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Pretreatment glasgow prognostic score predicts survival among patients administered first-line atezolizumab plus carboplatin and etoposide for small cell lung cancer.

There are no established predictive biomarkers for the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with small-cell lung cancer (SCLC). Therefore, the current study aimed to investigate whether the Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) can predict the effectiveness of first-line atezolizumab plus carboplatin and etoposide therapy in patients with extensive-disease SCLC. We reviewed data from 84 patients who received first-line atezolizumab plus carboplatin and etoposide therapy for SCLC at nine Japanese institutions between August 2019 and May 2021. Further, we evaluated the prognostic value of the GPS, NLR, and BMI. The Kaplan-Meier and Cox proportional hazard models were used to examine differences in progression-free survival (PFS) and overall survival (OS). Moreover, the GPS, NLR, and BMI consisted of C-reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively. The response rate was 72.6% (95% confidence interval 63.0-82.1%). The median PFS and OS from the initiation of treatment were 5.4 (95% CI 4.9-5.9) months and 15.4 (95% CI 11.4-16.8) months, respectively. The GPS independently predicted the effectiveness of first-line atezolizumab plus carboplatin and etoposide treatment, as a favorable GPS (GPS 0-1) was correlated with significantly better PFS and OS rates compared to a poor GPS (GPS 2) (PFS 5.8 vs. 3.8 months, This is the first analysis to evaluate the association between the GPS, NLR, and BMI and the treatment effectiveness of survival among patients receiving first-line atezolizumab plus carboplatin and etoposide therapy for SCLC. Among patients receiving this treatment for SCLC, GPS was significantly associated with the PFS and OS rates, suggesting that GPS might be useful for evaluating therapeutic outcomes in these patients.

Whole-lesion histogram analysis of multiple diffusion metrics for differentiating lung cancer from inflammatory lesions.

Whole-lesion histogram analysis can provide comprehensive assessment of tissues by calculating additional quantitative metrics such as skewness and kurtosis however, few studies have evaluated its value in the differential diagnosis of lung lesions. To compare the diagnostic performance of conventional diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and diffusion kurtosis imaging (DKI) in differentiating lung cancer from focal inflammatory lesions, based on whole-lesion volume histogram analysis. Fifty-nine patients with solitary pulmonary lesions underwent multiple The ADC Whole-lesion histogram analysis of DWI, IVIM and DKI parameters is a promising approach for differentiating lung cancer from inflammatory lesions, and

Case Report Octreotide plus CVD chemotherapy for the treatment of multiple metastatic paragangliomas after double resection for functional bladder paraganglioma and urothelial papilloma.

Metastatic pheochromocytomas and paragangliomas are rare neuroendocrine tumors with a poor prognosis. Bladder paraganglioma concomitant with urothelial papilloma is even rarer. However, the rate of tumor response to cyclophosphamide-vincristine-dacarbazine (CVD) chemotherapy and 5-year overall survival for patients with metastatic PPGLs remained lower. We described, for the first time, a case of a patient with multiple metastatic bladder PGL who received octreotide LAR combined with CVD chemotherapy after urological surgery and then octreotide therapy was continued during follow-up. A 43-year-old male patient was admitted to the urology department for frequent micturition syncope concomitant with malignant hypertension. Preoperative findings were elevated levels of normetanephrine in 24-h urine or plasma. CT and MRI indicated diagnosis of suspicious bladder paraganglioma. Transurethral resection of bladder tumor combined with laparoscopic partial cystectomy was performed successfully after preoperative phenoxybenzamine with aggressive volume repletion for 7 days. The result of postoperative pathology was immediate-risk functional bladder paraganglioma (T2N0M0, Stage II) concomitant with urothelial papilloma, and the immunohistochemistry results of PPGL were positive for Ki-67 (15%), SDHB, CgA, and SSTR2. The patient achieved enhanced recovery with normal urination and no syncope after surgery. However, the results of Octreotide long-acting repeatable plus CVD chemotherapy after surgery could achieve stable disease in the case with multiple metastatic bladder PGLs, and the following octreotide therapy could maintain a state of stable disease during the period of 6-month follow-up.

Folate receptor-positive circulating tumor cell count, lymphocyte count and derived neutrophil-to- lymphocyte ratio for diagnosing lung cancer relapse.

The folate receptor-positive circulating tumor cell (FR

Case Report Endoscopic radiofrequency ablation with radial-EBUS and ROSE.

Single pulmonary nodules are a common issue in everyday clinical practice. Currently, there are navigation systems with radial-endobronchial ultrasound and electromagnetic navigation for obtaining biopsies. Moreover, rapid on-site evaluation can be used for a quick assessment. These small lesions, even when they do not have any clinically significant information with positron emission tomography, are important to investigate. Radiofrequency and microwave ablation have been evaluated as local treatment techniques. These techniques can be used as therapy for a patient population that cannot be operated on. Currently, one verified operating system is used for endoscopic radiofrequency ablation through the working channel of a bronchoscope. In our case, a new system was used to perform radiofrequency ablation with long-term follow-up.

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1PD-L1 therapy in non-small cell lung cancer patients.

Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokineschemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatmentmonitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p0.0413) and exosomal-PD-1 (p0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p0.0008 CD80, p0.0182 IDO, p0.0443 Arginase, p<0.0001 Nectin-2, p<0.0001 NT5E, p<0.0001 Siglec-7, p<0.0001 Siglec-9, p0.0335 CD28, p0.0092 GITR, p<0.0001 MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteinscytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p0.0156), E-Cadherin (p0.0312), ULBP1 (p0.0156), ULBP3 (p0.0391), MICA (p0.0391), MICB (p0.0469), Siglec7 (p0.0078) and significant upregulation of exosomal PD-1 (p0.0156) and IFN- γ (p0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p0.0070), and downregulation of ULBP1 (p0.0137) and Siglec-7 (p0.0037). Non-responding patients had significant-downregulation of ULBP3 (p0.0317) in patient without brain-metastasis and significant-upregulationdownregulation of PD-L1 and ULBP3 (p0.02620.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteinscytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.

The association of

Lung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between Using TaqMan probes we genotyped seven We found that rs1982809 within Our results indicate that

The diagnosis and treatment for a patient with cancer of unknown primary A case report.

Role of MicroRNA-214 in Dishevelled1-Modulated β-catenin Signalling in Non-Small Cell Lung Cancer Progression.

Analyzing bronchoalveolar fluid derived small extracellular vesicles using single-vesicle SERS for non-small cell lung cancer detection.

An emerging body of research by biologists and clinicians has demonstrated the clinical application of small extracellular vesicles (sEVs, also commonly referred to as exosomes) as biomarkers for cancer detections. sEVs isolated from various body fluids such as blood, saliva, urine, and cerebrospinal fluid have been used for biomarker discoveries with highly encouraging outcomes. Among the biomarkers discovered are those responsible for multiple cancer types and immune responses. These biomarkers are recapitulated from the tumor microenvironments. Yet, despite numerous discussions of sEVs in scientific literature, sEV-based biomarkers have so far played only a minor role for cancer diagnostics in the clinical setting, notably less so than other techniques such as imaging and biopsy. In this paper, we report the results of a pilot study (

Evaluation of a biosensor-based graphene oxide-DNA nanohybrid for lung cancer.

Lung cancer is nowadays among the most prevalent diseases worldwide and features the highest mortality rate among various cancers, indicating that early diagnosis of the disease is of paramount importance. Given that the conventional methods of cancer detection are expensive and time-consuming, special attention has been paid to the provision of less expensive and faster techniques. In recent years, the dramatic advances in nanotechnology and the development of various nanomaterials have led to activities in this context. Recent studies indicate that the graphene oxide (GO) nanomaterial has high potential in the design of nano biosensors for lung cancer detection owing to its unique properties. In the current article, a nano biosensor based on a DNA-GO nanohybrid is introduced to detect deletion mutations causing lung cancer. In this method, mutations were detected using a FAM-labeled DNA probe with fluorescence spectrometry. GO was synthesized according to Hummers method and examined and confirmed using Fourier Transform Infrared (FT-IR) Spectrometry and UV-vis spectrometry methods and Transmission Electron Microscopy (TEM) images.

Postoperative ctDNA detection predicts relapse but has limited effects in guiding adjuvant therapy in resectable stage I NSCLC.

To date, identifying resectable stage I non-small cell lung cancer (NSCLC) patients likely to benefit from adjuvant therapy (ADT) remains a major challenge. Previous studies suggest that circulating tumor DNA (ctDNA) is emerging as a promising biomarker for NSCLC. However, the effectiveness of ctDNA detection in guiding ADT for resectable stage I NSCLC patients remains elusive. This study aimed to elucidate the role of ctDNA detection in estimating prognosis and guiding ADT for resectable stage I NSCLC patients. Individual patient data and ctDNA results data were collected from 270 patients across four independent cohorts. The detection of ctDNA was conducted at 3 days to 1 month after surgery. The endpoint for this study was relapse-free survival (RFS) and overall survival (OS). Of the 270 resectable stage I NSCLC patients, 9 patients with ctDNA-positive and 261 patients with ctDNA-negative. We found that the risk of recurrence was significantly lower in the ctDNA-negative group compared to the ctDNA-positive group(HR0.11, p<0.0001). However, there is no difference in the risk of death between the two groups (p 0.39). In the ctDNA-positive group, there were no significant differences in RFS between patients who received ADT and patients who did not receive ADT (p 0.58). In the ctDNA-negative group, those who received ADT had a worse RFS in comparison with those who did not receive ADT (HR2.36, p 0.029). No difference in OS was seen between patients who received ADT and patients who did not receive ADT in both the ctDNA-positive group and the ctDNA-negative group (All p values>0.05). Furthermore, there was no difference in RFS and OS between patients who received chemotherapy-based or tyrosine kinase inhibitor-based ADT and patients who did not receive ADT in both the ctDNA-positive group and the ctDNA-negative group (All p values>0.05). Postoperative ctDNA detection can be a prognostic marker to predict recurrence but has limited effects in guiding ADT for resectable stage I NSCLC. Future prospective investigations are needed to verify these results.

