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Time to Pain Relapse After Palliative Radiotherapy for Bone Metastasis A Prospective Multi-institutional Study.

Low risk asymptomatic bone metastasis (LRABM) without gross osteolytic changes tends to be out of indication for radiotherapy. The aim of this study was to evaluate the time between the end of palliative radiotherapy of bone metastasis (BM) until the start of new pain, in patients with painful BM. Patients with BM were prospectively assessed for location and strength of pain every month for one year after radiotherapy. The correlation of pain relapse at irradiated site, and pain onset outside the irradiated site was evaluated with sex, age, primary tumor, pathology of tumor, visceral metastases, baseline scores for Eastern Cooperative Oncology Group performance status (PS), and baseline verbal rating scale (VRS). A hundred and thirty-two patients were included (79 males and 53 females). Median age was 66 years. Primary sites were lung (n60), breast (n17), colon (n12), prostate (n11), and others (n33) (one patient had two primary sites). Median follow-up was 185 days. Pain relief was observed in 92 patients (86.0%). Out of them, pain progression was observed in 69.6%. Median time to pain progression was 75.5 days. Pain onset outside the irradiated site was observed in 57 patients (43.2%). Median time to pain onset was 109 days. Out of the 57 patients, 13 (22.8%) had LRABM which existed before the start of radiotherapy. There were 54 patients with LRABM in this study and because many patients had more than one LRABM, the total LRABM sites were 123. Out of them, pain onset was observed within one year after irradiation in 44 (36%) lesions. Median time to pain onset was 67 days, which was the shortest of the three irradiated site, out of the irradiated site, and LRABM site. Risk factors for high probability of pain onset within one year in LRABM lesions were female sex (showing a trend in univariate analysis), and pelvic, skull and spine metastasis (significant in multivariate analysis). Time to pain onsets in LRABM are relatively short, especially in female patients with pelvic, skull and spine metastasis. In these patients, prophylactic radiotherapy could be an option to consider.

Real-world Efficacy and Safety of Atezolizumab Plus Bevacizumab, Paclitaxel and Carboplatin for First-line Treatment of Japanese Patients With Metastatic Non-squamous Non-small Cell Lung Cancer.

Platinum-doublet chemotherapy plus either programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitors has been reported to improve the survival of patients with advanced non-small cell lung cancer (NSCLC). The IMpower150 study showed significant improvements in progression-free survival and overall survival with atezolizumab in combination with bevacizumab, a humanized anti-VEGF monoclonal antibody, paclitaxel, and carboplatin (ABCP therapy) in chemotherapy-naïve patients with non-squamous NSCLC. We herein report the efficacy and safety of ABCP therapy in Japanese patients with non-squamous NSCLC in clinical practice. We retrospectively evaluated the efficacy and safety of ABCP therapy in 30 patients treated at our hospital from February 2019 to December 2021. The median age of patients was 69 years, 24 (80.0%) patients were male, 29 (96.7%) patients had a performance status of 0 or 1, 28 (93.3%) patients had adenocarcinoma histology, and 7 (23.3%) patients had epidermal growth factor receptor mutations. Evaluation of the PD-L1 tumor proportion score (TPS) showed that 12 (40.0%), 8 (26.7%), and 6 (20.0%) patients had a TPS of ≥50%, 1% to 49%, and <1%, respectively. The objective response rate of the intention-to-treat wild-type population was 73.9%, and the median progression-free survival was 8.3 months. Immune checkpoint inhibitor (ICI)-induced pneumonitis occurred in one (3.3%) patient. ABCP therapy for Japanese non-squamous NSCLC patients in a clinical setting achieved a high response rate with low incidence of ICI-induced pneumonitis equivalent to those observed in IMpower150 study.

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis.

Efficacy and toxicity of concurrent chemoradiotherapy (CCRT) and durvalumab for locally advanced non-small cell lung cancer (LA-NSCLC) with N3 lymph node metastasis remain unclear. We aimed to evaluate the clinical outcomes of patients who received CCRT and durvalumab (durvalumab cohort) and compare their outcomes with those of patients who received CCRT alone (CCRT-alone cohort). The data of patients who had received treatment between November 2008 and February 2022 and were followed up for at least 3 months were retrospectively analyzed. Local control, progression-free survival, and overall survival were evaluated using Kaplan-Meier analysis and compared using the log-rank test. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The data of 29 patients were analyzed (median follow-up period 22 months). Among them, 17 received CCRT alone and 12 received CCRT and durvalumab. There were 14 patients with stage IIIB and 15 with stage IIIC LA-NSCLC. The durvalumab cohort (89%) had a significantly higher 1-year local control rate than the CCRT-alone cohort (47% p0.035). No significant difference was observed in either progression-free or overall survival between the two cohorts. Grade ≥2 pneumonitis was observed in 6 (50%) and 7 (41%) patients in the durvalumab and CCRT-alone cohorts, respectively. CCRT with durvalumab may be effective against LA-NSCLC with N3 lymph node metastasis. The incidence of grade 2 pneumonitis was slightly higher in the durvalumab cohort than in the CCRT-alone cohort, suggesting the need for careful patient monitoring after treatment.

Relationship Between Osimertinib Concentration and Clinical Response in Japanese Patients With Non-small Cell Lung Cancer.

Osimertinib is the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The present study aimed to determine the previously unclarified association of osimertinib plasma trough concentrations with efficacy, adverse events, and genetic polymorphisms in Japanese patients with NSCLC harboring EGFR mutations. In this prospective study, blood samples of 25 patients who received osimertinib were collected to measure plasma osimertinib concentrations and to genotypically characterize ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2 polymorphisms. Plasma osimertinib concentrations were analyzed using validated multiple reaction monitoring mode-based liquid chromatography-tandem mass spectrometry. Osimertinib concentration necessary to achieve optimal median progression-free survival (PFS) was determined using receiver operating characteristic curve analysis. PFS and overall survival were analyzed using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Plasma osimertinib concentrations between different patient groups were compared using the Mann-Whitney U-test. Patients were divided into high and low concentration groups based on a plasma osimertinib cut-off concentration of 211 ngml. Median PFS was longer in the high trough concentration group than that in the low trough concentration group (46.3 vs. 16.8 months, p0.029). Plasma osimertinib concentrations adjusted for dose and body weight did not differ between the patients with and without variant polymorphisms. Monitoring plasma trough concentrations during maintenance might improve osimertinib treatment efficacy in patients with NSCLC harboring EGFR mutations.

A rare case of pulmonary benign metastasising leiomyomatosis in a woman with a previous history of hysterectomy for uterine fibroids.

Benign metastasising leiomyomatosis (BML) is a rare disease, predominantly seen in premenopausal women. It poses a diagnostic dilemma and can be misdiagnosed as malignancy. Here we present a case of 41-year-old woman with a previous history of hysterectomy 10 years ago for multiple fibroids. She presented with shortness of breath and chest discomfort. Chest X-ray showed pulmonary infiltrates. She was diagnosed with sarcoidosis and treated with steroids without any improvement. Further investigations including CT scan and bronchoscopy and lavage failed to confirm a diagnosis. Subsequently she underwent video-assisted thoracoscopic surgery and histopathology revealed leiomyomatosis (so-called leiomyomatous hamartomasbenign metastasising leiomyomatosis). Oestrogen and progesterone receptors showed diffuse and strong nuclear staining. The patient was commenced on tamoxifen and a repeat chest X-ray in 8 weeks showed significant improvement. In women of reproductive age with previous hysterectomy and multiple lung nodules on imaging, the diagnosis of BML should be taken into consideration.

Next-generation sequencing and molecular therapy.

Cancers contain a plethora of mutations, few of which are critical to maintaining a state of malignancy. With our ever-expanding understanding of the genomic complexity of cancer, potentially actionable biomarkers whose inhibition could cripple cancer growth are increasingly being elucidated. Modern cancer drug development has largely switched from cytotoxic agents to targeted therapies and immunotherapy, with noteworthy success in several cancer types including non-small-cell lung cancer (NSCLC), breast cancer and melanoma. Next-generation sequencing offers high-throughput, widescale genomic interrogation in a far more efficient and affordable manner than previous sequencing methods. This facilitates detection of potentially actionable mutations and fusions for individual patients and contributes to the identification of novel predictive and prognostic biomarkers in a population. Challenges in the technical aspects of biopsy and sequencing, interpretation, and development of targeted therapies against common genomic aberrations will need to be addressed for personalised medicine to become a reality for more patients with cancer.

Lung cancer recovery focus post pandemic an income-deprived area paradigm.

Stage shift has been proposed as a marker of impact of Coronavirus 2019 (COVID-19) in lung cancer services however, there are no data available specifically from income-deprived areas. Thus, this study evaluated the impact of the COVID-19 pandemic on lung cancer care in our area (Corby among the most income deprived in England) and identified focus recovery areas. The study was a retrospective observational study of 668 consecutive patients with lung cancer at a district general hospital, pre-, during and after the COVID peak. Outcomes were the overall number of cases, presenting staging and treatment pathway. Overall, 32 fewer patients were diagnosed during the pandemic, with more inpatient diagnoses (p0.01) and fewer primary care referrals (p<0.0001). There were no differences observed in treatment intent or stage shift. Our results suggest that COVID-19 negatively affected the whole lung cancer pathway in our area. However, stage shift might not be ideal to assess the impact of COVID-19 in income-deprived areas. Further studies will help the strategic rollout of a screening programme to identify patients with lung cancer earlier on in such areas.

The sodium new houttuyfonate suppresses NSCLC via activating pyroptosis through TCONS-14036miR-1228-5pPRKCDBP pathway.

Several studies have suggested the potential value of Houttuynia cordata as a therapeutic agent in lung cancer, but direct evidence is still lacking. The study aimed to determine the regulatory impact of a major H. cordata constituent derivative (sodium new houttuyfonate SNH) on lncRNA networks in non-small cell lung cancer (NSCLC) to identify new potential therapeutic targets. After exposing NSCLC cells to SNH, we analysed the following cell death (via flow cytometry, TUNEL and ASC speck formation assays), immune factors (via ELISA), gene transcription (via RT-qPCR), subcellular localisation (via FISH), gene-gene and gene-protein interactions (via dual-luciferase reporter and RNA immunoprecipitation assays, respectively) and protein expression and distribution (via western blotting and immunocytochemistry or immunohistochemistry). In addition, statistical analysis (via one-way ANOVA or unpaired t-tests) was performed. Exposure to SNH promoted NSCLC cell pyroptosis, concomitant with significant up-regulation of TCONS-14036, a novel lncRNA. Mechanistic research demonstrated that TCONS-14036 functions as a competing endogenous (ce)RNA by sequestering microRNA (miR)-1228-5p, thereby up-regulating PRKCDBP-encoding transcript levels. Indeed, PRKCDBP promoted pyroptosis by activating the NLRP3 inflammasome, resulting in CASP1, IL-1β and GSDMD cleavage. Our findings elucidate the potential molecular mechanisms underlying the ability of SNH to suppress NSCLC growth through activation of pyroptosis via the TCONS-14036miR-1228-5pPRKCDBP pathway. Thus, we identify a new potential therapeutic targets for NSCLC.

Secondary metabolites from the underground parts of Valeriana sisymbriifolia Vahl. and their in vitro cytotoxic activities.

Cytotoxic activity-guided isolation studies on the underground parts of Valeriana sisymbriifolia Vahl. led to the isolation of 12 secondary metabolites including two undescribed iridoids, sisymbriifolivaltrate and sisymbriifolioside, and two unreported sesquiterpene lactones, sisymbriifolins A and B. Chemical structures of the isolates were established by extensive 1D and 2D NMR analyses as well as HR-ESI-MS. The in vitro cytotoxic activities of the extract, sub-fractions and isolates on lung (A549), breast (MCF7), gastric (HGC27) and prostate (PC3) cancer cell lines were evaluated by MTS assay. Sisymbriifolivaltrate, didrovaltrate, valtrate, 7-homovaltrate and 1-α-acevaltrate exhibited promising cytotoxic activity on MCF7 cell line with IC

Sentiment analysis of medical record notes for lung cancer patients at the Department of Veterans Affairs.

Natural language processing of medical records offers tremendous potential to improve the patient experience. Sentiment analysis of clinical notes has been performed with mixed results, often highlighting the issue that dictionary ratings are not domain specific. Here, for the first time, we re-calibrate the labMT sentiment dictionary on 3.5M clinical notes describing 10,000 patients diagnosed with lung cancer at the Department of Veterans Affairs. The sentiment score of notes was calculated for two years after date of diagnosis and evaluated against a lab test (platelet count) and a combination of data points (treatments). We found that the oncology specific labMT dictionary, after re-calibration for the clinical oncology domain, produces a promising signal in notes that can be detected based on a comparative analysis to the aforementioned parameters.

Esophageal cancer-related gene 4 and solid tumors a brief literature review.

Esophageal cancer-related gene 4 (ECRG4) plays key roles in various malignancies, including lung cancer, prostate cancer, esophageal cancer, and breast cancer, and has potential applications in the early diagnosis, prevention, treatment, and prognosis of cancer. However, the mechanisms underlying the role of ECRG4 in cancer remain elusive. An association between ECRG4 and proliferation, migration, cell cycle, apoptosis, methylation, and ubiquitination in cancer has been found. Additionally, some studies have investigated the regulatory mechanism of the relationship between ECRG4 and long non-coding RNAs, co-factors, and resistance to chemotherapy. Drugs that demethylate ECRG4 are in clinical use. Thus, further investigation of the mechanisms by which ECRG4 influences tumorigenesis, and its clinical significance, are needed. The present study outlines the current understanding of the functions of ECRG4 in cancer and discusses its potential value in cancer therapy.

Variation in Use of Lung Cancer Targeted Therapies Across State Medicaid Programs, 2020-2021.

