in this manner (baclofen and acetazolamide) exerted various impacts on several gait aspects, we used deep learning neural networks to more comprehensively assess drug effects. Using this method, 49 locomotor parameters differentiated G1D from control mice. Thus, we used parameter modifiability to quantify efficacy on gait. We tested this by measuring the effects of saline as control and glucose as G1D therapy. The results indicate that this

High Throughput Confined Migration Microfluidic Device for Drug Screening.

Cancer metastasis is the major cause of cancer-related death. Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors, creating confined spaces for tumor cell migration and metastasis. Confined migration is involved in all metastasis steps. However, confined and unconfined migration inhibitors are different and drugs available to inhibit confined migration are rare. The main challenges are the modeling of confined migration, the suffering of low throughput, and others. Microfluidic device has the advantage to reduce reagent consumption and enhance throughput. Here, a microfluidic chip that can achieve multi-function drug screening against the collective migration of cancer cells under confined environment is designed. This device is applied to screen out effective drugs on confined migration among a novel mechanoreceptors compound library (166 compounds) in hepatocellular carcinoma, non-small lung cancer, breast cancer, and pancreatic ductal adenocarcinoma cells. Three compounds that can significantly inhibit confined migration in pan-cancer mitochonic acid 5 (MA-5), SB-705498, and diphenyleneiodonium chloride are found. Finally, it is elucidated that these drugs targeted mitochondria, actin polymerization, and cell viability, respectively. In sum, a high-throughput microfluidic platform for screening drugs targeting confined migration is established and three novel inhibitors of confined migration in multiple cancer types are identified.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea.

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

Oxygen Uptake and Heart Rate On-Kinetics during Prehabilitation in Patients with Scheduled Non-Small Cell Lung Cancer Resection.

Oxygen uptake (V̇O2) and heart rate (HR) kinetics during a constant work-rate test (CWRT) are used to evaluate the response to exercise in healthy subjects as well as subjects with various pathologies. This study aimed to explore the feasibility of these measures and their responsiveness to a prehabilitation program in patients with non-small cell lung cancer (NSCLC). This study is preregistered (NCT04041297) ancillary analysis of a subgroup of individuals with NSCLC included in the Preo-Dens study (NCT03936764). Thirty individuals performed a moderate-CWRT before and after a 15-session prehabilitation program between July 2019 and April 2021. V̇O2 and HR on-kinetics were extracted from the first 240 s of breath-by-breath data using Box-Jenkins transfer functions. Prepost V̇O2 on-kinetic feature values were reliable for 2530 participants, and prepost HR kinetic feature values were reliable for 1930. V̇O2 time constant (τ) and mean response time reduced from pre-post prehabilitation (mean difference -7.8 s 95% CI -14.6 to -1.0, and -8.4 s 95% CI -14.7 to -2.0, respectively). For HR on-kinetics, τ did not change from pre-post prehabilitation (median difference -4.0 s 95% CI -36.0 to 11.0). V̇O2 and HR response amplitudes reduced significatively from pre-post prehabilitation (mean difference -38.6 mLmin 95% CI -73.3 to -3.9, and -3.1 beatsmin 95% CI -6.4 to -0.2, respectively). V̇O2 on-kinetic analysis during moderate-CWRT is feasible in individuals with scheduled NSCLC resection, and results are responsive to prehabilitation. These results support a true speeding of the adaptation of aerobic metabolism after a 15-session prehabilitation program.

Genomic Characteristics and the Potential Clinical Implications in Oligometastatic Non-Small Cell Lung Cancer.

Oligometastatic non-small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome. However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis. We performed next-generation sequencing (NGS) to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity. We found ERBB2, ALK, MLL4, PIK3CB and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden (TMB) of oligometastasis was 5.00 mutationsMb, which was significantly associated with smoking, DNA damage repair (DDR) genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation. Our results shall help redefine oligometastasis beyond simple lesion enumeration that will ultimately improve the selection of patients with real oligometastatic state and optimize personalized cancer therapy for oligometastatic NSCLC.

Expression landscapes in non-small cell lung cancer shaped by the thyroid transcription factor 1.

TTF-1-expressing non-small cell lung cancer (NSCLC) is one of the most prevalent lung cancer types worldwide. However, theparadoxical activity of TTF-1 in both lung carcinogenesis and tumor suppression is believed to be context-dependentwhich calls for a deeper understanding about the pathological expression of TTF-1. In addition, the expression circuitry of TTF-1-target genes in NSCLC has not been well examined which necessitates to revisit the involvement of TTF-1- in a multitude of oncologic pathways. We used RNA-seq and clinical data of patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), including ChIP-seq data from different NSCLC cell lines, and mapped the proteome of NSCLC tumor. Our analysis showed significant variability in TTF-1 expression among NSCLC,and further clarified that this variability is orchestrated at the transcriptional level. We also found that high TTF-1 expression could negatively influence the survival outcomes of stage 1 LUAD which may be attributed to growth factor receptor-driven activation of mitogenic and angiogenic pathways. Mechanistically, TTF-1 may also control the genes associated with pathways involved in acquired TKI drug resistance or response to immune checkpoint inhibitors. Lastly, proteome-based biomarker discovery in stage 1 LUAD showed that TTF-1 positivity is potentially associated with the upregulation of several oncogenes which includes interferon proteins, MUC1, STAT3, and EIF2AK2. Collectively, this study highlights the potential involvement of TTF-1 in cell proliferation, immune evasion, and angiogenesis in early-stage NSCLC.

The value of prognostic and predictive parameters in early-stage lung adenocarcinomas A comparison between biopsies and resections.

Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters. We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated. The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively. Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up.