Ground glass opacity resection extent assessment trial

With widely use of computed tomography (CT) screening, an increasing number of early-stage lung cancers appearing as ground glass opacity (GGO) have been detected. Therefore, attempts have been made to investigate the feasibility of segmentectomy instead of lobectomy for those patients with GGO. However, the two recently released phase III trials failed to distinguish between GGO-containing lesions from pure solid nodules in the inclusion criteria, and the surgical methods did not distinguish between minimally invasive surgery and open thoracotomy. In addition, total lesion size≤ 2cm was taken as the inclusion criterion, instead of the solid part size recommended in the eighth edition of Union for International Cancer ControlInternational Association for the Study of Lung CancerAmerican Joint Committee on Cancer (UICCIASLCAJCC) staging system. Hence, this present trial aims to figure out whether minimally invasive segmentectomy shows superiority in perioperative outcomes and non-inferiority in oncological prognosis over minimally invasive lobectomy among patients with GGO-containing clinical stage T1a-T1b lung invasive adenocarcinoma (IADC). Sample sizes are 1024 patients, who will be randomized into minimally invasive segmentectomy and lobectomy groups . Patients will be collected from 19 hospitals in China. Patients with peripheral mixed ground glass opacity (mGGO) with 0.5cm<total lesion size ≤ 3cm and 0.5cm<solid component size ≤ 2cm in lung window on CT scan are enrolled. The primary endpoint is 5-year recurrence-free survival (RFS). The secondary endpoints are 5-year overall survival (OS), perioperative outcomes and pulmonary function preservation. Kaplan-Meier curves are plotted to compare the survival outcomes between the two arms. Subgroup analyses are also performed to investigate the benefit of segmentectomy among different clinical variables. If the primary endpoint shows at least non-inferiority in 5-year RFS of segmentectomy to lobectomy, minimally invasive segmentectomy can be recommended as an alternative to minimally invasive lobectomy. If second endpoints show non-inferior 5-year OS along with better perioperative outcomes andor better pulmonary function preservation of segmentectomy compared with lobectomy after the primary endpoint has reached, minimally invasive segmentectomy may become a preferred procedure for patients with GGO-containing clinical stage T1a-T1b IADCs. Chinese Clinical Trial Registry. Trial registration number ChiCTR2000037065. httpswww.chictr.org.cn, identifier ChiCTR2000037065.

Emerging patterns and trends in global cancer burden attributable to metabolic factors, based on the Global Burden of Disease Study 2019.

The exponential growth of the cancer burden attributable to metabolic factors deserves global attention. We investigated the trends of cancer mortality attributable to metabolic factors in 204 countries and regions between 1990 and 2019. We extracted data from the Global Burden of Disease Study (GBD) 2019 and assessed the mortality, age-standardized death rate (ASDR), and population attributable fractions (PAFs) of cancers attributable to metabolic factors. Average annual percentage changes (AAPCs) were calculated to assess the changes in the ASDR. The cancer mortality burden was evaluated according to geographic location, SDI quintiles, age, sex, and changes over time. Cancer attributable to metabolic factors contributed 865,440 (95% UI, 447,970-140,590) deaths in 2019, a 167.45% increase over 1990. In the past 30 years, the increase in the number of deaths and ASDR in lower SDI regions have been significantly higher than in higher SDI regions (from high to low SDIs the changes in death numbers were 108.72%, 135.7%, 288.26%, 375.34%, and 288.26%, and the AAPCs were 0.42%, 0.58%, 1.51%, 2.36%, and 1.96%). Equatorial Guinea (AAPC 5.71%), Cabo Verde (AAPC4.54%), and Lesotho (AAPC4.42%) had the largest increase in ASDR. Large differences were observed in the ASDRs by sex across different SDIs, and the male-to-female ratios of ASDR were 1.42, 1.50, 1.32, 0.93, and 0.86 in 2019. The core population of death in higher SDI regions is the age group of 70 years and above, and the lower SDI regions are concentrated in the age group of 50-69 years. The proportion of premature deaths in lower SDI regions is significantly higher than that in higher SDI regions (from high to low SDIs 2%, 4%, 7%, 7%, and 9%). Gastrointestinal cancers were the core burden, accounting for 50.11% of cancer deaths attributable to metabolic factors, among which the top three cancers were tracheal, bronchus, and lung cancer, followed by colon and rectum cancer and breast cancer. The cancer mortality burden attributable to metabolic factors is shifting from higher SDI regions to lower SDI regions. Sex differences show regional heterogeneity, with men having a significantly higher burden than women in higher SDI regions but the opposite is observed in lower SDI regions. Lower SDI regions have a heavier premature death burden. Gastrointestinal cancers are the core of the burden of cancer attributable to metabolic factors.

Shear stress control of vascular leaks and atheromas through Tie2 activation by VE-PTP sequestration.

Vascular endothelial protein tyrosine phosphatase (VE-PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by examining the influence of arterial shear stress on VE-PTP, Tie2 activation, plasma leakage, and atherogenesis. We found that exposure to high average shear stress led to downstream polarization and endocytosis of VE-PTP accompanied by Tie2 activation at cell junctions. In aortic regions with disturbed flow, VE-PTP was not redistributed away from Tie2. Endothelial cells exposed to high shear stress had greater Tie2 activation and less macromolecular permeability than regions with disturbed flow. Deleting endothelial VE-PTP in VE-PTP

SEER-Based Survival Nomogram (1998-2015) Based on Stage, Lymph Node Dissection, Tumor Size and Degree of Differentiation, and Therapies for Prognosis of Primary Pulmonary Sarcoma.

Alectinib in a patient with ALK-positive non-small lung cancer unable to swallow capsules.

The treatment landscape of metastatic non-small-cell lung cancer (NSCLC) has changed dramatically in the last decade. Anaplastic lymphoma kinase (ALK) rearrangement has been a focus of interest since ALK inhibitors produced outstanding clinical results compared with chemotherapy with cytotoxic agents in patients with ALK-positive NSCLC. We present the case of a 56-year-old woman with metastatic ALK-positive NSCLC and an inability to swallow capsules or tablets. Unfortunately, all ALK inhibitors are capsule or tablet formulations. We, therefore, decided to administer alectinib orally by opening the capsules and suspending the contents in water. Clinical imaging performed 12 months after initiating alectinib therapy indicated a complete response (CR). After 54 months of follow-up, CR has been maintained, and oral alectinib therapy has continued with no recurrence of the swallowing disturbance. There are no current guidelines for oral targeted therapy in patients with swallowing disturbance, but alectinib administered orally by opening the capsules and suspending the contents in water can be a treatment option in patients with ALK-positive NSCLC and swallowing difficulty.

Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice.

Although gut microbiota has been linked to cancer, little is known about the crosstalk between gut- and intratumoral-microbiomes. The goal of this study was to determine whether gut Akkermansia muciniphila (Akk) is involved in the regulation of intratumoral microbiome and metabolic contexture, leading to an anticancer effect on lung cancer. We evaluated the effects of gut endogenous or gavaged exogenous Akk on the tumorigenesis using the Lewis lung cancer mouse model. Feces, blood, and tumor tissue samples were collected for 16S rDNA sequencing. We then conducted spatially resolved metabolomics profiling to discover cancer metabolites in situ directly and to characterize the overall Akk-regulated metabolic features, followed by the correlation analysis of intratumoral bacteria with metabolic network. Our results showed that both endogenous and exogenous gavaged Akk significantly inhibited tumorigenesis. Moreover, we detected increased Akk abundance in blood circulation or tumor tissue by 16S rDNA sequencing in the Akk gavaged mice, compared with the control mice. Of great interest, gavaged Akk may migrate into tumor tissue and influence the composition of intratumoral microbiome. Spatially resolved metabolomics analysis revealed that the gut-derived Akk was able to regulate tumor metabolic pathways, from metabolites to enzymes. Finally, our study identified a significant correlation between the gut Akk-regulated intratumoral bacteria and metabolic network. Together, gut-derived Akk may migrate into blood circulation, and subsequently colonize into lung cancer tissue, which contributes to the suppression of tumorigenesis by influencing tumoral symbiotic microbiome and reprogramming tumoral metabolism, although more studies are needed.

CircANKRD28 inhibits cisplatin resistance in non-small-cell lung cancer through the miR-221-3pSOCS3 axis.

Non-small-cell lung cancer (NSCLC) is a common cancer. Chemotherapeutic drug resistance limits the therapeutic effect of NSCLC and leads to poor prognosis. As a result, new specific targets may be better identified by studying the mechanism of drug resistance to cisplatin in NSCLC. In this study, we performed RT-qPCR and western blotting to detect mRNA and protein levels. The proliferation of cells was analyzed by CCK-8 and colony formation assay. Cell invasion was measured via transwell assay. Scratch assay was performed to measure cell migration in DDP-resistant NSCLC cells. Apoptosis of cells was examined using flow cytometry. We found that circANKRD28 was notably decreased in NSCLC. The results showed that circANKRD28 expression was not affected, and its half-life was more than 12 hours. Functional experiments revealed that circANKRD28 overexpression inhibited DDP resistance in NSCLC cells in vitro. Mechanistic findings demonstrated that circANKRD28 regulated tumor cell progression and DDP sensitivity through the miR-221-3pSOCS3 axis. This study revealed the regulatory effects and molecular mechanism of circANKRD28 on the development and cisplatin resistance in NSCLC, which may provide experimental basis and theoretical support to identify new targets for therapy of DDP resistance NSCLC.