Targeted therapies for EGFR (OMIM 131550)- and ALK (OMIM 105590)-altered metastatic non-small cell lung cancer (NSCLC) substantially improve outcomes for some patients. However, use of these therapies is lower among Medicaid patients, and access to oncology care varies across state Medicaid programs. Evidence is lacking on how use of targeted therapies for metastatic NSCLC varies across state Medicaid programs. To characterize state-level variation in the use of targeted therapies among Medicaid patients with metastatic NSCLC and to describe factors associated with this variation. This cross-sectional study used publicly available data from the Medicaid Drug Utilization Database from 2020 and 2021 and peer-reviewed data on NSCLC incidence, the prevalence of EGFR and ALK alterations, and expected treatment durations to estimate expected use of targeted therapies for EGFR- and ALK-altered NSCLC in 33 states. State-specific Medicaid programs and state policies and characteristics. The primary outcome was the estimated proportion of person-time of Medicaid patients with EGFR- or ALK-altered NSCLC associated with receipt of targeted therapy in each state Medicaid program. Nested linear regression models examined associations between the observed variation and state policies and characteristics. There were an estimated 3461 person-years in which EGFR- and ALK-targeted therapies were indicated in 2020 and 2021. During these years, only 2281 person-years of EGFR- and ALK-targeted therapies were dispensed to Medicaid patients, suggesting that an estimated 66% of Medicaid patients with EGFR- and ALK-altered metastatic disease received indicated targeted therapies across all states. Rates of targeted therapy use ranged from 18% in Arkansas to 113% in Massachusetts 30 of 33 states (91%) had lower rates of targeted therapy use than expected. The observed variation across state Medicaid programs was associated with Medicaid policies, the density of oncologists, and state gross domestic product per capita. This study suggests that rates of targeted therapy use among Medicaid patients with EGFR- and ALK-altered NSCLC were lower than expected and varied across state Medicaid programs. State policies and characteristics were associated with the observed variation, indicating where interventions could improve access to treatment and outcomes for patients with NSCLC.

Hyperglycaemia following immune checkpoint inhibitor therapy-Incidence, aetiology and assessment.

We systematically studied the presence of hyperglycaemia during treatment with Immune Checkpoint Inhibitors (ICPI) for cancer, in those with and without diabetes at baseline, and determined the cause of new-onset hyperglycaemia, METHODS Retrospective review of electronic records of those receiving an ICPI for melanoma, lung or renal cancer. Overall, 959 participants were included. In this study, 103 had diabetes at baseline (10.7%). Those with lung cancer had the highest frequency of diabetes 131 people had hyperglycaemia (defined as at least one glucose ≥11.1 mmolL) in the year after starting an ICPI. The incidence was 55% in those with diabetes at baseline, and 8.6% in those without baseline diabetes. Among 74 with new-onset hyperglycaemia (without pre-existing diabetes) 76% was attributable to steroid induced diabetes, with 9.5% due to ICPI Induced diabetes resembling type 1 diabetes. Hyperglycaemia is common in persons receiving an ICPI for cancer, including 8.6% of those without known diabetes. While much of this is due to glucocorticoid use, care is needed to avoid missing those with ICPI-induced diabetes who are at risk of diabetic ketoacidosis, which is a medical emergency.

The application of patient-derived organoid in the research of lung cancer.

Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. However, mechanisms of its progression remained unclear and new treatments against this disease are rapidly emerging. As a novel preclinical model, patient-derived organoid (PDO) can also be established from the patients tumor tissue and cultured in the laboratory, which preserves the key biological characteristics of the original tumor. Compared to the patient-derived xenograft (PDX) model of lung cancer, the culture success rate is improved, and the time and cost of model establishment are largely reduced. PDO is also expected to provide a more individual model to predict the efficacy of anti-cancer treatment in vitro. This paper summarizes the current application of PDO in the translational research of lung cancer.

Survival after resection of brain metastasis impact of synchronous versus metachronous metastatic disease.

Patients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM. Between 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis. Non-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5-16.5) compared to 13 months (95% CI 9.6-16.4) for patients with metachronous BM diagnosis (p 0.97). The present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.

Solitary Lung Nodule CT-Guided Transthoracic Biopsy vs Transbronchial Biopsy With Endobronchial Ultrasound and Flexible Bronchoscope, a Meta-Analysis of Randomized Controlled Trials.

Transbronchial lung biopsy with radial endobronchial ultrasound (rEBUS-TBB) and Computed tomography (CT) scan-guided transthoracic biopsy (CT-TTB) are commonly used to investigate peripheral lung nodules but high-quality data are still not clear about the diagnostic and safety profile comparison of these two modalities. We included all randomized controlled trials (RCT) comparing rEBUS-TBB with a flexible bronchoscope and CT-TTB for solitary lung nodules. Two reviewers extracted data independently on diagnostic performance and complication rates. 170 studies were screened, 4 RCT with a total of 325 patients were included. CT-TTB had a higher diagnostic yield than rEBUS-TBB (83.45% vs 68.82%, risk difference - 0.15, 95% CI, - 0.24, - 0.05), especially for lesion size 1-2 cm (83% vs 50%, risk difference - 0.33, 95% CI, - 0.51, - 0.14). For malignant diseases, rEBUS-TBB had a diagnostic yield of 75.75% vs 87.7% of CT-TTB. rEBUS-TBB had a significant better safety profile with lower risks of pneumothorax (2.87% vs 21.43%, OR 0.12, 95% CI 0.05-0.32) and combined outcomes of hospital admission, hemorrhage, and pneumothorax (8.62% vs 31.81%, OR 0.21, 95% CI, 0.11-0.40). Factors increasing diagnostic yield of rEBUS were lesion size and localization of the probe but not the distance to the chest wall and hilum. CT-TTB had a higher diagnostic yield than rEBUS-TBB in diagnosing peripheral lung nodules, particularly for lesions from 1 to 2 cm. However, rEBUS-TBB was significantly safer with five to eight times less risk of pneumothorax and composite complications of hospital admission, hemorrhage, and pneumothorax. The results of this study only apply to flexible bronchoscopy with radial ebus without navigational technologies. More data are needed for a comparison between CT-TTB with rEBUS-TBB combined with advanced navigational modalities.

Association of Surgical Timing with Outcomes in Early Stage Lung Cancer.

Optimal time to surgery for lung cancer is not well established. We aimed to assess whether time to surgery correlates with outcomes. We assessed patients 18-84 years old who were diagnosed with stage III lung cancer at our integrated healthcare system from 2009 to 2019. Time to surgery was defined to start with disease confirmation (imaging or biopsy) prior to the surgery scheduling date. Outcomes of unplanned return to care within 30 days of lung cancer surgery, all-cause mortality, and disease recurrence were compared based on time to surgery before and after 2, 4, and 12 weeks. Of 2861 included patients, 70% were over 65 years old and 61% were female. Time to surgery occurred in 1-2 weeks for 6%, 3-4 weeks for 31%, 5-12 weeks for 58%, and 13-26 weeks for 5% of patients. Patients with time to surgery > 4 (vs. ≤ 4) weeks had greater risk of both death (hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00-1.39) and recurrence (HR 1.33, 95% CI 1.10-1.62). Associations were not statistically significant when dichotomizing time to surgery at 2 or 12 weeks for death (2 week HR 1.23, 95% CI 0.93-1.64 12 week HR 1.35, 95% CI 0.97-1.88) and recurrence (2 week HR 1.54, 95% CI 0.85-2.80 12 week HR 2.28, 95% CI 0.80-6.46). Early stage lung cancer patients with time to surgery within 4 weeks experienced lower rates of recurrence. Optimal time to surgical resection may be shorter than previously reported.

CD16

Acute and chronic rejections limit the long-term survival after lung transplant. Pulmonary antibody-mediated rejection (AMR) is an incompletely understood driver of long-term outcomes characterized by donor-specific antibodies (DSAs), innate immune infiltration, and evidence of complement activation. Natural killer (NK) cells may recognize DSAs via the CD16 receptor, but this complement-independent mechanism of injury has not been explored in pulmonary AMR. CD16

Successful lung transplantation using an allograft from a COVID-19-recovered donor a potential role for subgenomic RNA to guide organ utilization.

Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well described when using pulmonary organs from COVID-19-recovered donors. We describe successful lung transplantation for a COVID-19-related lung injury using lungs from a COVID-19-recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection.

Productivity loss and productivity loss costs to United States employers due to priority conditions a systematic review.

To summarize published studies evaluating productivity loss and productivity loss costs associated with cancer, chronic lung disease, depression, pain, and cardiometabolic disease among US employees. A PubMed search from the past 10 years was conducted using the terms productivity, absenteeism, presenteeism, cancer, bronchitis, asthma, chronic obstructive pulmonary disease, depression, pain, heart disease, hypertension, and diabetes (limited to English-language publications and studies of adults aged 19-64). Study endpoints included annual incremental time (work hours lost and Work Productivity and Impairment WPAI questionnaire overall work impairment) and monetary estimates of productivity loss. Studies were critically appraised using a modified Oxford Centre for Evidence-Based Medicine (OCEBM) Quality Rating Scheme. Of 2,037 records identified from the search, 183 studies were included. The most common observed condition leading to productivity loss was pain (24%), followed by cancer (22%), chronic lung disease (17%), cardiometabolic disease (16%), and depression (16%). Nearly three-quarters of the studies ( Study heterogeneity. Despite some gaps in evidence for the cost of productivity loss, sufficient data highlight the substantial employer burden of lost productivity among priority conditions. Investment in workforce health and well-being is a practice pursued by high-performing companies as health improvement strategies have produced excellent returns on investment. This literature review sought to gain a better understanding of employee productivity loss for important diseases (i.e. cancer, chronic lung disease bronchitis, asthma, or chronic obstructive pulmonary disease, depression, pain, and cardiometabolic disease heart disease, hypertension, or diabetes to help employers and healthcare payers prioritize investment in workforce health. The findings highlight the substantial burden of lost productivity among these conditions. Most studies found employees lost up to 80 annual work hours and employees with cancer and cardiometabolic disease had the greatest annual incremental number of work hours lost. The proportion of work impairment ranged from 10% to 70% and was higher for employees with pain and depression. The annual cost of lost work productivity ranged from $100 to $10,000 and was higher among employees with cancer, pain, and depression.

Lamin AC phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress.

The heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin AC (LAC), encoded by LMNA gene, contributes towards altered gene expression during HS, but the underlying mechanisms are poorly understood. Here we show that upon HS, LAC is reversibly phosphorylated at Ser22 in concert with HSF1 activation in human cells, mouse cells and D. melanogaster in vivo. Consequently, the phosphorylation facilitated nucleoplasmic localization of LAC and nuclear sphericity in response to HS. Interestingly, LAC knock-out cells showed deformed nuclei after HS and were rescued by ectopic expression of wild-type LA, but not by a phosphomimetic (S22D) LA mutant. Furthermore, HS triggered concurrent downregulation of lamina-associated protein 2α (Lap2α) in wild-type LAC expressing cells but a similar response was perturbed in LAC knock-out cells and in LMNA mutant patient fibroblasts which showed impaired cell cycle arrest under HS and compromised survival at the recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of LAC provides an evolutionary conserved mechanism to regulate lamina structure and serve nuclear adaptation and cell survival during HS.

Eupafolin regulates non-small-cell lung cancer cell proliferation,migration, and invasion by suppressing MMP9 and RhoA via FAKPI3KAKT signaling pathway.

Non-small-cell lung cancer (NSCLC) predominates lung cancer with a striking percentage of 85%. Eupafolin is documented to possess anti-tumor efficacy, which prompts efforts to uncover its impacts on the pathology of diseases including cancers. Focal adhesion kinase (FAK)-mediated phosphatidylinositol 3-kinase (PI3K)protein kinase B (AKT) has been found to be associated with several carcinomas. Nevertheless, how eupafolin exerts its effects in NSCLC and whether FAKPI3KAKT is related to the corresponding mechanism remain unclear. Thus, the relevant experiments were carried out with NSCLC cells treated with eupafolin andor LY294002 at first. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, and transwell assays were used to assess cell viability, proliferation, migration, and invasion, respectively. Western blot assay was performed to measure the relative protein expressions of phosphorylated (p)-FAKFAK, p-PI3K PI3K, p-AKTAKT, matrix metalloproteinase 9 (MMP9), and

Increasing Cancer Rehabilitation Awareness and Referrals in the Veterans Health Administration - A Quality Improvement Initiative.

To expand access to comprehensive rehabilitation services among Veterans with cancer by increasing cancer rehabilitation referrals in a Veterans Affairs (VA) hospital. A rapid cycle improvement approach based on the Institute of Healthcare Improvements Model for Improvement was used to assess and optimize the cancer rehabilitation referral process. In this quality improvement project, our cancer rehabilitation workgroup developed an electronic screening tool within the VA electronic patient record system to streamline cancer rehabilitation referrals. Providers could complete an optional Cancer Rehabilitation (CaRe) Screen that consisted of 12 questions related to patient symptoms and function. If the screen was positive, a non-visit electronic consult was automatically generated and sent to a physiatrist for review. The physiatrist would then triage patients to appropriate services including physiatry, physical therapy, occupational therapy, speech therapy, rehab psychology, and other rehabilitation services. A total of 90 referrals were placed between 2019-2021. Eighty-four percent of the patients referred were male, 73% were white. The top cancer types referred were lung (22%), blood (21%), gastrointestinal (11%), and prostate (10%). There were 19 referrals in 2019, 13 in 2020, and 58 in 2021. The electronic screening tool was implemented in mid-2021. Advanced practice providers placed 48% of consults. Of the referrals placed in 2021, 13% of consults were initiated through the electronic screening tool. The most common rehabilitation related referrals placed after initial cancer rehablitation triage included physical therapy (n 47, 35.1%), physiatry (n 28, 20.9%), and occupational therapy (n 24, 17.9%). Implementing an electronic screening tool can streamline cancer rehabilitation referrals and increase access to cancer rehabilitation services for Veterans with cancer. Ongoing work is required to refine the referral process and educate providers and patients on the importance of cancer rehabilitation in the cancer care continuum. This article is protected by copyright. All rights reserved.

Navigating patient journey in early diagnosis of lung cancer in India.

Lung cancer (LC) is one of the leading causes of cancer deaths worldwide. In India, the incidence of LC is increasing rapidly, and a majority of the patients are diagnosed at advanced stages of the disease when treatment is less likely to be effective. Recent therapeutic developments have significantly improved survival outcomes in patients with LC. Prompt specialist referral remains critical for early diagnosis for improved patient survival. In the Indian scenario, distinguishing LC from benign and endemic medical conditions such as tuberculosis can pose a challenge. Hence, awareness regarding the red flags-signs and symptoms that warrant further investigations and referral-is vital. This review is an effort toward encouraging general physicians to maintain a high index of clinical suspicion for those at risk of developing LC and assisting them in refering patients with concerning symptoms to specialists or multidisciplinary teams as early as possible.

Lung cancer in Asian Indian females Identification of disease-specific characteristics and outcome measures over a 12-year period.