Edible and cation-free kiwi fruit derived vesicles mediated EGFR-targeted siRNA delivery to inhibit multidrug resistant lung cancer.

Clinically, activated EGFR mutation associated chemo-drugs resistance has severely threaten NSCLC patients. Nanoparticle based small interfering RNA (siRNA) therapy representing another promising alternative by silencing specific gene while still suffered from charge associated toxicity, strong immunogenicity and poor targetability. Herein, we reported a novel EGFR-mutant NSCLC therapy relying on edible and cation-free kiwi-derived extracellular vesicles (KEVs), which showed sevenfold enhancement of safe dosage compared with widely used cationic liposomes and could be further loaded with Signal Transducer and Activator of Transcription 3 interfering RNA (siSTAT3). siSTAT3 loaded KEVs (STAT3KEVs) could be easily endowed with EGFR targeting ability (STAT3EKEVs) and fluorescence by surface modification with tailor-making aptamer through hydrophobic interaction. STAT3EKEVs with a controlled size of 186 nm displayed excellent stability, high specificity and good cytotoxicity towards EGFR over-expressing and mutant PC9-GR4-AZD1 cells. Intriguingly, the systemic administration of STAT3EKEVs significantly suppressed subcutaneous PC9-GR4-AZD1 tumor xenografts in nude mice by STAT3 mediated apoptosis. This safe and robust KEVs has emerged as the next generation of gene delivery platform for NSCLC therapy after multiple drug-resistance.

Pleurectomy and decortication are associated with better survival for bicavitary cytoreductive surgery for mesothelioma compared with extrapleural pneumonectomy.

Mesothelioma is a nearly uniformly fatal tumor. Multimodality therapy including cytoreductive surgery and chemotherapy is associated with long-term survival in some patients. Cytoreductive surgery for thoracic disease includes a lung-sparing operation called an extended pleurectomydecortication or a lung-sacrificing surgery called an extrapleural pneumonectomy. The benefit of cytoreductive surgery for bicavitary disease (chest and abdomen) is poorly understood. Our objective was to evaluate the long-term survivals for patients undergoing cytoreductive surgery for bicavitary disease and to determine whether any prognostic factors were associated with outcome. We reviewed our Institutional Review Board-approved, institutional, International Association for the Study of Lung Cancer Mesothelioma Staging Project database. Inclusion criteria were all patients who underwent cytoreductive surgery for bicavitary disease. Overall survival was calculated by Kaplan-Meier methodology. All International Association for the Study of Lung Cancer database elements were evaluated by univariable analysis. From February 2014 to August 2021, 440 patients with mesothelioma were evaluated. Fourteen patients (3%) underwent cytoreductive surgery of both chest and abdomen as a planned 2-stage operation. Most patients (1314 93%) underwent chest surgery before abdomen surgery. For the entire cohort, the median overall survival was 33.6 months with a 5-year survival of 20%. Extended pleurectomydecortication was associated with a better outcome compared with extrapleural pneumonectomy, with median overall survivals of 58.2 versus 13.5 months, respectively. For a highly selected group of patients with bicavitary mesothelioma, long-term survival can be achieved with an aggressive, staged surgical approach. The patients who undergo extended pleurectomydecortication with preservation of the lung appear to have more favorable outcomes compared with patients undergoing extrapleural pneumonectomy.

YAPTAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations.

The Hippo signalling pathway is dysregulated across a wide range of cancer types and, although driver mutations that directly affect the core Hippo components are rare, a handful is found within pleural mesothelioma (PM). PM is a deadly disease of the lining of the lung caused by asbestos exposure. By pooling the largest-scale clinical datasets publicly available, we here interrogate associations between the most prevalent driver mutations within PM and Hippo pathway disruption in patients, while assessing correlations with a variety of clinical markers. This analysis reveals a consistent worse outcome in patients exhibiting transcriptional markers of YAPTAZ activation, pointing to the potential of leveraging Hippo pathway transcriptional activation status as a metric by which patients may be meaningfully stratified. Preclinical models recapitulating disease are transformative in order to develop new therapeutic strategies. We here establish an isogenic cell-line model of PM, which represents the most frequently mutated genes and which faithfully recapitulates the molecular features of clinical PM. This preclinical model is developed to probe the molecular basis by which the Hippo pathway and key driver mutations affect cancer initiation and progression. Implementing this approach, we reveal the role of NF2 as a mechanosensory component of the Hippo pathway in mesothelial cells. Cellular NF2 loss upon physiological stiffnesses analogous to the tumour niche drive YAPTAZ-dependent anchorage-independent growth. Consequently, the development and characterisation of this cellular model provide a unique resource to obtain molecular insights into the disease and progress new drug discovery programs together with future stratification of PM patients.

Bronchoscopic manifestations and interventional treatment of pulmonary mucormycosis.

Restrictive Ventilatory Impairment as a Poor Prognostic Factor in Patients Who Undergo Surgical Resection for Metachronous Second Primary Lung Cancer.

To evaluate the prognostic impact of restrictive ventilatory impairment in patients who undergo pulmonary resection of metachronous second primary lung cancer. The clinical characteristics and surgical outcomes of 70 patients with metachronous second primary lung cancer were analyzed. The surgical procedures consisted of wedge resection in 40 patients, segmentectomy in 17, lobectomy in 12, and completion pneumonectomy in one. Patients who underwent ipsilateral pulmonary resection developed more perioperative complications (p 0.0339). Three-year and 5-year overall survival rates were 78.2% and 69.2%, respectively. In univariate analysis, sex, restrictive ventilatory impairment, and histology of second primary lung cancer were significantly poor prognostic factors (all p <0.05). Multivariate analysis identified restrictive ventilatory impairment to be an independent predictor of a poor prognosis (p 0.0193). In the 22 patients who died, the cause of death was lung cancer in 11 and other diseases, including pneumonia and respiratory failure, in 11. Death from another disease was significantly more common in patients with restrictive ventilatory impairment (p 0.0216). Restrictive ventilatory impairment was an independent predictor of a poor prognosis in patients with a second primary lung cancer. Restrictive ventilatory impairment as a result of repeated thoracic surgery may increase the likelihood of death from another disease.

A Study of laser dose in Photodynamic Therapy with Talaporfin Sodium for Malignant Central Airway Stenosis.

Photodynamic therapy (PDT) has been shown to be effective and safe in the treatment of malignant central airway stenosis. However, the laser dose for talaporfin PDT is unclear. We herein review cases where talaporfin PDT was used to treat malignant central airway stenosis. A total of 17 lesions were treated with talaporfin PDT at laser doses of 50-150 Jcm

Distinguishing multiple primary lung cancers from intrapulmonary metastasis using CT-based radiomics.

To develop CT-based radiomics models that can efficiently distinguish between multiple primary lung cancers (MPLCs) and intrapulmonary metastasis (IPMs). This retrospective study included 127 patients with 254 lung tumors pathologically proved as MPLCs or IPMs between May 2009 and January 2020. Radiomics features of lung tumors were extracted from baseline CT scans. Particularly, we incorporated tumor-focused, refined radiomics by calculating relative radiomics differences from paired tumors of individual patients. We applied the L1-norm regularization and analysis of variance to select informative radiomics features for constructing radiomics model (RM) and refined radiomics model (RRM). The performance was assessed by the area under the receiver operating characteristic curve (AUC-ROC). The two radiomics models were compared with the clinical-CT model (CCM, including clinical and CT semantic features). We incorporated both radiomics features to construct fusion model1 (FM1). We also, build fusion model2 (FM2) by combing both radiomics, clinical and CT semantic features. The performance of the FM1 and FM2 were further compared with that of the RRM. On the validation set, the RM achieved an AUC of 0.857. The RRM demonstrated improved performance (validation set AUC, 0.870) than the RM, and showed significant differences compared with the CCM (validation set AUC, 0.782). Fusion models further led prediction performance (validation set AUC, FM10.885 FM20.889). There were no significant differences among the performance of the FM1, the FM2 and the RRM. The CT-based radiomics models presented good performance on the discrimination between MPLCs and IPMs, demonstrating the potential for early diagnosis and treatment guidance for MPLCs and IPMs.

Mycobacterium indicus pranii therapy suppresses systemic dissemination of tumor cells in B16F10 murine model of melanoma.

Cancer associated morbidity is mostly attributed to the dissemination of tumor cells from their primary niche into the circulation known as metastasis. Mycobacterium indicus pranii (MIP) an approved immunotherapeutic agent against lung cancer (NSCLC) has shown potent anti-tumor activity in prior studies. While evaluating anti-tumor activity of MIP in mouse model, MIP treated animals typically exhibited less metastatic lesions in their pulmonary compartment. To study the role of MIP in metastasis closely, B16F10 melanoma cells were implanted subcutaneously in the mice, and the dissemination of tumor cells from the solid tumor was evaluated over a period of time. When B16F10 melanoma cells were treated with MIP in vitro, downregulation of epithelial mesenchymal transition markers was observed in these cells, which in turn suppressed the invasion, migration and adhesion of tumor cells. Notably, MIP therapy was found to be effectively reducing the metastatic burden in murine model of melanoma. Molecular characterization of MIP treated tumor cells substantiated that MIP upregulates the PPARγ expression within the tumor cells, which attenuates the NFκBp65 levels within the nucleus, resulting in the suppression of Mmp9 expression in tumor cells. Besides that, MIP also downregulated the surface expression of chemokine receptor CXCR4 in murine melanoma cells, where chromatin immunoprecipitation confirmed the impeded recruitment of p50 and c-Rel factors to the Cxcr4 promoter, resulting in its downregulation transcriptionally. Taken together, MIP suppressed the dissemination of tumor cells in vivo, by regulating the expression of MMP9 and CXCR4 on these cells.

Dihydroartemisinin elicits immunogenic death through ferroptosis-triggered ER stress and DNA damage for lung cancer immunotherapy.

The immunosuppressive microenvironment of lung cancer serves as an important endogenous contributor to treatment failure. The present study aimed to demonstrate the promotive effect of DHA on immunogenic cell death (ICD) in lung cancer as well as the mechanism. The lewis lung cancer cells (LLC), A549 cells and LLC-bearing mice were applied as the lung cancer model. The apoptosis, ferroptosis assay, western blotting, immunofluorescent staining, qPCR, comet assay, flow cytometry, confocal microscopy, transmission electron microscopy and immunohistochemistry were conducted to analyze the functions and the underlying mechanism. An increased apoptosis rate and immunogenicity were detected in DHA-treated LLC and tumor grafts. Further findings showed DHA caused lipid peroxide (LPO) accumulation, thereby initiating ferroptosis. DHA stimulated cellular endoplasmic reticulum (ER) stress and DNA damage simultaneously. However, the ER stress and DNA damage induced by DHA could be abolished by ferroptosis inhibitors, whose immunogenicity enhancement was synchronously attenuated. In contrast, the addition of exogenous iron ions further improved the immunogenicity induced by DHA accompanied by enhanced ER stress and DNA damage. The enhanced immunogenicity could be abated by ER stress and DNA damage inhibitors as well. Finally, DHA activated immunocytes and exhibited excellent anti-cancer efficacy in LLC-bearing mice. In summary, the current study demonstrates that DHA triggers ferroptosis, facilitating the ICD of lung cancer thereupon. This work reveals for the first time the effect and underlying mechanism by which DHA induces ICD of cancer cells, providing novel insights into the regulation of the immune microenvironment for cancer immunotherapy by Chinese medicine phytopharmaceuticals.

Frequently mutated genes in predicting the relapse of stage I lung adenocarcinoma.

Approximately, 45-65% stage I non-small cell lung cancer (NSCLC) patients with surgical resection relapse within 5 years. Therefore, it is urgent to identify the predictors involved in the relapse of stage I NSCLC. Targeted sequencing was used to examine the mutation of tumor tissues and matched adjacent normal tissues from 35 patients with stage I lung adenocarcinoma (LUAD). Then, tissue microarrays containing tumor tissues from 149 stage I LUAD patients were used to assess protein expression of frequently mutated genes by immunohistochemistry. COX regression model was used to evaluate the impacts of frequently mutated genes and their protein expression on relapse-free survival (RFS) in stage I LUAD. Three hundred and twenty-nine non-synonymous somatic variants were identified in 161 genes among these 35 patients. EGFR, TP53, LRP1B, RBM10, KRAS, NTRK3, RB1, ALK, APC, FAT2, KEAP1, MED12 and MLL3 were described as frequently mutated genes with prevalence more than 10%. Patients harboring KRAS mutation had more relapse in 1 year after surgical resection. For the expression of these frequently mutated genes in 149 stage I patients, multivariate Cox regression analyses showed that the expression of RBM10 was positively associated with RFS in all patients (HR 0.40, 95% CI 0.15-1.0, p 0.052), and the expression of APC was negative associated with RFS in patients with EGFR mutations (HR 3.10, 95% CI 1.54-6.26, p 0.002). Stage I LUAD patients with KRAS mutation or low RBM10 expression are inclined to receive more positive intervention rather than just disease surveillance.

The preoperative assessment of thoracic wall adhesions using four-dimensional computed tomography.

Pleural adhesions are challenging during lung cancer surgery and may be associated with a long surgery time and excessive blood loss due to pleural adhesiolysis. We used preoperative four-dimensional computed tomography to quantitatively assess parietal pleural adhesions and determine its diagnostic accuracy. A total of 216 patients with lung cancer underwent four-dimensional computed tomography during the study period. Pleural adhesions were subsequently confirmed by surgery in 85 of these patients, whereas 126 patients had no adhesions. The movements of the tumor or target vessels (α) was tracked. Receiver-operating characteristic curve analysis was used to identify the relationship between adhesions and (α). The movement of (α) was smaller in patients with adhesions than in those without adhesions. The greater the adhesion, the shorter the movement distance (p < 0.001). Receiver-operating characteristic curve analysis demonstrated an area under the curve for the moving (α) point at 0.71 (95% confidence interval 0.62-0.80) in the upper lung field and at 0.75 (95% confidence interval 0.64-0.85) in the lower field. To identify adhesions, a cut off of 11.3 mm (sensitivity 43.6%, specificity 93.2%) in the upper lung field and a cut off of 41.2 mm (sensitivity 71.4%, specificity 66.0%) in the lower lung field were established. Four-dimensional computed tomography is a novel and helpful modality for predicting the presence of parietal pleural adhesions. To obtain robust evidence, further accumulation of cases and re-examination of the analysis methods are needed.

Establishing a simple perfusion cell culture system for light-activated liposomes.

The off-target effects of light-activated or targeted liposomes are difficult to distinguish in traditional well plate experiments. Additionally, the absence of fluid flow in traditional cell models can lead to overestimation of nanoparticle uptake. In this paper, we established a perfusion cell culture platform to study light-activated liposomes and determined the effect of flow on the liposomal cell uptake. The optimal cell culturing parameters for the A549 cells under flow conditions were determined by monitoring cell viability. To determine optimal liposome treatment times, particle uptake was measured with flow cytometry. The suitability of commercial QuasiVivo flow-chambers for near-infrared light activation was assessed with a calcein release study. The chamber material did not hinder the light activation and subsequent calcein release from the liposomes. Furthermore, our results show that the standard cell culturing techniques are not directly translatable to flow cultures. For non-coated liposomes, the uptake was hindered by flow. Interestingly, hyaluronic acid coating diminished the uptake differences between the flow and static conditions. The study demonstrates that flow affects the liposomal uptake by lung cancer cell line A549. The flow also complicates the cell attachment of A549 cells. Moreover, we show that the QuasiVivo platform is suitable for light-activation studies.

Durable responses to alectinib in murine models of EML4-ALK lung cancer requires adaptive immunity.

Lung cancers bearing oncogenic EML4-ALK fusions respond to targeted tyrosine kinase inhibitors (TKIs e.g., alectinib), with variation in the degree of shrinkage and duration of treatment (DOT). However, factors that control this response are not well understood. While the contribution of the immune system in mediating the response to immunotherapy has been extensively investigated, less is known regarding the contribution of immunity to TKI therapeutic responses. We previously demonstrated a positive association of a TKI-induced interferon gamma (IFNγ) transcriptional response with DOT in EGFR-mutant lung cancers. Herein, we used three murine models of EML4-ALK lung cancer to test the role for host immunity in the alectinib therapeutic response. The cell lines (EA1, EA2, EA3) were propagated orthotopically in the lungs of immunocompetent and immunodeficient mice and treated with alectinib. Tumor volumes were serially measured by μCT and immune cell content was measured by flow cytometry and multispectral immunofluorescence. Transcriptional responses to alectinib were assessed by RNAseq and secreted chemokines were measured by ELISA. All cell lines were similarly sensitive to alectinib in vitro and as orthotopic tumors in immunocompetent mice, exhibited durable shrinkage. However, in immunodeficient mice, all tumor models rapidly progressed on TKI therapy. In immunocompetent mice, EA2 tumors exhibited a complete response, whereas EA1 and EA3 tumors retained residual disease that rapidly progressed upon termination of TKI treatment. Prior to treatment, EA2 tumors had greater numbers of CD8 T cells and fewer neutrophils compared to EA1 tumors. Also, RNAseq of cancer cells recovered from untreated tumors revealed elevated levels of CXCL9 and 10 in EA2 tumors, and higher levels of CXCL1 and 2 in EA1 tumors. Analysis of pre-treatment patient biopsies from ALK tumors revealed an association of neutrophil content with shorter time to progression. Combined, these data support a role for adaptive immunity in durability of TKI responses and demonstrate that the immune cell composition of the tumor microenvironment is predictive of response to alectinib therapy.

Ang-(1-7)MasR axis promotes functional recovery after spinal cord injury by regulating microgliamacrophage polarization.

Inflammatory response is an essential part of secondary injury after spinal cord injury (SCI). During this period, the injury may be exacerbated through the release of a large number of inflammatory factors and the polarization of infiltrating macrophages and microglia towards M1. Ang-(1-7), mainly generated by Ang II via angiotensin-converting enzyme 2 (ACE2), can specifically bind to the G protein-coupled receptor Mas (MasR) and plays an important role in regulating inflammation and alleviating oxidative stress. We aimed to investigate whether activating the Ang-(1-7)MasR axis in rats after SCI can regulate local neuroinflammation to achieve functional recovery and obtain its potential mechanism. MasR expression of bone marrow-derived macrophages was determined by Western blot. Immunofluorescence, Western blot, Flow cytometry, and RT-qPCR were applied to evaluate the polarization of Ang-(1-7) on macrophages and the regulation of inflammatory cytokines. Previous evaluation of the spinal cord and bladder after SCI was conducted by hematoxylin-eosin staining, Basso, Beattie, and Bresnahan (BBB) score, inclined plate test, electrophysiology, and catwalk were used to evaluate the functional recovery of rats. MasR expression increased in macrophages under inflammatory conditions and further elevated after Ang-(1-7) treatment. Both in vivo and in vitro results confirmed that Ang-(1-7) could regulate the expression of inflammatory cytokines by down-regulating proinflammatory cytokines and up-regulating anti-inflammatory cytokines, and bias the polarization direction of microgliamacrophages to M2 phenotypic. After SCI, Ang-(1-7) administration in situ led to better histological and functional recovery in rats, and this recovery at least partly involved the TLR4NF-κB signaling pathway. As shown in our data, activating Ang-(1-7)MasR axis can effectively improve the inflammatory microenvironment after spinal cord injury, promote the polarization of microgliamacrophages towards the M2 phenotype, and finally support the recovery of motor function. Therefore, we suggest using Ang-(1-7) as a feasible treatment strategy for spinal cord injury to minimize the negative consequences of the inflammatory microenvironment after spinal cord injury.