Globally, the incidence of lung cancer amongst women appears to be increasing. We aimed to compare the socio-epidemiological and clinical characteristics of lung cancer amongst men and women from a large cohort at a tertiary care hospital in Northern India. Records of patients diagnosed with lung cancer between January 2008 and March 2020 were reviewed. Baseline epidemiological data, clinical characteristics, histologic profiles, treatment administered, and survival were compared between males and females. A total of 2054 male and 438 female patients were included in analysis. Compared to males, female patients were younger median age, 56 vs. 60 years, P < 0.001), less likely to be working, less educated beyond secondary level and less likely to be smokers (29.1% vs. 84.9%, P < 0.0001). No difference in baseline performance status was observed. Females were more frequently diagnosed with adenocarcinoma (54.2% vs. 30.2%, P <0.0001), stage IV disease (70.8% vs. 63%, P 0.001), and had higher rate of EGFR mutation (37.2% vs. 21.5%, P < 0.0001). There was no difference in the proportion of females receiving cancer-specific therapy. Multivariate Cox proportional hazards model revealed higher progression-free survival median 9.17 vs. 7.23 months P 0.007 and overall survival median 13.80 vs. 9.10 months respectively, P 0.001 amongst females compared to males. Amongst a large cohort of lung cancer, females demonstrated several distinct and characteristic demographics as well as disease-related features, especially better survival outcomes.

Positron emission tomography - Computed tomography for staging of mediastinal lymph nodes in patients with non-small cell lung cancer.

The tumor involvement of lymph nodes (LN) in N2 station is a very important factor for the further therapy decision and the prognosis of lung cancer patients. Today, integrated positron emission tomography-computed tomography (PET-CT) is considered to be the new standard in the staging of bronchial carcinoma. The aim of this study is to investigate the correctness of the clinical staging of the mediastinal LNs in operated patients and to investigate the sensitivity and specificity of the PET-CT examination for mediastinal LNs. In the years 2010-2014, 359 patients underwent surgery for bronchial carcinoma. The histological examination of all mediastinal and hilar LNs was used as a reference to the data from the PET-CT examinations. The correctness of the PET staging, overestimation, and underestimation for the N stage was analyzed. In addition, the sensitivity, specificity, and overall accuracy of the PET-CT examination with regard to the N2 LNs were calculated. It was found that in 8.9% the staging of the mediastinal N2N3 LN stations was rated too high by the PET and in 11.2% too low. The study showed a sensitivity of 47.37%, a specificity of 90.07%, and an accuracy of 81.01% for the mediastinal LNs. Our study confirms the limited ability of integrated PET-CT in staging the mediastinal LNs. We, therefore, recommend a histological examination of the LNs in patients with PET-positive N2 LNs to avoid false-positive results and to initiate correct therapy.

FHL1 as a novel prognostic biomarker and correlation with immune infiltration levels in lung adenocarcinoma.

The advent of immunotherapy has considerably changed non-small-cell lung cancer (NSCLC) treatment, allowing a subset of patients to live longer and have a better prognosis. However, not all patients benefit from immunotherapy. Therefore it is urgently necessary to develop universal and effective biomarkers of NSCLC for diagnosis and prognostic evaluation to effectively diagnose the disease and increase the utility of immunotherapy. In this study, a protein called FHL1 was identified as a potential predictive biomarker according to NSCLC databases, and we further investigated the underlying relationship between FHL1 and immunotherapy. In conclusion, FHL1 is a promising biomarker for the diagnosis, prognosis and immune infiltration level of lung adenocarcinoma.

Poor response to sintilimab plus chemotherapy in a pulmonary epithelioid hemangioendothelioma patient a case report.

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. The authors report the case of a young woman diagnosed with PEH. DNA and RNA analysis by next-generation sequencing was performed on the tumor tissue. A novel germline Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. Although PD-1 inhibitors have dramatically improved the prognosis of some tumors, the efficacy is unknown in PEH patients. The authors report an advanced PEH patient treated with sintilimab plus platinum-based chemotherapy, who died after two cycles of treatment. The authors inferred that PEH patients with a germline

CircRNA hsacirc0070659 predicts poor prognosis and promotes non-small cell lung cancer (NSCLC) progression via microRNA-377 (miR-377) Ras-Associated Binding Protein 3C (RAB3C) pathway.

A large number of circular RNAs (circRNAs) are dysregulated in lung cancer and affect the progression and prognosis of lung disease. Herein, this study selected specific circular RNA (circ0070659) by bioinformatics analysis and aimed to investigate the role of circ0070659 in non-small cell lung cancer (NSCLC). The differentially expressed circRNA (hsacirc0070659) in NSCLC was screened from public databases (GEO), and real-time quantitative polymerase chain reaction (RT-qPCR) was carried out to identify the circ0070659 levels in cancer tissues and cells. NSCLC cell proliferation, migration, and invasion abilities after circ0070659 silencing was detected by colony formation assay, Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Targeted binding between microRNA-377 (miR-377) and circ0070659 or Ras-Associated Binding Protein 3C (RAB3C) was verified by western blot, dual-luciferase reporter assay, and RNA pull-down assay. Our experimental results showed that circ0070659 levels were largely increased in tumor tissues and cells. Biologically, knockdown of circ0070659 obviously inhibited proliferation, migration, and invasion of NSCLC cells. Mechanistically, circ0070659 promoted RAB3C-mediated proliferation and invasion through sponging miR-377. Furthermore, miR-377 inhibitor reversed the inhibitory ability of circ0070659 silencing on malignant biological behavior of NSCLC cells. Our study revealed a novel signaling pathway that circ0070659miR-377RAB3C axis regulates tumor progression, and it may become a new therapeutic target for NSCLC.

Complete heart block associated with paraneoplastic hypercalcemia a case report.

Complete heart block (CHB) means a lack of association between the atrium and the ventricle. Hypercalcemia is an electrolyte disorder that rarely causes CHB. Hereby, we report the case of a 59-year-old male who was admitted with general weakness. The electrocardiography (ECG) changes revealed CHB, short QT interval due to short ST segment, and generalized ST elevation. The initial calcium level was 15.8 mgdL (high), and serum levels of parathyroid hormone (PTH), vitamin D, and phosphorus were normal. A chest computed tomography scan showed a large, central mass with cavitation in the right lung. After an initial diagnosis of lung cancer and paraneoplastic hypercalcemia, the patient was treated with normal saline, calcitonin, and zoledronic acid, whose calcium levels decreased to 10.4 mgdL after 4 days. Pathological ECG findings were also resolved after the correction of serum levels of calcium. Hypercalcemia sometimes occurs as a paraneoplastic syndrome following the production of PTH-related peptide by malignant cells, including squamous cell carcinoma of the lung. Complete heart block associated with paraneoplastic syndrome has been reported so far in only one study.

circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARSmiR-1252-5pHDGF ceRNA pathway.

This study aims to explore the role and mechanism of circ-IARS in non-small-cell lung cancer (NSCLC) progression. Expression of circ-IARS, microRNA (miR)-1252-5p, and hepatoma-derived growth factor (HDGF) was measured by real-time quantitative PCR and western blotting. The interactions among circ-IARS, miR-1252-5p, and HDGF were determined by dual-luciferase reporter assay and RNA immunoprecipitation. Cell behaviors were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2-deoxyuridine (EdU) assay, flow cytometry, scratch wound assay, and transwell assay, and validated in

Preferential delivery of lipid-ligand conjugated DNARNA heteroduplex oligonucleotide to ischemic brain in hyperacute stage.

Antisense oligonucleotide (ASO) is a major tool used for silencing pathogenic genes. For stroke in the hyperacute stage, however, the ability of ASO to regulate genes is limited by its poor delivery to the ischemic brain owing to sudden occlusion of the supplying artery. Here we show that, in a mouse model of permanent ischemic stroke, lipid-ligand conjugated DNARNA heteroduplex oligonucleotide (lipid-HDO) was unexpectedly delivered 9.6 times more efficiently to the ischemic area of the brain than to the contralateral non-ischemic brain and achieved robust gene knockdown and change of stroke phenotype, despite a 90% decrease in cerebral blood flow in the 3 h after occlusion. This delivery to neurons was mediated via receptor-mediated transcytosis by lipoprotein receptors in brain endothelial cells, the expression of which was significantly upregulated after ischemia. This study provides proof-of-concept that lipid-HDO is a promising gene-silencing technology for stroke treatment in the hyperacute stage.

Long non-coding RNA LINC01270 is an onco-promotor in lung adenocarcinoma by upregulating LARP1 via sponging miR-326.

Accumulating evidence have proved the key role of long non-coding RNA in lung adenocarcinoma (LUAD) progression. Bioinformatics analysis is used to seek the differentially expressed lncRNA LINC01270 from TCGA database. The overexpression of LINC01270 was then verified in LUAD tumor tissues and cell lines by qRT-PCR. LINC01270 knockdown resulted in impaired cell proliferative and invasive ability via CCK-8 assay, EdU assay, colony formation assay, transwell assay, while aberrant upregulation of LINC01270 led to enhanced cell growth and invasion. Moreover, LINC01270 was found inhibiting miR-326 and thereby overexpressing the abundance of LARP1 to promote LUAD development via PI3KAKT pathway. It was also proved that LINC01270 knockdown could suppress LUAD tumor growth in vivo. All of these findings demonstrate thatLINC01270 is a tumor promotor in LUAD via enhancing LARP1 expressed by sponging miR-326 to facilitate the development of LUAD. LINC01270 play a significant role in LUAD, which could serve as biomarkers for early diagnosis and a novel targeted remedy.

NLR family CARD domain containing 5 promotes hypoxia-induced cancer progress and carboplatin resistance by activating PI3KAKT via carcinoembryonic antigen related cell adhesion molecule 1 in non-small cell lung cancer.

It is well known that non-small cell lung cancer (NSCLC) is a malignant tumor with high incidence in the world. We aimed to clarify a possible target and identify its precise molecular biological mechanism in NSCLC. NLR family CARD domain containing 5 (NLRC5) is widely expressed in tissues and exerts a vital role in anti-tumor immunity. We determined NLRC5 expression by RT-qPCR and western blot assay. The role of NLRC5 in the development of NSCLC was assessed by a loss-of-function assay. CCK-8, Annexin-V-FITCPI Apoptosis Detection Kit, Transwell, and wound healing assays were used to determine the cell functions. Drug resistance-related proteins were analyzed by western blot assay. Furthermore, the modulation of NLRC5 on carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression and subsequent PI3KAKT signaling was assessed. In this study, a hyper-expression of NLRC5 was found in NSCLC tissues and cell lines. Knockdown of NLRC5 suppressed cell viability, invasion, and migration, and furthermore promoted cell apoptosis in NSCLC cells. Moreover, under normoxia or hypoxia treatment, the upregulation of NLRC5 was related to carboplatin resistance. NLRC5 silencing increased carboplatin-resistant cell chemosensitivity, as evidenced by the increase in the cell inhibition rate and decrease in drug resistance-related protein expression. Mechanistically, NLRC5 knockdown inhibited the expression of CEACAM1 and subsequently blocked the PI3KAKT signaling pathway. In conclusion, NLRC5 promotes the malignant biological behaviors of NSCLC cells by activating the PI3KAKT signaling pathway via the regulation of CEACAM1 expression under normoxia and hypoxia.

Primary Alveolar Soft-Part Sarcoma (ASPS) of the Prostate Report of a Deceptive Case.

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor that primarily involves the extremities. We report a case of a 30-year-old never-smoker man who presented with hematuria, dysuria, and constipation at an outside hospital. He was diagnosed with and treated for multiple episodes of urinary tract infection. However, he continued to have voiding symptoms for which a cystoscopy was performed and revealed a bladder neck mass. He underwent transurethral resection of a bladder tumor and was diagnosed with muscle-invasive urothelial carcinoma, nested variant, at an outside hospital. Subsequent to this diagnosis he transferred his care to our center. In-house imaging revealed a large vascular mass involving the prostate and pushing against the bladder base. Prostate needle biopsies were performed and revealed an epithelioid neoplasm with a nested growth pattern composed of cells with a moderate amount of eosinophilic cytoplasm, mildly pleomorphic nuclei, and occasional prominent nucleoli. Since the findings were not classic for urothelial carcinoma or for prostate cancer, we included a wider differential of poorly differentiated carcinoma, sarcoma, and paraganglioma. A wide panel of keratin stains was negative, ETS (erythroblast transformation-specific)-related gene highlighted an extensive vascular network and neuroendocrine stains were all negative. A transcription factor E3 fluorescent in-situ hybridization was positive and subsequently, an

Research on Segmentation Technology in Lung Cancer Radiotherapy Based on Deep Learning.

Lung cancer has the highest mortality rate among cancers. Radiation therapy (RT) is one of the most effective therapies for lung cancer. The correct segmentation of lung tumors (LTs) and organs at risk (OARs) is the cornerstone of successful RT. we searched four databases for relevant material published in the last 10 years Web of Science, PubMed, Science Direct, and Google Scholar. The advancement of deep learning-based segmentation technology for lung cancer radiotherapy (DSLC) research was examined from the perspectives of LTs and OARs. In this paper, Most of the dice similarity coefficient (DSC) values of LT segmentation in the surveyed literature were above 0.7, whereas the DSC indicators of OAR segmentation were all over 0.8. The contribution of this review is to summarize DSLC research methods and the issues that DSLC faces are discussed, as well as possible viable solutions. The purpose of this review is to encourage collaboration among experts in lung cancer radiotherapy and DL and to promote more research into the use of DL in lung cancer radiotherapy.

Impact of vitamin D on the occurrence and development of intestinal diseases a systematic review and meta-analysis of randomized controlled trials.

To determine the impact of vitamin D on the occurrence and progression of intestinal disorders, the authors of this study have conducted a systematic review and meta-analysis. Vitamin D regulates inflammation and immunity in association with reducing the disease symptoms of several gastrointestinal diseases, including inflammatory bowel diseases (IBD), Crohns disease (CD), ulcerative colitis (UC), and colorectal cancer (CRC). However, the exact role of vitamin D in the occurrence and development of intestinal diseases is unclear so far. The relevant studies were searched in PubMed and screened based on inclusion and exclusion criteria. The quality of full-text studies was assessed using National Heart, Lung, and Blood Institute (NIH) scale. The study was conducted as per the PRISMA guidelines. The overall estimate was calculated in terms of risk ratio with a 95% confidence interval. The publication bias was assessed qualitatively using a funnel plot, and heterogeneity among studies was calculated using I2 statistics. All analyses were done using RevMan 5.0. The overall risk ratio using random effect model was found to be 0.89 0.70, 1.12, which indicates the non-significant role of vitamin D in the occurrence and development of intestinal diseases as compared to the non-vitamin D group. However, after exclusion of studies with low and high sample sizes, a significant reduction in intestinal diseases was observed in the vitamin D group as compared to the non-vitamin D group. Further, no heterogeneity among the studies was observed. Based on available evidence, vitamin D might play a significant role in the reduction of intestinal diseases however, more studies with high sample sizes are required to draw a valid conclusion.

PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapyimmunotherapy combination in mouse models of lung cancer.