Epidemiology and comorbidities in idiopathic pulmonary fibrosis a nationwide cohort study.

Idiopathic pulmonary fibrosis (IPF) is frequently accompanied by comorbidities, with the management of these comorbidities crucial for clinical outcomes. This study investigated the prevalence, incidence, changes over time, and clinical impact of comorbidities in IPF patients, based on nationwide claims data in South Korea. This retrospective cohort study utilised nationwide health claim data in South Korea between 2011 and 2019. Patients with IPF were defined as those with ICD-10 code J84.1 and Rare Intractable Disease code V236 who made at least one claim per year. Patients were classified by sex, age, pirfenidone use and burden of comorbidities, and differences among groups were determined. The yearly prevalence rate of IPF increased from 7.50 to 23.20 per 100,000 people, and the yearly incidence rate increased from 3.56 to 7.91 per 100,000 person-years over time. The most common respiratory comorbidity was chronic obstructive pulmonary disease (37.34%), followed by lung cancer (3.34%), whereas the most common non-respiratory comorbidities were gastro-oesophageal reflux disease (70.83%), dyslipidaemia (62.93%) and hypertension (59.04%). The proportion of some comorbidities differed by sex, age and use of pirfenidone. The proportion of lung cancer was higher in patients treated with pirfenidone, whereas the proportion of anxiety and depression were lower in patients not treated with pirfenidone. Charlson comorbidity index ≥ 4 was associated with increases in hospitalisations and total medical costs. The yearly prevalence and incidence of IPF and comorbidities in Korea increased over time. These comorbidities affected the use of pirfenidone and medical resources.

Radiomic phenotyping of the lung parenchyma in a lung cancer screening cohort.

High-throughput extraction of radiomic features from low-dose CT scans can characterize the heterogeneity of the lung parenchyma and potentially aid in identifying subpopulations that may have higher risk of lung diseases, such as COPD, and lung cancer due to inflammation or obstruction of the airways. We aim to determine the feasibility of a lung radiomics phenotyping approach in a lung cancer screening cohort, while quantifying the effect of different CT reconstruction algorithms on phenotype robustness. We identified low-dose CT scans (n 308) acquired with Siemens Healthineers scanners from patients who completed low-dose CT within our lung cancer screening program between 2015 and 2018 and had two different sets of image reconstructions kernel available (i.e., medium (I30f.), sharp (I50f.)) for the same acquisition. Following segmentation of the lung field, a total of 26 radiomic features were extracted from the entire 3D lung-field using a previously validated fully-automated lattice-based software pipeline, adapted for low-dose CT scans. The lattice in-house software was used to extract features including gray-level histogram, co-occurrence, and run-length descriptors. The lattice approach uses non-overlapping windows for traversing along pixels of images and calculates different features. Each feature was averaged for each scan within a range of lattice window sizes (W) of 4, 8 and 20 mm. The extracted imaging features from both datasets were harmonized to correct for differences in image acquisition parameters. Subsequently, unsupervised hierarchical clustering was applied on the extracted features to identify distinct phenotypic patterns of the lung parenchyma, where consensus clustering was used to identify the optimal number of clusters (K 2). Differences between phenotypes for demographic and clinical covariates including sex, age, BMI, pack-years of smoking, Lung-RADS and cancer diagnosis were assessed for each phenotype cluster, and then compared across clusters for the two different CT reconstruction algorithms using the cluster entanglement metric, where a lower entanglement coefficient corresponds to good cluster alignment. Furthermore, an independent set of low-dose CT scans (n 88) from patients with available pulmonary function data on lung obstruction were analyzed using the identified optimal clusters to assess associations to lung obstruction and validate the lung phenotyping paradigm. Heatmaps generated by radiomic features identified two distinct lung parenchymal phenotype patterns across different feature extraction window sizes, for both reconstruction algorithms (P < 0.05 with K 2). Associations of radiomic-based clusters with clinical covariates showed significant differences for BMI and pack-years of smoking (P < 0.05) for both reconstruction kernels. Radiomic phenotype patterns were more similar across the two reconstructed kernels, when smaller window sizes (W 4 and 8 mm) were used for radiomic feature extraction, as deemed by their entanglement coefficient. Validation of clustering approaches using cluster mapping for the independent sample with lung obstruction also showed two statistically significant phenotypes (P < 0.05) with significant difference for BMI and smoking pack-years. Radiomic analysis can be used to characterize lung parenchymal phenotypes from low-dose CT scans, which appear reproducible for different reconstruction kernels. Further work should seek to evaluate the effect of additional CT acquisition parameters and validate these phenotypes in characterizing lung cancer screening populations, to potentially better stratify disease patterns and cancer risk.

Purinergic signaling during Mareks disease in chickens.

Purinergic receptors (PRs) have been reported as potential therapeutic targets for many viral infections including herpesviruses, which urges the investigation into their role in Mareks disease (MD), a herpesvirus induced cancer in chickens that is an important pathogen for the poultry industry. MD is caused by MD virus (MDV) that has a similar viral life cycle as human varicella zoster virus in that it is shed from infected epithelial skin cells and enters the host through the respiratory route. In this report, PR responses during natural MDV infection and disease progression was examined in MD-resistant white Leghorns (WL) and MD-susceptible Pure Columbian (PC) chickens during natural infection. Whole lung lavage cells (WLLC) and liver tissue samples were collected from chickens infected but showing no clinical signs of MD (Infected) or presenting with clinical disease (Diseased). RNA was extracted followed by RT-qPCR analysis with gene specific primers against members of the P1, P2X, and P2Y PR families. Differential expression (p < 0.05) was observed in breed and disease conditions. Some PRs showed tissue specific expression (P1A1, P2X1, and P2X6 in WLLC) whereas others responded to MDV infection only in MD-susceptible (PC) chickens (P1A2A, P2X1, P2X5, P2X7). P2Y PRs had differential expression in both chicken lines in response to MDV infection and MD progression. This study is the first to our knowledge to examine PR responses during MDV infection and disease progression. These results suggest PR signaling may an important area of research for MDV replication and MD.

All Together Now Standardization of Nomenclature for Neuroendocrine Neoplasms across Multiple Organs.

Neuroendocrine neoplasms (NENs) span virtually all organ systems and exhibit a broad spectrum of behavior, from indolent to highly aggressive. Historically, nomenclature and grading practices have varied widely across, and even within, organ systems. However, certain core features are recapitulated across anatomic sites, including characteristic morphology and the crucial role of proliferative activity in prognostication. A recent emphasis on unifying themes has driven an increasingly standardized approach to NEN classification, as delineated in the World Health Organizations Classification of Tumours series. Here, we review recent developments in NEN classification, with a focus on NENs of the pancreas and lungs.

Screening Chest CT Prior to Allogenic Hematopoietic Stem Cell Transplantation.

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplant (alloHSCT) period. While Chest X-ray (CXR) is customarily used for screening, we have utilized chest computed tomography (CT). To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplant, we conducted a retrospective analysis utilizing real-world data collected at our center for adult patients who were evaluated for alloHSCT from January 2013 through December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia in 49% of patients, followed by myelodysplastic syndrome in 23%, lymphoma in 11%, and acute lymphocytic leukemia in 10%. Abnormal screening chest CT was found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only about half of the patients (48%) with an abnormal chest CT. Among 199 patients with abnormal chest CT, 98 patients (49%) underwent further assessment andor intervention before transplant. The most common work up was pulmonary consultation in 32%, infectious diseases consultation in 24%. Lung biopsy was obtained in 20% and antimicrobial therapy was initiated after confirming an infection diagnosis in 20% of patients. Patients with abnormal chest CT demonstrated worse overall survival (P 0.032), non-relapse mortality (P0.015), and pulmonary related death (P < 0.001) compared to those who had normal chest CT. Our study suggests that pre-transplant screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows appropriate interventions before alloHSCT to prevent potentially serious post-transplant complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplant may be associated with overall worse prognosis.

Empagliflozin mediated miR-128-3p upregulation promotes differentiation of hypoxic cancer stem-like cells in breast cancer.

The hsa-miR-128-3p expression is downregulated in advanced breast cancer patients. Empagliflozin (EMPA) is an anti-diabetic drug with anticancer potential. The present study investigated the effect of EMPA on cancer cell differentiation by acting as a miR-128-3p mimicking drug in breast cancer. Our results first demonstrate SP1 and PKM2 as the downstream effectors of hsa-miR-128-3p. Further, transfection with siPKM2, miR-128-3p mimics, and inhibitors was performed to assess their involvement in cancer stemness using flow cytometry. Further, EMPA as miR-128-3p mimicking drug was screened and explored on cancer cell differentiation. Then, we treated the 4T1-Red-FLuc allograft breast tumor with EMPA to assess its inhibitory potential toward tumor growth using IVIS® Spectrum. Immunohistochemistry was performed to evaluate cancer cell differentiation and cell proliferation. We found that hsa-miR-128-3p is the upstream regulator of SP1 and PKM2 in hypoxic breast cancer cells. Overexpression of miR-128-3p with mimics downregulate SP1 and PKM2, whereas miR-128-3p inhibitor shows an opposite effect. The enhanced expression of miR-128-3p and PKM2 knockdown diminishes hypoxia-induced CD44 expression and enhance CD44 EMPA could be a promising drug in combination with other chemotherapeutic drugs in advanced breast cancer.

Risk factors for recurrence of stage I epidermal growth factor receptor mutated lung adenocarcinoma.