Cumulative preclinical and clinical evidences showed radiotherapy might augment systemic antitumoral responses to immunotherapy for metastatic non-small cell lung cancer, but the optimal timing of combination is still unclear. The overall infiltration and exhausted subpopulations of tumor-infiltrating CD8 Basing on tumor-bearing mice model, we investigated the dynamics of overall infiltration and exhausted subpopulations of CD8 CD8 We proposed a non-invasive imaging predictor which accurately assessed heterogeneous T cell exhaustion status relevant to ICI treatment and irradiation, and might serve as a promising solution to timely estimate immune-responsiveness of tumor microenvironment and the optimal timing of combined therapy.

Activation of NLRP3 inflammasome in lung epithelial cells triggers radiation-induced lung injury.

Radiation-induced lung injury (RILI) is the most common and serious complication of chest radiotherapy. However, reported radioprotective agents usually lead to radiation resistance in tumor cells. The key to solving this problem is to distinguish between the response of tumor cells and normal lung epithelial cells to radiation damage. RNA-Seq was used to recognize potential target of alleviating the progression of RILI as well as inhibiting tumor growth. The activation of NLRP3 inflammasome in lung epithelial cells was screened by qRT-PCR, western blotting, immunofluorescence, and ELISA. An in vivo model of RILI and in vitro conditioned culture model were constructed to evaluate the effect of NLRP3interleukin-1β on fibroblasts activation. ROS, ATP, and (NADP) NLRP3 activation in epithelial cells after radiation depends on glycolysis-related reactive oxygen species accumulation. DPYSL4 is activated and acts as a negative regulator of this process. The NLRP3 inflammasome triggers interleukin-1β secretion, which directly affects fibroblast activation, proliferation, and migration, eventually leading to lung fibrosis. Our study suggests that NLRP3 inflammasome activation in lung epithelial cells is essential for radiation-induced lung injury. These data strongly indicate that targeting NLRP3 may be effective in reducing radiation-induced lung injury in clinical settings.

Individual frailty excess hazard models in cancer epidemiology.

Unobserved individual heterogeneity is a common challenge in population cancer survival studies. This heterogeneity is usually associated with the combination of model misspecification and the failure to record truly relevant variables. We investigate the effects of unobserved individual heterogeneity in the context of excess hazard models, one of the main tools in cancer epidemiology. We propose an individual excess hazard frailty model to account for individual heterogeneity. This represents an extension of frailty modeling to the relative survival framework. In order to facilitate the inference on the parameters of the proposed model, we select frailty distributions which produce closed-form expressions of the marginal hazard and survival functions. The resulting model allows for an intuitive interpretation, in which the frailties induce a selection of the healthier individuals among survivors. We model the excess hazard using a flexible parametric model with a general hazard structure which facilitates the inclusion of time-dependent effects. We illustrate the performance of the proposed methodology through a simulation study. We present a real-data example using data from lung cancer patients diagnosed in England, and discuss the impact of not accounting for unobserved heterogeneity on the estimation of net survival. The methodology is implemented in the R package IFNS.

Clinical significance of MYC family protein expression in surgically resected high-grade neuroendocrine carcinoma of the lung.

MYC family genes including MYC, MYCN, and MYCL are amplified and overexpressed as oncogenic drivers in high-grade neuroendocrine carcinoma of the lung (HGNEC), but little is known about their clinical significance. This study evaluated the prognostic impact of MYC family protein expression in patients with surgically resected HGNEC. Immunohistochemical analyses were performed on 83 resected specimens of HGNEC using antibodies against MYC family proteins (c-MYC, n-MYC, and l-MYC). When nuclear staining of any intensity in ≥10% of tumor cells showed immunoreactivity with any one or more of c-MYC, n-MYC, or l-MYC, the specimens were defined as MYC family-positive. A total of 83 patients were analyzed. MYC family-positive status was observed in 33.7% (28 of 83 cases) and was not correlated with clinicopathological factors. The protein expression was mutually exclusive and no duplicate cases were observed. A log-rank test showed that MYC family-positive status was significantly associated with shorter overall survival (OS) (p 0.003) and recurrence-free survival (RFS) (p 0.039). According to Cox multivariate analysis, MYC family-positive status had a significant effect on shorter OS (hazard ratio HR 2.217, 95% confidence interval CI 1.179-4.169, p 0.014) and RFS (HR 1.802, 95% CI 1.014-3.202, p 0.045). In patients with pathological stage I, MYC family-positive status also showed significantly poor OS (HR 2.847, 95% CI 1.236-6.557, p 0.014) and RFS (HR 2.088, 95% CI 1.006-4.332, p 0.048) in the multivariate analysis. MYC family protein expression could be an independent unfavorable prognostic factor in patients with surgically resected HGNEC.

Specific organ metastases and prognosis in lung adenocarcinoma.

This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis-associated factors. Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, raceethnicity, marital status, insurance, location, TNM stage, organ-specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65-2.01, p < 0.01). Patients received surgery of lobectomy or extended (251 of 571, 43.96%) displayed the longest average survival (35.16 months) patients (294 of 571, 51.49%) received sub-lobar resection, had the average survival (19.90 months) patients received local tumor destruction (26 of 571, 4.55%) had the shortest average survival (13.73 months). This study provides insights into the specific organ metastatic rates and prognosis in LUAD patients on a population level. These findings suggest that surgery resection should be taken into consideration in the treatment for these LUAD patients.

Dual color pH probes made from silica and polystyrene nanoparticles and their performance in cell studies.

Ratiometric green-red fluorescent nanosensors for fluorometrically monitoring pH in the acidic range were designed from 80 nm-sized polystyrene (PS) and silica (SiO

High Yield of Pleural Cell-Free DNA for Diagnosis of Oncogenic Mutations in Lung Adenocarcinoma.

Pleural cytology is currently used to assess targetable mutations in patients with advanced lung adenocarcinoma. However, it is fraught with low diagnostic yield. Can pleural cell-free DNA (cfDNA) be used to assess targetable mutations in lung adenocarcinoma patients with malignant pleural effusions (MPE) Patients with lung adenocarcinoma MPE were recruited prospectively between January 2017 and September 2021. Oncogenic mutations were assessed by treating providers using pleural fluid cytology or lung cancer biopsies. Pleural and plasma cfDNA were used to assess the mutations using next-generation sequencing (NGS). Fifty-four pleural fluid samples were collected from 42 patients. The diagnostic yield to detect oncogenic mutations for pleural cfDNA, pleural cytology, biopsy and plasma cfDNA was 4954 (90.7%), 1633 (48.5%), 2225 (88%), and 2432 (75%), respectively, P < .001. The agreement of mutations in positive samples between pleural cfDNA and pleural cytology was 100%, whereas the agreement of pleural cfDNA with biopsies was 89.4%. The median concentration (Q1-Q3) of pleural cfDNA was higher than plasma 28,444 (4,957-67,051) vs 2,966.5 (2,167-5,025) copies of amplifiable DNA per mL, P < .01. Median of 5 mL (interquartile range, Q1-Q3, 4.5-5) of pleural fluid supernatant was adequate for cfDNA testing. The diagnostic yield of pleural cfDNA NGS for oncogenic mutations in lung adenocarcinoma patients is comparable to tumor biopsies and higher than pleural cytology and plasma cfDNA. The pleural cfDNA can be longitudinally collected, can be readily incorporated in clinical workflow, and may decrease the need for additional biopsies.

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9CXCL10CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67 We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen.

GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations from Morphologic Mimics.

Glioma-associated oncogene 1 (GLI1) alterations have been described in pericytoma with t(712), gastroblastoma, plexiform fibromyxoma, and an emerging class of GLI1-rearranged or amplified mesenchymal neoplasms including nested glomoid neoplasm. The immunophenotype of these tumor types is nonspecific, making some cases difficult to diagnose without sequencing. The utility of GLI1 immunohistochemistry (IHC) in distinguishing nested glomoid neoplasms and pericytomas with t(712) from morphologic mimics is unknown. To investigate the diagnostic value of GLI1 IHC, we determined its sensitivity and specificity in a test cohort of 23 mesenchymal neoplasms characterized by GLI1 alterations, including 12 nested glomoid neoplasms (7 GLI1-rearranged, 4 GLI1 amplified, and 1 unknown GLI1 status), 9 pericytomas with t(712), 1 gastroblastoma, and 1 malignant epithelioid neoplasm with PTCH1GLI1 fusion. GLI1 IHC was 91.3% sensitive in this cohort all tumors except 2 pericytomas with t(712) expressed GLI1. GLI1 was also expressed in 1 of 8 (12%) plexiform fibromyxomas. Nineteen of 22 GLI1-positive tumors showed nuclear and cytoplasmic staining, while 3 showed nuclear staining only. GLI1 IHC was 98.0% specific among morphologic mimics 40 well-differentiated neuroendocrine tumors, 10 atypical lung carcinoids, 20 paragangliomas, 20 glomus tumors, 20 solitary fibrous tumors, 10 Ewing sarcomas, 10 alveolar rhabdomyosarcomas (ARMS), 10 BCOR-altered sarcomas, 10 myoepitheliomas, 9 myopericytomas, 9 epithelioid schwannomas, 9 ossifying fibromyxoid tumors, 10 biphasic synovial sarcomas, 10 PEComas, 31 gastrointestinal stromal tumors, 10 inflammatory fibroid polyps, 11 pseudoendocrine sarcomas, 5 of 249 tumors expressed GLI1 (2 well-differentiated neuroendocrine tumors, 1 ARMS, 1 Ewing sarcoma, 1 BCOR-altered sarcoma). GLI1 IHC was also performed on a separate cohort of 13 molecularly characterized mesenchymal neoplasms in which GLI1 copy number gain was identified as a putatively secondary event by DNA sequencing (5 dedifferentiated liposarcoma DDLPS, 2 adenosarcomas, 2 unclassified uterine sarcomas, 1 leiomyosarcoma, 1 ARMS, 1 intimal sarcoma, 1 osteosarcoma) 2 DDLPS, 1 ARMS, and 1 unclassified uterine sarcoma expressed GLI1. Lastly, because pleomorphic sarcomas sometimes show GLI1 amplification or copy number gain, GLI1 IHC was performed on a separate pleomorphic sarcoma cohort GLI1 was expressed in 1 of 27 DDLPS, 1 of 9 leiomyosarcomas, and 2 of 10 pleomorphic liposarcomas, and it was negative in 23 well-differentiated liposarcomas and 9 unclassified pleomorphic sarcomas. Overall, GLI1 IHC was 91.3% sensitive and 98.0% specific for mesenchymal tumor types with driver GLI1 alterations among morphologic mimics. GLI1 expression was less frequent in other tumor types with GLI1 copy number gain. Given its specificity, in the appropriate morphologic context, GLI1 IHC may be a useful diagnostic adjunct for mesenchymal neoplasms with GLI1 alterations.

Late Health Outcomes Among Survivors of Wilms Tumor Diagnosed Over Three Decades A Report From the Childhood Cancer Survivor Study.

To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens. Cumulative incidence of late mortality (≥ 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA doxorubicin abdominal radiotherapy (VAD ART), VAD ART whole lung radiotherapy, or receipt of ≥ 4 chemotherapy agents. Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5 rate ratio RR compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity. With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortalitymorbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.

Impact of delineation errors on the estimated organ at risk dose and of dose errors on the normal tissue complication probability model.

Normal tissue complication probability (NTCP) models are often based on doses retrieved from delineated volumes. For retrospective dose-response studies focusing on organs that have not been delineated historically, automatic segmentation might be considered. However, automatic segmentation risks generating considerable delineation errors and knowledge regarding how these errors impact the estimated organ dose is important. Furthermore, organ-at-risk (OAR) dose uncertainties cannot be eliminated and might affect the resulting NTCP model. Therefore, it is also of interest to study how OAR dose errors impact the NTCP modeling results. To investigate how random delineation errors of the proximal bronchial tree, heart, and esophagus impact the estimated OAR dose, and to investigate how random errors in the doses used for dose-response modeling affect the estimated NTCPs. We investigated the impact of random delineation errors on the estimated OAR dose using the treatment plans of 39 patients treated with conventionally fractionated radiation therapy of non-small-cell lung cancer. Study-specific reference structures were defined by manually contouring the proximal bronchial tree, heart and esophagus. For each patient and organ, 120 reshaped structures were created by introducing random shifts and margins to the entire reference structure. The mean and near-maximum dose to the reference and reshaped structures were compared. In a separate investigation, the impact of random dose errors on the NTCP model was studied performing dose-response modeling with study sets containing treatment outcomes and OAR doses with and without introduced errors. Universal patient populations with defined population risks, dose-response relationships and distributions of OAR doses were used as ground truth. From such a universal population, we randomly sampled data sets consisting of OAR dose and treatment outcome into reference populations. Study sets of different sizes were created by repeatedly introducing errors to the OAR doses of each reference population. The NTCP models generated with dose errors were compared to the reference NTCP model of the corresponding reference population. A total of 14 040 reshaped structures with random delineation errors were created. The delineation errors resulted in systematic mean dose errors of less than 1% of the prescribed dose (PD). Mean dose differences above 15% of PD and near-maximum doses differences above 25% of PD were observed for 211 and 457 reshaped structures, respectively. Introducing random errors to OAR doses used for dose-response modeling resulted in systematic underestimations of the median NTCP. For all investigated scenarios, the median differences in NTCP were within 0.1 percentage points (p.p.) when comparing different study sizes. Introducing random delineation errors to the proximal bronchial tree, heart and esophagus resulted in mean dose and near-maximum dose differences above 15% and 25% of PD, respectively. We did not observe an association between the dose level and the magnitude of the dose errors. For the scenarios investigated in this study, introducing random errors to OAR doses used for dose-response modeling resulted in systematic underestimations of the median NTCP for reference risks higher than the universal population risk. The median NTCP underestimation was similar for different study sizes, all within 0.1 p.p.

Antibody-exatecan conjugates with a novel self-immolative moiety overcome resistance in colon and lung cancer.

Antibody-drug conjugates (ADCs) using DNA Topoisomerase I inhibitor DXdSN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent Topoisomerase I inhibitor with less sensitivity to multidrug (MDR) resistance. Characterized by enhanced therapeutic indices, higher stability and improved intra-tumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, TROP2 overcome intrinsic or treatment-resistance of equivalent DXdSN-38 ADCs in low-target expression, large-size and MDR tumors. T moiety-exatecan ADCs display durable antitumor activity in PDX and organoid models representative of unmet clinical needs including EGFR-del19T790MC797S triple mutation lung cancer and BRAFKRAS-TP53 double-mutant colon cancer, and show synergy with PARPATR inhibitor and anti-PD-1 treatment. High tolerability of T moiety-exatecan ADC class in non-human primate supports its potential to expand responding patient population and tumor types beyond current ADCs.

Robustness of VMAT to setup errors in postmastectomy radiotherapy of left-sided breast cancer Impact of bolus thickness.

Volumetric modulated arc therapy (VMAT) with varied bolus thicknesses has been employed in postmastectomy radiotherapy (PMRT) of breast cancer to improve superficial target coverage. However, impact of bolus thickness on plan robustness remains unclear. The study enrolled ten patients with left-sided breast cancer who received radiotherapy using VMAT with 5 mm and 10 mm bolus (VMAT-5B and VMAT-10B). Inter-fractional setup errors were simulated by introducing a 3 mm shift to isocenter of the original plans in the anterior-posterior, left-right, and inferior-superior directions. The plans (perturbed plans) were recalculated without changing other parameters. Dose volume histograms (DVH) were collected for plan evaluation. Absolute dose differences in DVH endpoints for the clinical target volume (CTV), heart, and left lung between the perturbed plans and the original ones were used for robustness analysis. VMAT-10B showed better target coverage, while VMAT-5B was superior in organs-at-risk (OARs) sparing. As expected, small setup errors of 3 mm could induce dose fluctuations in CTV and OARs. The differences in CTV were small in VMAT-5B, with a maximum difference of -1.05 Gy for the posterior shifts. For VMAT-10B, isocenter shifts in the posterior and right directions significantly decreased CTV coverage. The differences were -1.69 Gy, -1.48 Gy and -1.99 Gy, -1.69 Gy for ΔD95% and ΔD98%, respectively. Regarding the OARs, only isocenter shifts in the posterior, right, and inferior directions increased dose to the left lung and the heart. Differences in VMAT-10B were milder than those in VMAT-5B. Specifically, mean heart dose were increased by 0.42 Gy (range 0.10 0.95 Gy) and 0.20 Gy (range -0.11 0.72 Gy), and mean dose for the left lung were increased by 1.02 Gy (range 0.79 1.18 Gy) and 0.68 Gy (range 0.47 0.84 Gy) in VMAT-5B and VMAT-10B, respectively. High-dose volumes in the organs were increased by approximate 0 2 and 1 3 percentage points, respectively. Nevertheless, most of the dosimetric parameters in the perturbed plans were still clinically acceptable. VMAT-5B appears to be more robust to 3 mm setup errors than VMAT-10B. VMAT-5B also resulted in better OARs sparing with acceptable target coverage and dose homogeneity. Therefore 5 mm bolus is recommended for PMRT of left-sided breast cancer using VMAT.

Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells.

1-Nitropyrene (1-NP) is a constituent of diesel exhaust and classified as a group 2A probable human carcinogen. The metabolic activation of 1-NP by nitroreduction generates electrophiles that can covalently bind DNA to form mutations to contribute to cancer causation. NADPH-dependent P450 oxidoreductase (POR), xanthine oxidase (XO), aldehyde oxidase (AOX), and NAD(P)Hquinone oxidoreductase 1 (NQO1) may catalyze 1-NP nitroreduction. We recently found that human recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze 1-NP nitroreduction.

Mix-and-Detection Assay with Multiple Cyclic Enzymatic Repairing Amplification for Rapid and Ultrasensitive Detection of Long Noncoding RNAs in Breast Tissues.

Long noncoding RNAs (lncRNAs) are valuable biomarkers and therapeutic targets, and they play essential roles in various pathological and biological processes. So far, the reported lncRNA assays usually suffer from unsatisfactory sensitivity and time-consuming procedures. Herein, we develop a mix-and-read assay based on multiple cyclic enzymatic repairing amplification (ERA) for sensitive and rapid detection of mammalian metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1). In this assay, we design two three-way junction (3WJ) probes including a 3WJ template and a 3WJ primer to specifically recognize lncRNA MALAT1, and the formation of a stable 3WJ structure induces cyclic ERA to generate triggers. The resulting triggers subsequently hybridize with a free 3WJ template and act as primers to initiate new rounds of cyclic ERA, generating abundant triggers. The hybridization of triggers with signal probes forms stable double-stranded DNA duplexes that can be specifically cleaved by apurinicapyrimidinic endonuclease 1 to produce a high fluorescence signal. This assay can be carried out in a mix-and-read manner within 10 min under an isothermal condition (50 °C), which is the rapidest and simplest method reported so far for the lncRNA MALAT1 assay. This method can sensitively detect lncRNA MALAT1 with a limit of detection of 0.87 aM, and it can accurately measure endogenous lncRNA MALAT1 at the single-cell level. Moreover, this method can distinguish lncRNA MALAT1 expression in breast cancer patient tissues and their corresponding healthy adjacent tissues. Importantly, the extension of this assay to different RNAs detection can be achieved by simply replacing the corresponding target recognition sequences.

Cardiotoxicity of Anti-Cancer Radiation Therapy a Focus on Heart Failure.

As the percentage of patients achieving long-term survival following treatment of their cancer grows, it is increasingly important to understand the long-term toxicities of cancer-directed treatment. In this review, we highlight the recent findings regarding radiation-induced cardiotoxicity across multiple disease sites, with a particular focus on heart failure. Despite its relative lack of study historically, radiation-induced heart failure has now recently been implicated in several studies of breast cancer, lung cancer, esophageal cancer, and lymphoma as a non-trivial potential consequence of thoracic radiotherapy. Data regarding specific cardiac dosimetric endpoints relevant to cardiotoxicity continue to accumulate. Radiation-induced heart failure is a rare but significant toxicity of thoracic radiotherapy, that is likely underreported. Important areas for future focus include understanding the interplay between thoracic radiotherapy and concurrent cardiotoxic systemic therapy as well as development of potential mitigation strategies and novel therapeutics.

Predictors and impact of survivorship care plans and survivorship care visits.

We performed this study to characterize the population at the Lifespan Cancer Institute (LCI) who received a survivorship care plan (SCP) with or without a survivorship care visit (SCV) to determine both the impact on specialty referrals and the demographic and clinical predictors of SCPs and SCVs. We retrospectively reviewed EMR records on 1960 patients at LCI between 2014 and 2017 for SCPs and SCVs and extracted demographics, distress thermometer (DT) scores collected at the time of initial presentation, and subsequent referrals. We evaluated the bivariate associations of SCP and SCV with continuous and categorical factors and assessed the adjusted effect of these factors on receipt of SCP and SCV independently. All analyses were performed in R v4.0.2. SCPs were completed in 740 (37.8%) patients, and of those, 65.9% had a SCV. The mean age was 63.9, 67% were female, and 51.2% were married or partnered. Patients treated for breast, lung, and prostate cancers most received an SCP. Compared to SCP alone, the SCV was associated with more specialty referrals. Those who were younger and had breast cancer were more likely to receive a SCP, and those who were younger and female and had breast cancer were more likely to receive a SCV. Gender, age, and type of cancer are significant predictors of receipt of SCP and SCV. Patients who received either SCP, SCV, or both were more likely to receive specialty referrals than those who received neither. Identifying predictive factors of SCP and SCV can help facilitate earlier receipt of specialty services and specialty referrals as needed.

Metabolic heterogeneity in early-stage lung adenocarcinoma revealed by RNA-seq and scRNA-seq.

Cancer cells maintain cell growth, division, and survival through altered energy metabolism. However, research on metabolic reprogramming in lung adenocarcinoma (LUAD) is limited METHODS We downloaded TCGA and GEO sequencing data. Consistent clustering with the ConsensusClusterPlus package was employed to detect the scores for four metabolism-related pathways. The LUAD samples in the TCGA dataset were clustered with ConsensusClusterPlus, and the optimal number of clusters was determined according to the cumulative distribution function (CDF). The cell score for each sample in the TCGA dataset was calculated using the MCPcounter estimate function of the MCPcounter package. We identified two subtypes by scoring the samples based on the 4 metabolism-related pathways and cluster dimensionality reduction. The prognosis of cluster B was obviously poorer than that of cluster A in patients with LUAD. The analysis of single-nucleotide variation (SNV) data showed that the top 15 genes in the four metabolic pathways with the most mutations were TKTL2, PGK2, HK3, EHHADH, GLUD2, PKLR, TKTL1, HADHB, CPT1C, HK1, HK2, PFKL, SLC2A3, PFKFB1, and CPT1A. The IFNγ score of cluster B was significantly higher than that of cluster A. The immune T-cell lytic activity score of cluster B was significantly higher than that of cluster A. We further identified 5 immune cell subsets from single-cell sequencing data. The top 5 marker genes of B cells were IGHM, JCHAIN, IGLC3, IGHA1, and IGKC. The C0 subgroup of monocytes had a higher pentose phosphate pathway (PPP) score than the C6 subgroup. Metabolism-related subtypes could be potential biomarkers in the prognosis prediction and treatment of LUAD.

Tetrandrine Inhibits Cancer Stem Cell Characteristics and Epithelial to Mesenchymal Transition in Triple-Negative Breast Cancer via SOD1ROS Signaling Pathway.

Targeting the stemness of triple-negative breast cancer (TNBC) is a potential therapeutic approach for treating TNBC. Tetrandrine, a natural plant alkaloid, has several anticancer effects. Here, we aimed to evaluate the efficacy of tetrandrine in cancer stemness and epithelial to mesenchymal transition (EMT) in TNBC, and to explore the underlying mechanisms. The effects of tetrandrine on cell growth, cell viability, cell stemness capacity, cell migration, and cell invasion, as well as the molecules involved in these processes, were investigated in a cell culture system. An

Association of polypharmacy and potential drug-drug interactions with adverse treatment outcomes in older adults with advanced cancer.

Polypharmacy is common in older adults who are starting cancer treatment and is associated with an increased risk of potentially inappropriate medications (PIMs) and potential drug-drug interactions (PDIs). The authors evaluated the association of medication measures with adverse outcomes in older adults with advanced cancer who were receiving systemic therapy. This secondary analysis from GAP 70 Trial (ClinicalTrials.gov identifier NCT02054741 principal investigator, Supriya G. Mohile) enrolled patients aged 70 years and older with advanced cancer who planned to start a new treatment regimen (n 718). Polypharmacy was assessed before the initiation of treatment and was defined as the concurrent use of eight or more medications. PIMs were categorized using 2019 Beers Criteria and the Screening Tool of Older Persons Prescriptions. PDIs were evaluated using Lexi-Interact Online. Study outcomes were assessed within 3 months of treatment and included (1) the number of grade ≥2 and ≥3 toxicities according to the National Cancer Institute Common Toxicity Criteria, (2) treatment-related unplanned hospitalization, and (3) early treatment discontinuation. Multivariable regression models examined the association of medication measures with outcomes. The mean patient age was 77 years, and 57% had lung or gastrointestinal cancers. The median number of medications was five (range, 0-24 medications), 28% of patients received eight or more medications, 67% received one or more PIM, and 25% had one or more major PDI. The mean number of grade ≥2 toxicities in patients with polypharmacy was 9.8 versus 7.7 in those without polypharmacy (adjusted β 1.87 standard error, 0.71 p <.01). The mean number of grade ≥3 toxicities in patients with polypharmacy was 2.9 versus 2.2 in patients without polypharmacy (adjusted β 0.59 standard error, 0.29 p .04). Patients with who had one or more major PDI had 59% higher odds of early treatment discontinuation (odds ratio, 1.59 95% confidence interval, 1.03-2.46 p .03). In a cohort of older adults with advanced cancer, polypharmacy and PDIs were associated with an increased risk of adverse treatment outcomes. Providing meaningful screening and interventional tools to optimize medication use may improve treatment-related outcomes in these patients.

The

Voltage-gated K

Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications. A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells. A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated. In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.

Background There have been conflicting results regarding fluorine 18-labeled fluorodeoxyglucose (

Segmentectomy preserves better immune-nutritional status than lobectomy in patients with early-stage lung cancer.

This study aimed to compare the postoperative immune-nutritional status of patients undergoing segmentectomy and lobectomy for early-stage non-small cell lung cancer. Patients with clinical stage 0-IA non-small cell lung cancer who underwent lobectomy or segmentectomy were retrospectively analysed. Postoperative immune-nutritional indices (prognostic nutritional index, serum albumin levels, and total lymphocyte count) at 1, 6 months, 1, 2 and 3 years after surgery were compared using mixed effects linear models and mixed effects logistic regression models. There were 164 and 210 patients in the lobectomy and segmentectomy groups, respectively. Postoperative prognostic nutritional index and albumin levels were significantly higher in the segmentectomy group than those in the lobectomy group (P < 0.001 and P < 0.001, respectively), despite of the nonsignificant difference in the total lymphocyte count (P 0.563). In 130 propensity-score matched pairs adjusted for confounding variables affecting postoperative nutritional status, postoperative prognostic nutritional index PNI and albumin levels were significantly higher in the segmentectomy group than in the lobectomy group (P 0.009 and P 0.007, respectively). At each time point after surgery, these indices were higher in the segmentectomy group than the lobectomy group at 1 month, 2 years and 3 years postoperatively. There were significantly more patients with lower immune-nutritional indices (prognostic nutritional index <45, albumin <4.0 gdL) in the lobectomy group than segmentectomy group at 3 years postoperatively (P 0.026 and P 0.029, respectively), despite nonsignificant statistical differences throughout the study period (P 0.219 and P 0.113, respectively). Patients who underwent segmentectomy showed better postoperative immune-nutritional status than those who underwent lobectomy.

The Antiangiogenic and Antitumor Effects of Scoparasin B in Non-Small-Cell Lung Cancer.

Angiogenesis and vasculogenic mimicry (VM) are crucial for the growth and metastasis of non-small-cell lung cancer (NSCLC). Most tumor angiogenesis inhibitors mainly target endothelial cell-mediated angiogenesis, ignoring tumor-cell-mediated VM and frequently leading to tumor recurrence and metastasis. Thus, development of bioactive molecules interfering with both tumor angiogenesis and VM is necessary. Identifying novel angiogenesis inhibitors from natural products is a promising strategy. Scoparasin B, a pimarane diterpene extracted from a marine-derived fungus,

Assessing Impact of Nutrition Care by Registered Dietitian Nutritionists on Patient Medical and Treatment Outcomes in Outpatient Cancer Clinics A Cohort Feasibility Study.

More information is needed about the impact of outpatient nutrition care from a registered dietitian nutritionist (RDN) on patient outcomes. This study aimed to assess the feasibility of a cohort study design to evaluate impact of RDN nutrition care on patient outcomes, describe clinic malnutrition screening practices, and estimate statistical parameters for a larger study. Seventy-seven patients with lung, esophageal, colon, rectal, or pancreatic cancer from six facilities were included (41 received RDN care and 36 did not). RDN nutrition care was prospectively documented for six months and documented emergency room visits, unplanned hospitalizations and treatment changes were retrospectively abstracted from medical records. Most facilities used the Malnutrition Screening Tool (MST) to determine malnutrition risk. Patients receiving RDN care had, on average, five, half hour visits and had more severe disease and higher initial malnutrition risk, although this varied across sites. Documented medical and treatment outcomes were relatively rare and similar between groups. Estimated sample size requirements varied from 113 to 5856, depending on tumor type and outcome, and intracluster correlation coefficients (ICCs) ranged from 0 to 0.47. Overall, the methods used in this study are feasible but an interventional or implementation design might be advantageous for a larger study.