We aimed to clarify the risk factors for postoperative recurrence in patients with epidermal growth factor receptor (EGFR)-mutated stage I lung adenocarcinoma, using EGFR wild-type adenocarcinoma as a comparator, to select optimal candidates for adjuvant therapy with EGFR tyrosine kinase inhibitor (TKI). Data of patients with pathological stage I EGFR-mutated (n713) and wild-type (n673) adenocarcinoma who did not receive adjuvant therapy were retrospectively analyzed. The cumulative incidence of recurrence (CIR) was estimated using Grays method, and multivariable Fine-Gray competing risk models identified independent risk factors associated with recurrence. The CIR did not differ significantly between patients with EGFR-mutated and wild-type adenocarcinoma (P0.32). Multivariable analysis revealed that greater invasive tumor size (cm) (hazard ratio HR, 1.539 95% confidential interval CI, 1.077-2.201), lymphovascular invasion (HR, 5.180 95% CI, 2.208-12.15), pleural invasion (HR, 3.388 95% CI, 1.524-7.533), and high-grade histological subtype (HR, 4.295 95% CI, 1.539-11.99) were independent risk factors for recurrence in patients with EGFR-mutated adenocarcinoma. The 5-year CIR was significantly higher in patients with these factors (tumor size>2 cm, 15.9% lymphovascular invasion, 26.9% pleural invasion, 39.3% and high-grade subtype, 44.4%) than in those without (4.4%, 2.2%, 3.9%, and 5.0%, respectively) (P<0.001). In patients with EGFR wild-type adenocarcinoma, independent risk factors for recurrence were invasive tumor size, lymphovascular invasion, and pleural invasion, but not histological subtypes. Even in patients with EGFR-mutated stage I lung adenocarcinoma, recurrence risk is stratified. Adjuvant therapy may be considered if they have high-risk factors for recurrence.

The mechanism of rh-endostatin-induced cardiotoxicity and its protection by dihydromyricetinin vivoin vitro, C57BL6 mice, AC16 and hiPSC-CMs.

Recombinant human endostatin (rh-endostatin) is an anti-angiogenic drug, which is used for the treatment of advanced non-small-cell lung cancer (NSCLC) and other cancers. However, its side effects, especially the cardiotoxicity with unclear mechanisms limit its wide application in clinical practice. In this study, human cardiomyocyte cell line AC16 and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with different doses of rh-endostatin were used to analyze its effect on cardiac cell toxicity. The results revealed that rh-endostatin dose-dependently enhanced cardiomyocyte apoptosis through Apaf-1 apoptotic factor and apoptosis-related proteins such as p53. rh-endostatin-induced changes of mitochondrial function and mitophagy were involved in rh-endostatin-mediated cardiac cell toxicity. Rh-endostatin-induced cardiotoxicity was further verified in vivo in mice. Interestingly, Rh-endostatin-induced cardiotoxicity was inhibited by dihydromyricetin (DHM) both in cultured cells in vitro and in mouse hearts in vivo. The study provides new inside into rh-endostatin-induced cardiotoxicity and identified a novel potential medication DHM to overcome the serious adverse effect.

Distribution and Detectability of EGFR Exon 20 Insertion Variants in Non-small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent 5%-10% of EGFR mutations in non-small cell lung cancer (NSCLC). Identifying patients with EGFR ex20ins is challenging due to the limited coverage of polymerase chain reaction (PCR) assays and the relatively recent use of next-generation sequencing (NGS). This study analyzes the spectrum of EGFR ex20ins variants in a large patient population from a global clinical trial and several real-world cohorts and the ability of PCR kits to identify these alterations. We conducted this retrospective analysis in patients with NSCLC who underwent NGSsequencing testing and had a known EGFR ex20ins mutation. Patients were gathered from a clinical trial (NCT02716116), a chart review study in Germany, and the LC-SCRUM-Japan, GENIE, and US COTA databases. Proportions of patients with ex20ins variants that could have been detected by 6 commercially available and widely used PCR kits were calculated in each dataset. Overall, 636 patients with NSCLC harboring EGFR ex20ins mutations were included in this analysis, and 104 unique EGFR ex20ins variants were identified across the data sources. The proportion of patients whose ex20ins could have been detected by any PCR test alone ranged from 11.8% to 58.9% across the data sources. Our findings suggest that the PCR tests assessed would have missed >40% of patients with NSCLC harboring EGFR ex20ins mutations. NGS-based genetic testing is preferable over standard PCR assays and can substantially improve the identification of the diverse profile of EGFR ex20ins variants in NSCLC.

Demystifying the results of RTOG 0617 Identification of dose sensitive cardiac sub-regions associated with overall survival.

The RTOG 0617 trial presented worse survival for patients with lung cancer treated in the high-dose (74Gy) arm. In multivariable models, radiation level and whole heart volumetric dose parameters were associated with survival. In this work, we consider heart sub-regions to explain the observed survival difference between radiation levels. Voxel-based analysis identified anatomical regions where dose was associated with survival. Bootstrapping clinical and dosimetric variables into an elastic-net model selected variables associated with survival. Multivariable Cox regression survival models assessed significance of dose to the heart sub-region, compared to whole heart v5 and v30. Finally, trial outcome was assessed following propensity score matching of patients on lung dose, heart sub-region dose, and tumour volume. 458 patients were eligible for voxel-based analysis. A significance region (p<0.001) was identified in the base of the heart. Bootstrapping selected mean lung dose, radiation level, log tumour volume, and heart region dose. Multivariable Cox model showed dose to the heart region (p0.02), and tumour volume (p0.03) significantly associated with survival, radiation level was not significant (p0.07). Models showed whole heart v5 and v30 were not associated with survival, with radiation level significant (p<0.05). In the matched cohort, no significant survival difference was seen between radiation levels. Dose to the base of the heart is associated with overall survival, partly removing the radiation level effect, and explaining that worse survival in the high dose arm is due in part to heart subregion dose. By defining a heart avoidance region, future dose escalation trials may be feasible.

Efficacy, Safety, and Health-Related Quality of Life with Camrelizumab Plus Pemetrexed and Carboplatin as First-Line treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer with Brain Metastases (CAP-BRAIN) A Multicentre, Open-Label, Single-Arm, Phase 2 Study.

Systemic treatment options for non-small-cell lung cancer (NSCLC) with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in advanced non-squamous NSCLC patients with BMs. This was a multicentre, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients were treatment-naïve metastatic non-squamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy, and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mgm Forty-five patients were enrolled and treated (full analysis set FAS), with 40 patients having at least one post-baseline tumour assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% CI 9.2-17.3). The confirmed iORR was 52.5% (95% CI 36.1-68.5) in EAS and 46.7% (95% CI 31.7-62.1) in FAS. The extracranial ORR was 47.5% (95% CI 31.5-63.9) and 42.2% (95% CI 27.7-57.8), respectively. Median intracranial progression-free survival (iPFS) was 7.6 months (95% CI 4.6-not reached NR), median overall PFS was 7.4 months (95% CI 4.4-NR) and median overall survival was 21.0 months (95% CI 15.9-NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decreased (six 13.3%) and anemia (four 8.9%). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy-Lung scores (P 0.025, P < 0.001). Camrelizumab plus pemetrexed and carboplatin showed activity with manageable toxicity, and improved cognitive function and quality of life for non-squamous NSCLC patients with BMs in the first-line setting.

Effect of bariatric surgery on the incidence of heart failure A propensity score matched nationwide cohort study.

Bariatric surgery results in significant weight loss and a reduction in the incidence of cardiovascular disease in patients with obesity however, relatively little research considers its effect on the incidence of heart failure (HF). We aimed to determine whether bariatric surgery reduces the incidence of HF in patients with obesity, compared to non-surgical management. A propensity-score matched, retrospective cohort study using patients records from the nationwide Clinical Practice Research Database (CPRD) was conducted. 3052 patients who received bariatric surgery were matched with 3052 patients who did not, according to propensity to receive bariatric surgery, determined through a logistic regression model. Patients were eligible if >18 years old, BMI > 35 kgm Patients who received bariatric surgery had a significantly lower incidence of new HF (hazard ratio 0.45, 95% confidence interval 0.28-0.73, p 0.0011) and all-cause mortality (hazard ratio 0.56, 95% confidence interval 0.38-0.83, p 0.0036). This study provides evidence of lower rates of HF and all-cause mortality in patients who undergo bariatric surgery, compared to propensity-score matched controls. Future studies to understand the mechanism(s) involved in this reduction and explore the lifetime benefits in high-risk cohorts are paramount.

Integration of artificial intelligence in lung cancer Rise of the machine.

The goal of oncology is to provide the longest possible survival outcomes with the therapeutics that are currently available without sacrificing patients quality of life. In lung cancer, several data points over a patients diagnostic and treatment course are relevant to optimizing outcomes in the form of precision medicine, and artificial intelligence (AI) provides the opportunity to use available data from molecular information to radiomics, in combination with patient and tumor characteristics, to help clinicians provide individualized care. In doing so, AI can help create models to identify cancer early in diagnosis and deliver tailored therapy on the basis of available information, both at the time of diagnosis and in real time as they are undergoing treatment. The purpose of this review is to summarize the current literature in AI specific to lung cancer and how it applies to the multidisciplinary team taking care of these complex patients.

Targeting HER2 alterations in non-small cell lung cancer Therapeutic breakthrough and challenges.