The efficacy of trastuzumab-deruxtecan for the treatment of patients with advanced pretreated HER2-low breast cancer.

Targeting low levels of human receptor epidermal growth factor 2 (HER2) expression has reshaped the treatment paradigm for approximately half of patients with advanced breast cancer. HER2-low is currently defined as a HER2 immunohistochemical expression of 1 or 2 without amplification by in-situ hybridization. Until recently, HER2-targeted agents were ineffective in treating patients with HER2-low disease. In this narrative review, we summarize the current management of HER2-low breast cancer. We highlight the findings of the DESTINY-Breast 04 phase 3 trial, which confirmed the efficacy of trastuzumab-deruxtecan (T-DXd) for the treatment of patients with advanced, pretreated HER2-low breast cancer. We also discuss how to implement this new treatment option in treatment algorithms of hormone receptor (HR)-positive and triple-negative tumors, as well as how to optimally manage selected toxicities of T-DXd. T-DXd currently represents the standard of care treatment for patients with advanced, pretreated, HER2-low breast cancer. Based on the design of the DESTINY-Breast04 trial, the current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer. Up to 10-15% of patients receiving T-DXd are expected to develop interstitial lung disease, which in 1-2% of the cases can be fatal. Adequate monitoring and prompt management are required to minimize the impact of ILD and to safely implement T-DXd in clinical practice.

Compound K A systematic review of its anticancer properties and probable mechanisms.

Panax ginseng is a common natural product, which is well-known to have a wide range of pharmacological activities in cancer. Its metabolite, compound K (CK), has been reported to have anticancer activity. We aimed to systematically review the literature for evidence of anticancer effects of CK. We conducted a systematic search in eight databases. We included all in vitro and in vivo studies investigating the anticancer effects of CK with no restrictions. Quality assessment was applied by ToxRTool. Fifty-four articles were included in our study. The purity of CK in our included studies was at least 95%. The in vitro studies reported that CK had a potential anticancer activity on several cell lines including human lung cancer cell lines (A549, PC-9), nasopharyngeal carcinoma cell line (Hk-1), liver cancer cell line (BEL 7402), and pediatric acute myeloid leukemia cell lines (Kasumi-1, MV4-11). The in vivo studies reported a significant decrease in tumor volume in mice treated with CK. CK is a potential supplementary treatment in cancer chemotherapies. The safety and further clinical trials of CK should be explored for future drug development.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2 n 66), CCI intermediate (3-4 n 78), and CCI high (≥5 n 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Development of Cancer Care in Northeast India.

Northeast India, a region of geographic, cultural, and ethnic diversity comprises of Assam, Arunachal Pradesh, Manipur, Meghalaya, Mizoram, Tripura, and Sikkim. Geographically, two-thirds of the area is hilly terrain. The North Eastern Region (NER) shows marked diversity in customs, cultures, cuisines, traditions, and languages. The Aizawl district of Mizoram (269.4) and the Papumpare district of Arunachal Pradesh (219.8) have the highest age-adjusted incidence rates (AAR) of cancer among males and females, respectively. Meghalaya has the highest relative proportion of cancers associated with tobacco use, with 70.4% in men and 46.5% in women. This correlates with the high prevalence of tobacco use. The Dr Bhubaneswar Borooah Cancer Institute, Guwahati, was inaugurated in 1973. The Institute currently conducts M.Ch. Surgical Oncology, Head and Neck Oncology and Gynaecologic Oncology, and DM courses in Medical Oncology and Onco-pathology. The year 2019 saw the creation of a high-dose radioisotope therapy ward. Allogenic Bone Marrow Transplantation (BMT) was started in 2021-2022. State Cancer Institute (SCI), Guwahati, houses a medical cyclotron, which is the only one in Northeast India. Assam Cancer Care Foundation (ACCF) is a joint venture between the Government of Assam and the Tata Trusts, with a three-level cancer grid. The Cachar Cancer Hospital and Research Centre (CCHRC) offers holistic, subsidised cancer care to over 4000 new patients every year. North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS) offers endobronchial ultrasound (EBUS) and mediastinoscopy services, enabling accurate staging of lung cancers. While the cancer care facilities in NER have grown over the years, it is not commensurate with the high incidence of cancers in the region.

Response of Patients with Taxane-Refractory Advanced Urothelial Cancer to Enfortumab Vedotin, a Microtubule-Disrupting Agent.

Enfortumab vedotin (EV), a nectin-4-directed antibody conjugated to monomethyl auristatin E (MMAE), has been approved for patients with advanced urothelial carcinoma (aUC) previously treated with platinum-based chemotherapy and immune inhibitors. Taxane agents and MMAE share antitumor mechanisms through microtubule disruption, thus raising a notable concern regarding cross-resistance between these drugs. This case report describes two patients with taxane-based chemotherapy-refractory aUC who responded well to EV. A 71-year-old man (case 1) with pT3N0M0 renal pelvic UC showed a partial response to EV in metastatic lesions of the bilateral lungs and right pelvic lymph nodes after three cycles of paclitaxel plus gemcitabine chemotherapy. A 53-year-old man (case 2) with cT3bN2M0 bladder UC underwent platinum-based neoadjuvant chemotherapy and the following radial cystectomy (ypTis ypN0). He developed bilateral lung metastases and showed a complete response to EV in the metastatic lesions after 20 cycles of paclitaxel plus nedaplatin chemotherapy. Our experience of two cases demonstrated that tumor response to EV can be expected in patients with taxane-refractory aUC.

Tobacco smoking and cancer risk.

Smoking tobacco is the most important and potentially modifiable risk factor for cancer in Germany. Combining tobacco with alcohol can multiply cancer risks. Up to 30 % of cancer deaths are due to tobacco smoking. 23,3 % of 18-64 year-old Germans are current smokers in addition, 11 % of the population are regularly exposed to secondhand tobacco smoke. Tobacco smoking is causally associated with oropharyngeal, laryngeal, nose, paranasal sinus, lung, esophageal, gastric, pancreatic, hepatocellular, biliary, colorectal, kidney, ureter, urinary bladder, uterine cervix and ovary cancers and leukemia. Smokers should be supported to stop smoking and join programmes of cancer screening. Smoking cessation effectively reduces tobacco-associated cancer risk. Tabakrauchen ist die wichtigste vermeidbare Krebsursache in Deutschland. Je mehr und je länger jemand raucht, desto stärker steigt sein Krebsrisiko. Wird Tabakrauch kombiniert mit Alkohol, vervielfacht sich das Krebsrisiko. Bis zu 30 % der Krebstodesfälle können auf das Rauchen zurückgeführt werden. 23,3 % der 18- bis 64-jährigen Bevölkerung rauchen und weitere 11 % sind hierzulande regelmäßig einer Passivrauch­belastung ausgesetzt. Zu den Tabakrauch-assoziierten Malignomen zählen Karzinome der Mundhöhle, der Nase, der Nebenhöhlen, des Pharynx, des Larynx, der Lunge, des Ösophagus, des Magens, des Pankreas, der Leber, der Gallenwege, des Dickdarms, der Nieren, der Ureteren, der Harnblase, der Zervix und der Eierstöcke sowie Leukämien. Bei stattgehabter Tabakexposition soll den Betroffenen frühzeitig zu etablierten Krebsfrüh­erkennungsmaßnahmen geraten werden. Rauchern soll eine professionelle Tabakentwöhnung angeboten werden. Das tabakbedingte Krebsrisiko wird durch den Rauchstopp effektiv und zeitabhängig gesenkt.

Do fine needle aspirate cytomorphological features correlate with positron emission tomography findings of metastatic non-small cell lung carcinoma in lymph nodes

Our objective was to correlate cytomorphological features of metastatic non-small cell lung carcinoma (mNSCLC) with maximal standardized uptake value (mSUV) of positron emission tomography (PET) in Lymph nodes (LNs). Positive cytology slides of 114 LNs were reviewed from 100 patients with mNSCLC who had undergone PET study. Students t-test was used for statistical comparisons. Mean patients age 68.5, 54% male. LNs locations were mediastinum 99, lung hilum 13, peribronchial 1, axilla 1. Final diagnoses were Adenocarcinoma 86, squamous cell carcinoma 28 LNs. Within the adenocarcinoma subgroup, histological patterns correlate with mSUV. Acinar and papillary patterns were associated with significantly lower mSUVs (mean ± standard error (SE) 7.9 ± 0.9 and 9.2 ± 0.8, respectively) than solid pattern (13.0 ± 1.2 p values 0.001 and 0.009, respectively). Similar difference exists between patterns associated with low- and high-grade adenocarcinoma (Mean ± SE 9.2 ± 0.8 and 12.0 ± 1.0, respectively. p value 0.02). Interestingly, micropapillary pattern was associated with the lowest mSUV amongst all patterns (Mean ± SE 5.4 ± 1.1). Other features that correlated with higher mSUV were necrosis, moderatesevere nuclear atypia, lower lymphoid tissue yield, and contralateral LN involvement. In LNs with mNSCLC, certain cytomorphological features are associated with higher mSUV. Micropapillary, a pattern considered as high-grade, is associated with lower SUV values hence, a lower SUV threshold may raise concern for metastasis. Although high SUV is associated with LN metastasis, lower SUV levels in certain adenocarcinomas suggest correlation with clinical and morphological characteristics could be valuable in tailoring therapeutic management.

Stability and reproducibility comparisons between deep inspiration breath-hold techniques for left-sided breast cancer patients A prospective study.

Deep inspiration breath-hold (DIBH) is crucial in reducing the lung and cardiac dose for treatment of left-sided breast cancer. We compared the stability and reproducibility of two DIBH techniques Active Breathing Coordinator (ABC) and VisionRT (VRT). We examined intra- and inter-fraction positional variation of the left lung. Eight left-sided breast cancer patients were monitored with electronic portal imaging during breath-hold (BH) at every fraction. For each patient, half of the fractions were treated using ABC and the other half with VRT, with an equal amount starting with either ABC or VRT. The lung in each portal image was delineated, and the variation of its area was evaluated. Intrafraction stability was evaluated as the mean coefficient of variation (CV) of the lung area for the supraclavicular (SCV) and left lateral (LLat) field over the course of treatment. Reproducibility was the CV for the first image of each fraction. Daily session time and total imaging monitor units (MU) used in patient positioning were recorded. The mean intrafraction stability across all patients for the LLat field was 1.3 ± 0.7% and 1.5 ± 0.9% for VRT and ABC, respectively. Similarly, this was 1.5 ± 0.7% and 1.6 ± 0.8% for VRT and ABC, respectively, for the SCV field. The mean interfraction reproducibility for the LLat field was 11.0 ± 3.4% and 14.9 ± 6.0% for VRT and ABC, respectively. Similarly, this was 13.0 ± 2.5% and 14.8 ± 9% for VRT and ABC, respectively, for the SCV. No difference was observed in the number of verification images required for either technique. The stability and reproducibility were found to be comparable between ABC and VRT. ABC can have larger interfractional variation with less feedback to the treating therapist compared to VRT as shown in the increase in geometric misses at the matchline.

Tastin promotes non-small-cell lung cancer progression through the ErbB4, PI3KAKT, and ERK12 pathways.

Tastin might be involved in tumorigenesis, but its role in non-small-cell lung cancer (NSCLC) has not been adequately explored. This work aimed to examine tastins role in NSCLC and to explore the underlying mechanism. The Gene Expression Omnibus (GEO), Gene Expression Database of Normal and Tumor tissues (GENT), and Cancer Genome Atlas (TCGA) databases were used. Four GEO datasets (GSE81089, GSE40419, GSE74706, and GSE19188) containing gene expression data for NSCLC and normal tissue samples were analyzed for tastin mRNA expression. Tastin expression levels in different tissues were compared using the GENT website. TCGA biolinks were used to download gene expression quantification (

Surgical safety analysis and clinical experience sharing of myasthenia gravis patients aged 65 and over.

To evaluate the surgical safety in myasthenia gravis (MG) patients aged 65 and over. A total of 564 patients with MG who underwent surgery in the Department of Thoracic Surgery of Beijing Hospital from November 2011 to March 2022 were included in the study and divided into two groups taking the age of 65 as the boundary. Perioperative data of patients were recorded and statistically analyzed. Compared with young patients, FEV1, FEV1% and MVV in lung function of elderly MG patients were worse (p < 0.001, p < 0.001, p 0.002). Postoperative drainage time was longer (p < 0.001), combined with more drainage volume (p 0.002). The American Society of Anesthesiologists (ASA) score of elderly MG patients was higher (p < 0.001). Complications were more likely to occur (p 0.008) after surgery and Clavien-Dindo classification (CDC) of postoperative complications was also higher (p 0.003). Meanwhile, postoperative myasthenic crisis (POMC) was more likely to occur (p 0.038). Logistic regression showed that lower DLCO% (p 0.049) was an independent risk factor for postoperative complications. Surgical indications should be considered in each elderly MG patient on an individual basis. Moreover, most elderly MG patients safely survive the perioperative period and benefit from surgery through individualized consideration.

Circ0110498 facilitates the cisplatin resistance of non-small cell lung cancer by mediating the miR-1287-5pRBBP4 axis.

Circular RNAs (circRNAs) play vital roles in non-small cell lung cancer (NSCLC) progression. Our research analyzed the role of circ0110498 on the cisplatin (DDP) resistance of NSCLC. Cell glycolysis was analyzed by measuring glucose consumption and lactate production. Protein expression was determined by western blot analysis. The expression of circ0110498, microRNA (miR)-1287-5p and RBBP4 was detected by RT-qPCR assay. Cell counting kit-8, colony formation and transwell assays, together with flow cytometry were conducted to analyze cell DDP resistance, proliferation, metastasis and apoptosis. Circ0110498 expression was elevated in DDP-resistant NSCLC tissues and cells. Circ0110498 silencing not only suppressed the DDP resistance of NSCLC cells by inhibiting cell growth, metastasis and glycolysis, but also enhanced the DDP sensitivity of NSCLC tumors. MiR-1287-5p was sponged by circ0110498, and its inhibitor also reversed the effect of circ0110498 silencing on the DDP resistance of NSCLC cells. MiR-1287-5p interacted with RBBP4, and RBBP4 overexpression partly reversed the inhibitory effect of miR-1287-5p on the DDP resistance of NSCLC cells. Circ0110498 facilitated DDP resistance partly through mediating the miR-1287-5pRBBP4 signaling in NSCLC.