In non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) alterations, chemotherapy remains the standard treatment over a decade, due to the minor efficacy of traditional pan-HER tyrosine kinase inhibitors (TKIs) and HER2-targeted monoclonal antibodies. In recent years, novel selective HER2 TKIs have been developed for pretreated HER2-mutant patients. In particular, pyrotinib has shown moderate efficacy as well as a manageable safety profile, and it is now being further evaluated as monotherapy or combined with other existing therapies by contrast, while poziotinib has demonstrated promising preliminary results, the high rates of toxicity has hampered subsequent studies. Most notably, trastuzumab deruxtecan (T-DXd, DS-8201) has led to a significant breakthrough, with the most encouraging efficacy data (response rate of 55 %, median progression-free survival of 8.2 months and median overall survival of 17.8 months) among all the anti-HER2 agents. This is certainly remarkable progress, and T-DXd is undoubtedly the key drug for the treatment of this disease. Future developments regarding T-DXd are favourable, including shifting from monotherapy to combination strategies, improving structural design to optimise antitumour activity and minimise toxicity, identifying the potential resistance mechanisms and developing therapeutic strategies to overcome them. Several other challenges need to be addressed, such as the intracranial activity of anti-HER2 agents and the optimal sequencing of therapies. Here, we summarise recent therapeutic advances in targeting HER2 alterations in NSCLC and highlight the future perspectives of these patient populations.

Is pulmonary fibrosis a precancerous disease

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease (ILD) characterized by a histopathological pattern of usual interstitial pneumonia with progressive fibrosis of the pulmonary epithelium. The incidence of IPF is increasing worldwide as the population ages and with that, there is a concomitant increase in the incidence of lung cancer in these patients who are living longer with the disease. The average length of time for lung cancer development following an IPF diagnosis is 3 years. Given the high prevalence of lung cancer among patients with pulmonary fibrosis, we wondered if pulmonary fibrosis could be classified as a precancerous disease. We provided support from the Pubmed published literature to investigate whether pulmonary fibrosis meets the five criteria of the National Cancer Institutes definition of premalignant conditions for classification as a precancerous disease. We found out pulmonary fibrosis meets the five criteria of the National Cancer Institutes definition of a premalignant condition and can be considered a precancerous disease. To identify early lung cancer in patients with pulmonary fibrosis, regular screening with HRCT and PET-CT scans is highly recommended for these patients.

SOX2-associated signaling pathways regulate biological phenotypes of cancers.

SOX2 is a transcription factor involved in multiple stages of embryonic development. In related reports, SOX2 was found to be abnormally expressed in tumor tissues and correlated with clinical features such as TNM staging, tumor grade, and prognosis in patients with various cancer types. In most cancer types, SOX2 is a tumor-promoting factor that regulates tumor progression and metastasis primarily by maintaining the stemness of cancer cells. In addition, SOX2 also regulates the proliferation, apoptosis, invasion, migration, ferroptosis and drug resistance of cancer cells. However, SOX2 acts as a tumor suppressor in some cases in certain cancer types, such as gastric and lung cancer. These key regulatory functions of SOX2 involve complex regulatory networks, including protein-protein and protein-nucleic acid interactions through signaling pathways and noncoding RNA interactions, modulating SOX2 expression may be a potential therapeutic strategy for clinical cancer patients. Therefore, we sorted out the phenotypes related to SOX2 in cancer, hoping to provide a basis for further clinical translation.

The pharmacological and biological importance of EZH2 signaling in lung cancer.

Up to 18% of cancer-related deaths worldwide are attributed to lung tumor and global burden of this type of cancer is ascending. Different factors are responsible for development of lung cancer such as smoking, environmental factors and genetic mutations. EZH2 is a vital protein with catalytic activity and belongs to PCR2 family. EZH2 has been implicated in regulating gene expression by binding to promoter of targets. The importance of EZH2 in lung cancer is discussed in current manuscript. Activation of EZH2 significantly elevates the proliferation rate of lung cancer. Furthermore, metastasis and associated molecular mechanisms including EMT undergo activation by EZH2 in enhancing the lung cancer progression. The response of lung cancer to therapy can be significantly diminished due to EZH2 upregulation. Since EZH2 increases tumor progression, anti-cancer agents suppressing its expression reduce malignancy. In spite of significant effort in understanding modulatory function of EZH2 on other pathways, it appears that EZH2 can be also regulated and controlled by other factors that are described in current review. Therefore, translating current findings to clinic can improve treatment and management of lung cancer patients.

Microalga Chlorella sp. extract induced apoptotic cell death of cholangiocarcinoma via AKTmTOR signaling pathway.

Cancer is the leading cause of death worldwide. Drug resistance and relapse after current standard treatments frequently occur thus, alternative and effective treatments are required. Algae and cyanobacteria are abundant organisms that serve as bioresources of nutrientsmetabolites, which are attractive sources of numerous bioactive compounds for drug discovery. In the present study, we, therefore, investigated anti-cancer activities of crude polysaccharide and ethanolic extracts from Chlorella sp., Sargassum spp., and Spirulina sp. against cell lines of five top-leading cancers including lung cancer (A549), cervical cancer (Hela), breast cancer (MCF7), hepatocellular carcinoma (Huh7), and cholangiocarcinoma (CCA KKU213A). Only ethanolic extracts of Chlorella sp. showed consistent inhibition of growth of all cancer cell types. CCA was the most sensitive to Chlorella sp. ethanolic extract with CC50 of 277.4, 400.5, and 313.4 µgmL for KKU055, KKU100, and KKU213A cells, respectively. Flow cytometric analysis demonstrated that CCA cell death was triggered via apoptosis pathway in accompany with lowering procaspase-3, -8, and -9 and increasing caspase enzymatic activity in addition to reducing anti-apoptosis Bcl-2 protein. Interestingly, the treatment of the extract at 400 µgmL greatly inhibited the AKTmTOR survival signaling as evidenced by significant reduction of phosphorylated-AKT and phosphorylated-mTOR proteins. The presence of reported bioactive compounds, gallic acid, and lutein, were confirmed in Chlorella sp. extract by high-performance liquid chromatography. Gallic acid and lutein treatment caused a significant reduction of KKU055, KKU100, and KKU213A cell viability. This study demonstrated the anti-cancer effect of Chlorella sp. ethanolic extract to promote cancer cell death via inhibition of AKTmTOR pathway.

MUC1 promotes lung metastases of liver cancer by impairing anti-tumor immunity.

MUC1 is a membrane bound protein that can regulate tumor progression but its role in tumor metastasis and the metastatic microenvironment remains unclear. We performed differential gene analysis for primary liver cancer (n 31) and lung metastases (n 31) using the Gene Expression Omnibus (GEO) dataset (GSE141016) and obtained RNA sequencing data from 374 liver cancer and 50 normal tissues from The Cancer Genome Atlas (TCGA). We analyzed the prognostic value of MUC1 and the relationship between MUC1 and the TME using online databases and a clinical cohort. Immunohistochemistry detected MUC1 in normal liver, liver cancer, and lung metastases. Multiplex immunohistochemistry staining detected immune cells in the metastatic microenvironment. High MUC1 expression levels in hepatocellular carcinoma are associated with worse clinical prognosis and higher rates of lung metastasis. In addition, we observed a correlation between MUC1 and multiple immune cells in the metastatic microenvironment. In paired primary liver cancer and lung metastatic tumor tissues from the same patient, we observed higher MUC1 protein levels in lung metastases than in primary liver cancer. Furthermore, MUC1 was negatively correlated with CD8T and Treg cells in the metastatic tumor microenvironment and positively correlated with DC. In addition, we found that MUC1 was associated with CD8T cell activation and function using flow cytometry in another cohort of patients with liver cancer. These data confirm the potential of MUC1 as a prognostic marker and therapeutic target.

Machine learning predictive performance evaluation of conventional and fuzzy radiomics in clinical cancer imaging cohorts.

Hybrid imaging became an instrumental part of medical imaging, particularly cancer imaging processes in clinical routine. To date, several radiomic and machine learning studies investigated the feasibility of in vivo tumor characterization with variable outcomes. This study aims to investigate the effect of recently proposed fuzzy radiomics and compare its predictive performance to conventional radiomics in cancer imaging cohorts. In addition, lesion vs. lesionsurrounding fuzzy and conventional radiomic analysis was conducted. Previously published 11C Methionine (MET) positron emission tomography (PET) glioma, 18F-FDG PETcomputed tomography (CT) lung, and 68GA-PSMA-11 PETmagneto-resonance imaging (MRI) prostate cancer retrospective cohorts were included in the analysis to predict their respective clinical endpoints. Four delineation methods including manually defined reference binary (Ref-B), its smoothed, fuzzified version (Ref-F), as well as extended binary (Ext-B) and its fuzzified version (Ext-F) were incorporated to extract imaging biomarker standardization initiative (IBSI)-conform radiomic features from each cohort. Machine learning for the four delineation approaches was performed utilizing a Monte Carlo cross-validation scheme to estimate the predictive performance of the four delineation methods. Reference fuzzy (Ref-F) delineation outperformed its binary delineation (Ref-B) counterpart in all cohorts within a volume range of 938-354987 mm Fuzzy radiomics has the potential to increase predictive performance particularly in small lesion sizes compared to conventional binary radiomics in PET. We hypothesize that this effect is due to the ability of fuzzy radiomics to model partial volume effects and delineation uncertainties at small lesion boundaries. In addition, we consider that the lower redundancy of fuzzy radiomic features supports the identification of imaging biomarkers in future studies. Future studies shall consider systematically analyzing lesions and their surroundings with fuzzy and binary radiomics.

The role of spatial interplay patterns between PD-L1-positive tumor cell and T cell in recurrence of locally advanced non-small cell lung cancer.