A flexible liposomal polymer complex as a platform of specific and regulable immune regulation for individual cancer immunotherapy.

The applicability and therapeutic efficacy of specific personalized immunotherapy for cancer patients is limited by the genetic diversity of the host or the tumor. Side-effects such as immune-related adverse events (IRAEs) derived from the administration of immunotherapy have also been observed. Therefore, regulatory immunotherapy is required for cancer patients and should be developed. The cationic lipo-PEG-PEI complex (LPPC) can stably and irreplaceably adsorb various proteins on its surface without covalent linkage, and the bound proteins maintain their original functions. In this study, LPPC was developed as an immunoregulatory platform for personalized immunotherapy for tumors to address the barriers related to the heterogenetic characteristics of MHC molecules or tumor associated antigens (TAAs) in the patient population. Here, the immune-suppressive and highly metastatic melanoma, B16F10 cells were used to examine the effects of this platform. Adsorption of anti-CD3 antibodies, HLA-A2peptide, or dendritic cells membrane proteins (MP) could flexibly provide pan-T-cell responses, specific Th1 responses, or specific Th1 and Th2 responses, depending on the host needs. Furthermore, with regulatory antibodies, the immuno-LPPC complex properly mediated immune responses by adsorbing positive or negative antibodies, such as anti-CD28 or anti-CTLA4 antibodies. The results clearly showed that treatment with LPPCMPCD28 complexes activated specific Th1 and Th2 responses, including cytokine release, CTL and prevented T-cell apoptosis. Moreover, LPPCMPCD28 complexes could eliminate metastatic B16F10 melanoma cells in the lung more efficiently than LPPCMP. Interestingly, the melanoma resistance of mice treated with LPPCMPCD28 complexes would be reversed to susceptible after administration with LPPCMPCTLA4 complexes. NGS data revealed that LPPCMPCD28 complexes could enhance the gene expression of cytokine and chemokine pathways to strengthen immune activation than LPPCMP, and that LPPCMPCTLA4 could abolish the LPPCMP complex-mediated gene expression back to un-treatment. Overall, we proved a convenient and flexible immunotherapy platform for developing personalized cancer therapy.

Thymus and lung mucosa-associated lymphoid tissue lymphoma with adenocarcinoma of the lung a case report and literature review.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a common, low-grade, malignant B-cell lymphoma. However, simultaneous MALT lymphoma in the thymus and lung is extremely rare, and concomitant adenocarcinoma of the lung is even rarer. Herein, we report a rare case of a collision tumor in which MALT lymphoma was found in both the thymus and lung with Sjögrens syndrome (SS) and adenocarcinoma in the lung. A physical examination of a 32-year-old woman revealed an anterior superior mediastinal space-occupying lesion, and chest computed tomography (CT) indicated a nodular ground-glass opacity and irregular mixed-density focus in the right lung. All lung cancer-related tumor biomarkers were within normal ranges. The thymus and part of the lung tissue were surgically resected. The histopathology and molecular examinations confirmed MALT lymphoma of the thymus and lung with lung adenocarcinoma. SS was also diagnosed. No special postoperative treatment was performed for the MALT lymphoma, and the patient underwent immunosuppressive therapy for SS after 4 months of follow-up observation. MALT lymphoma of the thymus and lung tissues has no specific presentation on imaging and is difficult to differentiate from common malignant tumors, and the definite diagnoses of these tumors are highly dependent on histopathological examination in combination with molecular testing and cytogenetics. SS may be an important potential condition for the occurrence of MALT lymphoma in the thymus and lung. Additional similar cases are needed to clarify the biological pathways and potential molecular mechanisms of rare lymphomas and collision tumors.

FAM83B promotes the invasion of primary lung adenocarcinoma via PI3KAKTNF-κB pathway.

The family with sequence similarity 83B (FAM83B) is one of the markers for poor prognosis in several carcinomas, but the expression and the mechanism resulted in malignant phenotype in lung adenocarcinoma (LUAD) remain to be elucidated. Data of RNA-seq in LUAD were downloaded from the cancer genome atlas (TCGA) database for differential expression and survival analysis, and immunohistochemistry was employed to analyze the protein expression of FAM83B in 126 cases of primary LUAD. The LUAD cell lines were collected for the detection of the effects on migration and invasion. Then, western blot was performed to measure the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and activation of PI3KAKTNF-κB pathway. FAM83B was overexpressed in multiple types of carcinomas The differential expression analysis revealed that the level of FAM83B was higher in LUAD than that in para-carcinoma The patients with overexpression of FAM83B were with shorter overall survival (OS), disease specific survival (DSS) and progress free interval (PFI) Enrichment analysis suggested it was related to the focal adhesion of LUAD. Immunohistochemistry analysis demonstrated that higher FAM83B expression was positively related to lymph node metastasis in primary. Scratch assay and Borden chamber assay showed that the overexpression of FAM83B promoted migration and invasion activity in vitro. Furthermore, high level of FAM83B accelerated the tumorigenesis in vivo. Western blot showed that TIMP-1 was upregulated in H1299FAM83B OE cells accompanying by the activation of PI3KAKTNF-κB pathway. FAM83B was a marker for poor prognosis of LUAD and it might promote the expression of TIMP-1 by activating PI3KAKTNF-κB pathway and then affect the ECM balance, which resulted in the migration and invasion of LUAD.

Human papillomavirus 16 E6 promotes angiogenesis of lung cancer via SNHG1.

Human papillomavirus (HPV) is a risk factor for lung cancer. However, the underlying mechanisms are not known. Long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of lung cancer due to their particular characteristics. HPV-induced lung carcinogenesis is incompletely defined. We aimed to screen and clarify the functions of lncRNAs that are differentially expressed in HPV-related lung cancer. We found that lncRNA SNHG1 is upregulated in lung cancer cells infected with HPV16 E6 by qRT‒PCR. Further results demonstrated that SNHG1 overexpression facilitates the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Our results also indicated that SNHG1 might function in lung cancer by binding with EGFR. Further studies revealed that SNHG1 overexpression could activate the nuclear factor κb (NF-κB) pathway, which increases the expression of interleukin-6 (IL-6). We also found that IL-6 can activate the STAT3 pathway, which promotes VEGF-D expression. These results expanded our understanding of SNHG1 as a new avenue for therapeutic intervention against lung cancer progression. Upregulation of SNHG1 by HPV infection might be an undefined link between lung cancer and HPV.

Inequalities in cancer mortality trends in people with type 2 diabetes 20 year population-based study in England.

The aim of this study was to describe the long-term trends in cancer mortality rates in people with type 2 diabetes based on subgroups defined by sociodemographic characteristics and risk factors. We defined a cohort of individuals aged ≥35 years who had newly diagnosed type 2 diabetes in the Clinical Practice Research Datalink between 1 January 1998 and 30 November 2018. We assessed trends in all-cause, all-cancer and cancer-specific mortality rates by age, gender, ethnicity, socioeconomic status, obesity and smoking status. We used Poisson regression to calculate age- and calendar year-specific mortality rates and Joinpoint regression to assess trends for each outcome. We estimated standardised mortality ratios comparing mortality rates in people with type 2 diabetes with those in the general population. Among 137,804 individuals, during a median follow-up of 8.4 years, all-cause mortality rates decreased at all ages between 1998 and 2018 cancer mortality rates also decreased for 55- and 65-year-olds but increased for 75- and 85-year-olds, with average annual percentage changes (AAPCs) of -1.4% (95% CI -1.5, -1.3), -0.2% (-0.3, -0.1), 1.2% (0.8, 1.6) and 1.6% (1.5, 1.7), respectively. Higher AAPCs were observed in women than men (1.5% vs 0.5%), in the least deprived than the most deprived (1.5% vs 1.0%) and in people with morbid obesity than those with normal body weight (5.8% vs 0.7%), although all these stratified subgroups showed upward trends in cancer mortality rates. Increasing cancer mortality rates were also observed in people of White ethnicity and formercurrent smokers, but downward trends were observed in other ethnic groups and non-smokers. These results have led to persistent inequalities by gender and deprivation but widening disparities by smoking status. Constant upward trends in mortality rates were also observed for pancreatic, liver and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages. Compared with the general population, people with type 2 diabetes had a more than 1.5-fold increased risk of colorectal, pancreatic, liver and endometrial cancer mortality during the whole study period. In contrast to the declines in all-cause mortality rates at all ages, the cancer burden has increased in older people with type 2 diabetes, especially for colorectal, pancreatic, liver and endometrial cancer. Tailored cancer prevention and early detection strategies are needed to address persistent inequalities in the older population, the most deprived and smokers.

Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts.

Ectopic Cushing syndrome is a rare clinical disorder resulting from excessive adrenocorticotrophic hormone (ACTH) produced by non-pituitary neoplasms, mainly neuroendocrine neoplasms (NENs) of the lung, pancreas, and gastrointestinal tract, and other less common sites. The genetic background of ACTH-producing NENs has not been well studied. Inspired by an index case of ACTH-producing pancreatic NEN carrying a gene fusion, we postulated that ACTH-producing NENs might be enriched for gene fusions. We herein examined 21 ACTH-secreting NENs of the pancreas (10), lung (9), thymus (1), and kidney (1) using targeted RNA sequencing. The tumors were classified according to the most recent WHO classification as NET-G1typical carcinoid (n 4), NETG-2atypical carcinoid (n 14), and NET-G3 (n 3). Overall, targeted RNA sequencing was successful in 11 cases (4 of 10 pancreatic tumors, 5 of 9 pulmonary tumors, and in the one renal and one thymic tumor). All four successfully tested pancreatic tumors revealed a gene fusion two had a EWSR1BEND2 and one case each had a KMT2ABCOR and a TFGADGRG7 fusion, respectively. EWSR1 rearrangements were confirmed in both tumors with a EWSR1BEND2 by FISH. Gene fusions were mutually exclusive with ATRX, DAXX, and MEN1 mutations (the most frequently mutated genes in NETs) in all four cases. Using RNA-based variant assessment (n 16) or via the TSO500 panel (n 5), no pathogenic BCOR mutations were detected in any of the cases. Taken together, gene fusions were detected in 44 (100%) pancreatic versus 07 (0%) non-pancreatic tumors, respectively. These results suggest a potential role for gene fusions in triggering the ACTH production in pancreatic NENs presenting with ectopic Cushing syndrome. While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.

Real-world multicentre cohort of first-line pembrolizumab alone or in combination with platinum-based chemotherapy in non-small cell lung cancer PD-L1 ≥ 50.

Pembrolizumab alone (IO-mono) or in combination with platinum-based chemotherapy (CT-IO) is first-line standard of care for advanced non-small cell lung cancer (NSCLC) patients with PD-L1 ≥ 50%. This retrospective multicentre study assessed real-world use and efficacy of both strategies. Patients with advanced NSCLC PD-L1 ≥ 50% from eight hospitals who had received at least one cycle of IO-mono or CT-IO were included. Overall survival (OS) and real-word progression-free-survival were estimated using Kaplan-Meier methodology. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs, and a Cox model with inverse propensity treatment weighting was carried out. Among the 243 patients included, 141 (58%) received IO-mono and 102 (42%) CT-IO. Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. With a median follow-up of 11.5 months (95% CI 10.4-13.3), median OS was not reached, but no difference was observed between groups (p 0.51). Early deaths at 12 weeks were 11% (95% CI 4.6-16.9) and 15.2% (95% CI 9.0-20.9) in CT-IO and IO groups (p 0.32). After adjustment for age, gender, performance status, histology, brain metastases, liver metastases and tobacco status, no statistically significant difference was found for OS between groups, neither in the multivariate adjusted model HR 1.07 (95% CI 0.61-1.86), p 0.8 nor in propensity adjusted analysis HR 0.99 (95% CI 0.60-1.65), p 0.99. Male gender (HR 2.01, p 0.01) and PS ≥ 2 (HR 3.28, p < 0.001) were found to be negative independent predictive factors for OS. Younger patients, those with symptomatic disease and brain metastases were more likely to be proposed CT-IO. However, sparing the chemotherapy in first-line does not appear to impact survival outcomes, even regarding early deaths.

Exploratory analysis of the effect of a dexamethasone-sparing regimen for prophylaxis of cisplatin-induced emesis on food intake (LUNG-NEPA study).

We demonstrated the non-inferiority of a dexamethasone (DEX)-sparing (single-dose) regimen with NEPA, a netupitantpalonosetron fixed combination, for preventing chemotherapy-induced nausea and vomiting (CINV) caused by cisplatin. This pre-planned exploratory analysis assessed the effect of the DEX-sparing regimen on a patients food intake. Chemotherapy-naïve patients undergoing cisplatin (≥ 70 mgm

The NFIBCARM1 partnership is a driver in preclinical models of small cell lung cancer.

The coactivator associated arginine methyltransferase (CARM1) promotes transcription, as its name implies. It does so by modifying histones and chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1 substrate and show that this transcription factor utilizes CARM1 as a coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is important for its transforming activity. Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. Furthermore, CARM1 and methylated NFIB are responsible for maintaining similar open chromatin states in tumors. Together, these findings suggest that CARM1 might be a therapeutic target for SCLC.

The clinicopathological spectrum of sclerosing epithelioid fibrosarcoma report of an additional series with review of the literature.

We present a case series of sclerosing epithelioid fibrosarcoma (SEF) to further characterise its clinical and pathological features. Twenty-one patients with SEF were included in this study. There were 12 males and nine females (range 25-63 years median 38 years). Tumours were located in the kidney (n5), thigh (n3), chest wall (n3), head and neck (n2), bone (n2), abdominal wall (n1), psoas major (n1), retroperitoneum (n1), omentum (n1), popliteal space (n1) and lung (n1). Tumour sizes ranged from 2.5 to 16 cm (median 7 cm). Microscopically, epithelioid tumour cells were arranged in nests and cords and embedded in a dense sclerotic stroma. Some tumours showed myxoid areas, fibroma-like areas, acinar growth patterns and haemangiopericytoma-like appearance. A few tumour cells presented a rhabdomyoid shape. Calcification, ossification, cystic and necrosis were observed in some cases. The diagnosis was confirmed by immunoreactivity for MUC4, and by further fluorescence in situ hybridisation (FISH) or next generation sequencing (NGS) analysis. Clinical follow-up was available for 16 cases (median, 24 months range 6-62 months). Seven patients developed metastases to lung (n3), bone (n3), brain (n2) and back (n1). Four patients developed a local recurrence. Three patients died of disease. Overall survival (OS) of SEF was related to patient age (p0.001) and progression-free survival (PFS) was related to tumour size (p0.046). In addition to soft tissue, SEF is more likely to involve the viscera and the abdominal cavity and has morphological variants. Familiarity with its distinctive clinical and pathological features helps avoid misdiagnosis.

Oncogenic lncRNA MALAT-1 recruits E2F1 to upregulate RAD51 expression and thus promotes cell autophagy and tumor growth in non-small cell lung cancer.

LncRNA MALAT-1 expression is involved in regulating activities of non-small-cell lung cancer (NSCLC) cells. This study aimed to investigate the effects of lncRNA MALAT-1 on chemosensitivity of NSCLC cells by regulating autophagy. We first validated the expression of lncRNA MALAT-1 in NSCLC cell lines. NSCLC cell lines with high lncRNA MALAT-1 expression were exposed to doxorubicin (DOX) to assess chemosensitivity. Further LncMAP database retrieval and ChIP, RIP and luciferase activity assays were conducted to explore interplay between lncRNA MALAT-1, RAD51, and E2F1. Immunofluorescence staining was performed to evaluate formation of autophagosomes in NSCLC cells. Ectopic expression and knockdown methods were used for in vitro mechanism experiments and in vivo substantiation. LncRNA MALAT-1 was overexpressed in NSCLC cells, and could promote NSCLC cell autophagy and inhibit its chemosensitivity. In vitro cell mechanism verification experiments showed that lncRNA MALAT-1 could recruit transcription factor E2F1 to bind to the promoter of RAD51, so as to promote the transcriptional expression of RAD51. In addition, cell function experiments in vitro showed that ectopically expressed lncRNA MALAT-1 promoted NSCLC cell autophagy and inhibited its chemosensitivity, while RAD51 knockdown negated its effect. Finally, in vivo animal experiments confirmed that lncRNA MALAT-1 silencing could impede the tumor growth. Taken together, this study revealed that silencing lncRNA MALAT-1 enhanced chemosensitivity of NSCLC cells by promoting autophagy, highlighting a feasible approach to prevent chemoresistance in NSCLC treatment.

Survival prediction for stage I-IIIA non-small cell lung cancer using deep learning.

The aim of this study was to develop and evaluate a prediction model for 2-year overall survival (OS) in stage I-IIIA non-small cell lung cancer (NSCLC) patients who received definitive radiotherapy by considering clinical variables and image features from pre-treatment CT-scans. NSCLC patients who received stereotactic radiotherapy were prospectively collected at the UMCG and split into a training and a hold out test set including 189 and 81 patients, respectively. External validation was performed on 228 NSCLC patients who were treated with radiation or concurrent chemoradiation at the Maastro clinic (Lung1 dataset). A hybrid model that integrated both image and clinical features was implemented using deep learning. Image features were learned from cubic patches containing lung tumours extracted from pre-treatment CT scans. Relevant clinical variables were selected by univariable and multivariable analyses. Multivariable analysis showed that age and clinical stage were significant prognostic clinical factors for 2-year OS. Using these two clinical variables in combination with image features from pre-treatment CT scans, the hybrid model achieved a median AUC of 0.76 95 % CI 0.65-0.86 and 0.64 95 % CI 0.58-0.70 on the complete UMCG and Maastro test sets, respectively. The Kaplan-Meier survival curves showed significant separation between low and high mortality risk groups on these two test sets (log-rank test p-value < 0.001, p-value 0.012, respectively) CONCLUSION We demonstrated that a hybrid model could achieve reasonable performance by utilizing both clinical and image features for 2-year OS prediction. Such a model has the potential to identify patients with high mortality risk and guide clinical decision making.

Concurrent administration of immune checkpoint inhibitors and single fraction stereotactic radiosurgery in patients with non-small cell lung cancer, melanoma, and renal cell carcinoma brain metastases is not associated with an increased risk of radiation necrosis over non-concurrent treatment An international multicenter study of 657 patients.

Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. Additionally, as a secondary analysis, recursive partitioning analysis (RPA) was utilized for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Six hundred fifty-seven patients with 4,182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months in the concurrent and non-concurrent groups, respectively (p 0.03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90 In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy (1) < 12 cm Utilization of SRS and ICI results in a low risk of RN and SRN and is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

Telocinobufagin inhibits osteosarcoma growth and metastasis by inhibiting the JAK2STAT3 signaling pathway.

Osteosarcoma is the most common primary bone malignancy in children and adolescents it exhibits rapid growth and a high metastatic potential and may thus lead to relatively high mortality. The JAK2STAT3 signaling pathway, which plays a critical role in the occurrence and development of osteosarcoma, is a potential target for the treatment of osteosarcoma. Here, we identified the natural product telocinobufagin (TCB), which is a component isolated from toad cake, as a potent candidate with anti-osteosarcoma effects. TCB inhibited osteosarcoma cell growth, migration, invasion and induced cancer cell apoptosis. Mechanistically, TCB specifically inhibited the JAK2STAT3 signaling pathway. More importantly, TCB significantly suppressed tumor growth and metastasis in an osteosarcoma xenograft animal model. Moreover, TCB also showed strong inhibitory effects in other cancer types, such as lung cancer, liver cancer, colon cancer, breast cancer and gastric cancer. Hence, our study reveals TCB as a potent anti-osteosarcoma therapeutic agent that inhibits the JAK2STAT3 signaling pathway.

Immune checkpoint inhibitor-related pneumonitis in lung cancer patients with interstitial lung disease Significance of radiological pleuroparenchymal fibroelastosis.

Introduction Pleuroparenchymal fibroelastosis (PPFE) findings are associated with poor prognosis in interstitial lung disease (ILD). However, the effect of PPFE findings on the development of immune checkpoint inhibitor-related pneumonitis (ICI-pneumonitis), a life-threatening adverse event, in lung cancer patients with ILD has not been elucidated. We aimed to determine whether PPFE findings are a risk factor for ICI-pneumonitis in lung cancer patients with ILD. Methods We retrospectively examined 712 lung cancer patients, including 173 patients with background ILDs who received ICI therapy in our institute between December 2015 and May 2021. Background ILDs were radiologically classified into three types lone PPFE, other ILDs with PPFE, and other ILDs without PPFE. The cumulative ICI-pneumonitis incidence curves and median overall survival (mOS) were compared between the three radiological types, and risk factors for ICI-pneumonitis were evaluated. Results Of 173 eligible patients with ILD, 23 patients (13.3%) experienced ICI-pneumonitis. The Kaplan-Meier method and the log-rank test showed that lone PPFE patients had significantly lower incidence of ICI-pneumonitis (p 0.024) and longer mOS (575 versus 326 days p 0.0096) than other ILDs patients. ICI-pneumonitis (p 0.35) and mOS (p 0.29) were not significantly different between other ILDs with and without PPFE. A multivariate Cox proportional hazards regression analysis revealed that lone PPFE pattern was an independent predictive factor for ICI-pneumonitis (hazard ratio, 0.20 95% confidence interval, 0.043 to 0.93 p 0.040). Conclusion ICI therapy could be safer in lone PPFE patients than in other ILDs patients with lung cancer.

Centrilobular Emphysema Is Associated with Pectoralis Muscle Reduction in Current Smokers without Airflow Limitation.

Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2 SAT area (mean), 29.3 versus 36.8 cm2 BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.

Inappropriate dietary habits in tobacco smokers as a potential risk factor for lung cancer Pomeranian cohort study.

Little is known whether diet quality modulates lung cancer risk in smokers. The aim of the study was to assess the dietary habits of a large group of volunteers participating in the lung cancer screening program. The 62-item food frequency questionaire was completed by 5997 participants, 127 of whom (2.1%) were later diagnosed with lung cancer. Two approaches were applied to identify dietary habits. The non-healthy diet index was calculated, and a direct analysis of the frequency of consumption was used. A logistic regression analysis was performed to estimate the association between food product intake and the risk of lung cancer. The study population did not follow the Polish nutritional recommendations. They consumed fruits and vegetables too rarely and far too often ate non-recommended foods, such as processed meat, refined products, sugar, sweets, and salty snacks. Participants diagnosed with lung cancer more often consumed low-quality processed meat, red meat, fats, and refined bread and less often whole-grain products, tropical fruits, milk, fermented unsweetened milk drinks, nuts, honey, and wine. The non-healthy diet index score was significantly higher in those with cancer diagnosis compared with those without lung cancer (11.9 ± 5.2 versus 10.9 ± 5.3 P < 0.001). The surveyed population of smokers did not follow dietary recommendations there was a particularly high index of an unhealthy diet in by people diagnosed with lung cancer. Prevention programs should be based on encouraging smoking cessation, lifestyle modification, and methods of early detection of lung cancer. Lifestyle modification should include changing eating habits based on a healthy diet, which may be an additional factor in reducing the risk of developing cancer.

Tarlatamab, a First-In-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small Cell Lung Cancer An Open-Label, Phase I Study.

Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cell-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. This study evaluated tarlatamab in patients with relapsedrefractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg n 73) and expansion (100 mg n 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6) 49.5% received antiprogrammed death-1programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade ≥ 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

Association of metformin use and survival in patients with cutaneous melanoma and diabetes.

Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. To investigate the association between metformin use and survival among patients with CM and diabetes. All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS. Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.

The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity.

Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues andor organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.

Silencing TAB182 inhibits cell EMT, migration and invasion by downregulating EGFR in A549 NSCLC cells.

TAB182 is overexpressed in cancerous tissues and correlated with poor overall survival in lung cancer patients. Mechanistically, TAB182 participates in DNA damage repair and endows tumour cells with radio- and chemoresistance. However, its role in non-small cell lung cancer (NSCLC) remains unclear. Cells with stable TAB182 knockdown (KD) were generated using A549 NSCLC cells, and we demonstrated that depleting TAB182 inhibits cell EMT, proliferation, colony formation, migration and invasion. Analysis of the TCGA database showed a positive correlation between TAB182 and EGFR, a well-established NSCLC oncoprotein. Then, we verified that silencing TAB182 decreases EGFR expression at both the mRNA and protein levels. Moreover, both TAB182 and EGFR were reported to restore ionizing radiation (IR)-triggered DNA damage. We validated that IR elevates the protein level of EGFR and that silencing TAB182 can alleviate IR-induced EGFR upregulation. Furthermore, overexpressing EGFR abrogates the inhibitory effects of TAB182 KD on EMT, migration, and invasion in A549 cells. Our data demonstrated that EGFR expression is regulated by TAB182 and downregulation of TAB182 has a novel function to repress EMT, migration and invasion by decreasing EGFR, indicating TAB182 could regulate the malignant progression of NSCLC.

Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab.

Immunotherapy has changed the paradigm of treating non-small cell lung cancer (NSCLC). But, selecting patients who will achieve long-term benefits from treatment remains unsatisfactory. Here, we investigated the possible use of the soluble form of CD8 antigen (sCD8) in predicting durable disease control after PD-1PD-L1 blockade. CD8 is a marker of the cytotoxic T lymphocytes. Its soluble form (sCD8) is secreted under activation of the immune system but also has immunosuppressive properties. The data about serum sCD8 in patients dosed with anti-PD-1PD-L1 drugs are lacking. We included 42 NSCLC patients and collected samples at baseline and for the first 3 months of atezolizumab immunotherapy. The serum sCD8 concentrations were measured with the ELISA kit and correlated with treatment outcomes. Patients with durable (≥ 12 months) disease control presented lower serum sCD8 than those without long-term benefits. The sCD8 levels measured at the end of cycle 2 (sCD8.2) were the earliest time point that successfully differentiated patients (3.76 vs. 9.68 ngmL, respectively, p < 0.001). Individuals with low sCD8.2 (≤ 4.09 ngmL) presented longer progression-free survival (HR 0.061, p < 0.001) and overall survival (HR 0.104, p < 0.05) compared to individuals with high sCD8.2 (median values unreached vs. 4.4 months and 14.4 months for PFS and OS, respectively). Serum sCD8 could be an early biomarker of durable disease control after anti-PD-L1 treatment. Higher sCD8 in patients with worse outcomes could suggest the inhibitory effect of sCD8 on cytotoxic T-cells activation.

Preventive effect of tertiary lymphoid structures on lymph node metastasis of lung adenocarcinoma.

Ectopic lymphoid formations are called tertiary lymphoid structures (TLSs). TLSs in cancer have been reported to be associated with good prognosis and immunotherapy response. However, the relationship between TLSs and lymph node (LN) metastasis is unclear. We analyzed 218 patients with radically resected lung adenocarcinoma. TLSs were defined as the overlap of T cell zone and B cell zone. Granzyme B The mature TLS group was associated with significantly lower frequency of LN metastasis (P < 0.0001) and early cancer stage (P 0.0049). The mature TLS group had significantly more CD8 Mature TLSs were associated with an increased number of cytotoxic lymphocytes in draining LNs, a lower frequency of LN metastasis, and favorable outcomes. Mature TLSs may support antitumor immunity by lymphocyte activation.

Radiotherapy enhances CXCR3

Radiotherapy (RT) not only damages tumors but also induces interferon (IFN) expression in tumors. IFNs mediate PD-L1 to exhaust CD8

Ambient Fine Particulate Matter and Cancer Current Evidence and Future Perspectives.

The high incidence of cancer has placed an enormous health and economic burden on countries around the world. In addition to evidence of epidemiological studies, conclusive evidence from animal experiments and mechanistic studies have also shown that morbidity and mortality of some cancers can be attributed to ambient fine particulate matter (PM

The actin bundling activity of ITPKA mainly accounts for its migration-promoting effect in lung cancer cells.

Expression of Ins(1,4,5)P3-kinase-A (ITPKA), the neuronal isoform of Ins(1,4,5)P3-kinases, is up-regulated in many tumor types. In particular, in lung cancer cells this up-regulation is associated with bad prognosis and it has been shown that a high level of ITPKA increases migration and invasion of lung cancer cell lines. However, since ITPKA exhibits actin bundling and Ins(1,4,5)P3-kinase activity, it was not clear which of these activities account for ITPKA-promoted migration and invasion of cancer cells. To address this issue, we inhibited endogenous actin bundling activity of ITPKA in lung cancer H1299 cells by overexpressing the dominant negative mutant ITPKAL34P. Analysis of actin dynamics in filopodia as well as wound-healing migration revealed that ITPKAL34P inhibited both processes. Moreover, the formation of invasive protrusions into collagen I was strongly blocked in cells overexpressing ITPKAL34P. Furthermore, we found that ATP stimulation slightly but significantly (by 13%) increased migration of cells overexpressing ITPKA while under basal conditions up-regulation of ITPKA had no effect. In accordance with these results, overexpression of a catalytic inactive ITPKA mutant did not affect migration, and the Ins(1,4,5)P3-kinase-inhibitor GNF362 reversed the stimulating effect of ITPKA overexpression on migration. In summary, we demonstrate that under basal conditions the actin bundling activity controls ITPKA-facilitated migration and invasion and in presence of ATP the Ins(1,4,5)P3-kinase activity slightly enhances this effect.