To explore the relationship between the spatial interaction of programmed death-ligand 1(PD-L1)-positive tumor cell and T cell with specific functions and the recurrence of non-small cell lung cancer (NSCLC) and optimize prognostic stratification. This study retrospectively included 104 patients with locally advanced NSCLC who underwent radical surgery. Tissue microarrays were constructed including tumor center (TC) and invasion margin (IM), and CKCD4CD8PD-L1programmed death-1 (PD-1) was labeled using multiplex immunofluorescence to decipher the counts and spatial distribution of tumor cells and T cells. The immune microenvironment and recurrence stratification were characterized using the Mann-Whitney U test and Cox proportional hazards model. Compared with the IM, the proportion of tumor cells (especially PD-L1 Assessing the relative spatial proximity of PD-1PD-L1 contributes to a deeper understanding of tumor immune escape and generates prognostic information in locally advanced NSCLC patients.

Effects of vonoprazan and proton pump inhibitors on the efficacy of bevacizumab a multicentre retrospective study.

Gastric acid secretion inhibitors such as proton pump inhibitors (PPIs) and vonoprazan may change the duration of treatment with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for cancer. However, there are no data on this prolongation effect. Here, we aimed to determine whether the use of PPIs or vonoprazan in patients with cancer receiving bevacizumab affected the duration of bevacizumab treatment. This observational study was conducted at two national university hospitals in Japan and involved 222 patients using oral PPIs (N 190) or vonoprazan (N 32) at the start of bevacizumab treatment between January 2015 and December 2018. Patients who received only one course of bevacizumab were excluded. The primary endpoint was the duration of bevacizumab treatment. The duration of bevacizumab treatment varied significantly between the PPI and vonoprazan groups. For cancer types other than colorectal cancer (breast, lung, brain, and ovarian cancers), the median duration of treatment was 217 days (p < 0.05) and was longer in the vonoprazan group than in the PPI group. However, for colorectal cancer, the median duration of bevacizumab treatment was 147 days longer in the PPI group than in the vonoprazan group. Selection of appropriate gastric acid secretion inhibitors may improve the therapeutic efficacy of anti-VEGF drugs, including bevacizumab. Oestrogen is a key regulator of this effect and may be responsible for the varying association between PPI or vonoprazan administration and the difference in bevacizumab treatment duration between colon cancer and other cancer types.

Tumor cell vaccine combined with Newcastle disease virus promote immunotherapy of lung cancer.

Lung cancer is a fatal disease with the highest worldwide morbidity and mortality rates. Despite recent advances in targeted therapy and immune checkpoint inhibitors for cancer, their efficacy remained limited. Therefore, we designed a Newcastle disease virus (NDV)-modified tumor whole-cell vaccine as a therapeutic vaccine and identified its antigen presentation level to develop effective immunotherapy. Then, we calculated the therapeutic and immune-stimulating effects of NDV modified lung cancer cell vaccine and intratumoral NDV injection combination on tumor-bearing mice. The results showed that the immunogenic cell death (ICD) expression in NDV modified lung cancer cell vaccine stimulates dendritic cell maturation and T cell activation in vivo and in vitro. Moreover, NDV modified lung cancer cell vaccine combined with intratumoral NDV injection could significantly inhibit tumor growth and enhance the differentiation of Th1 cells and Inflammatory cell infiltration in vivo, leading to an excellent immunotherapeutic effect. Therefore, our results revealed that NDV modified lung cancer cell vaccine combined with intratumoral NDV injection could promote antigen presentation and induce a strong anti-tumor immune response, which provided a promising combined therapy strategy for tumor immunotherapy. This article is protected by copyright. All rights reserved.

Clinical value of second opinions in oncology A retrospective review of changes in diagnosis and treatment recommendations.

Data on the clinical value of second opinions in oncology are limited. We examined diagnostic and treatment changes resulting from second opinions and the expected impact on morbidity and prognosis. This retrospective cohort study included patients presenting in 2018 to a high-volume cancer center for second opinions about newly diagnosed colorectal, head and neck, lung, and myeloma cancers or abnormal results. Two sub-specialty physicians from each cancer type reviewed 30 medical records (120 total) using a process and detailed data collection guide meant to mitigate institutional bias. The primary outcome measure was the rate of treatment changes that were clinically meaningful, i.e., expected to impact morbidity andor prognosis. Among those with treatment changes, another outcome measure was the rate of clinically meaningful diagnostic changes that led to treatment change. Of 120 cases, forty-two had clinically meaningful changes in treatment with positive expected outcomes (7 colorectal, 17 head and neck, 11 lung, 7 myeloma 23-57%). Two patients had negative expected outcomes from having sought a second opinion, with worse short-term morbidity and unchanged long-term morbidity and prognosis. All those with positive expected outcomes had improved expected morbidity (short- andor long-term) 11 (0-23%) also had improved expected prognosis. Nine involved a shift from treatment to observation 21 involved eliminating or reducing the extent of surgery, compared to 6 adding surgery or increasing its extent. Of the 42 with treatment changes, 13 were due to clinically meaningful diagnostic changes (1 colorectal, 5 head and neck, 3 lung, 4 myeloma 3%-17%) . Second-opinion consultations sometimes add clinical value by improving expected prognoses more often, they offer treatment de-escalations, with corresponding reductions in expected short- andor long-term morbidity. Future research could identify subgroups of patients most likely to benefit from second opinions.

Cancer aggravation due to persistent pain signals with the increased expression of pain-related mediators in sensory neurons of tumor-bearing mice.

A growing body of evidence suggests that intractable pain reduces both the quality of life and survival in cancer patients. In the present study, we evaluated whether chronic pain stimuli could directly affect cancer pathology using tumor-bearing mice. For this purpose, we used two different models of chronic pain in mice, neuropathic pain and persistent postsurgical pain, with Lewis lung carcinoma (LLC) as tumor cells. We found that tumor growth was dramatically promoted in these pain models. As well as these pain models, tumor growth of LLC, severe osteosarcoma (AXT) and B16 melanoma cells was significantly promoted by concomitant activation of sensory neurons in AAV6-hM3Dq-injected mice treated with the designer drug clozapine-N-oxide (CNO). Significant increases in mRNA levels of vascular endothelial growth factor-A (Vegfa), tachykinin precursor 1 (Tac1) and calcitonin-related polypeptide alpha (Calca) in the ipsilateral side of dorsal root ganglion of AAV6-hM3Dq-injected mice were observed by concomitant activation of sensory neurons due to CNO administration. Moreover, in a model of bone cancer pain in which mice were implanted with AXT cells into the right femoral bone marrow cavity, the survival period was significantly prolonged by repeated inhibition of sensory neurons of AAV6-hM4Di-injected mice by CNO administration. These findings suggest that persistent pain signals may promote tumor growth by the increased expression of sensory-located peptides and growth factors, and controlling cancer pain may prolong cancer survival.

Dosimetric comparison of two dose expansion methods in intensity modulated radiotherapy for breast cancer.

To explore the dosimetric difference between IMRT-VB plan based on the establishment of external expansion structure and virtual bolus (VB) and IMRT-SF based on the skin flash (SF) tool of the Eclipse treatment planning system in postoperative chest wall target intensity modulation radiotherapy plan of breast cancer. Twenty patients with breast cancer were randomly selected as subjects to develop IMRT-VB plan based on virtual bolus and IMRT-SF plan based on skin flash tool of Eclipse treatment planning system. The planning target volume, monitor unit (MU) of every single treatment and the dosimetric parameters of organ at risk (OARs) were recorded. Paired t-test was used for normal distribution data while nonparametric paired Wilcoxon rank sum test was used for non-normal distribution data. Both IMRT-VB and IMRT-SF plan can expand outward to the chest wall skin and meet the dose requirements of clinical prescription. The conformal index, the homogeneity index, D Our study indicated that IMRT-SF plan displayed clinical application superiority compared to IMRT-VB plan, and the operation steps of which are simpler and faster. Besides, IMRT-SF plan took advantages in achieve effective external expansion of skin dose intensity and OARs protection.

Tinospora sinensis (Lour.) Merr alkaloid rich extract induces colon cancer cell death via ROS mediated, mTOR dependent apoptosis pathway an in-vitro study.

Colorectal cancer (CRC) is the second most mortality rate causing disease after lung cancer. Though there is a significant improvement in the treatment schedule offered to CRC. However, there is no notable decrease in terms of cases as well as death rate. Hence, there is an urgent need to discover novel cancer therapeutics to treat CRC. Since ancient times, the use of phytochemicals has drawn huge attention as chemo-preventive and chemotherapeutic agents. Earlier studies on Tinospora sinensis (TS) revealed the cytotoxic effect on human colorectal carcinoma (HCT-116) cells, yet the mechanism is to be uncovered. Therefore, the present study was designed to study the cell death mechanism of TS in HCT-116 cells. Different extracts such as n-hexane, ethyl acetate, and ethanol extracts from the root part of TS were prepared using a cold maceration process. The extracts were screened against cancer cell lines by methyl thiazoldiphenyltetrazolium bromide (MTT) assay. From the result, the most active extract was subjected to gas chromatography-mass spectrometry (GC-MS) and Fourier-Transform infrared spectroscopy (FTIR) analyses to identify the major constituents. Finally, the mechanism of cytotoxicity to cancer cells for the most active extract was evaluated using various experiments such as cell cycle analysis, Annexin-V assay, and Western blot. The results from the MTT assay indicated that the n-hexane extract of TS inhibits the growth of HCT-116 cells more effectively than other cancer cells like Henrietta Lacks cervical cancer cells (Hela), and Michigan cancer foundation-breast cancer (MCF-7). The GC-MS and FT-IR analyses revealed the presence of alkaloids in the n-hexane extract and were responsible for the apoptosis activity in HCT-cells via reactive oxygen species (ROS) generation, and phosphoinositide 3-kinase (PI3K) protein Kinase B (Akt) mammalian target of rapamycin (mTOR) down-regulation. This study concludes that this finding is unique of its kind, and for the first time. The anticancer effect of TS root is specific to colon cancer cells (HCT-116). This distinctive finding helps the researchers to investigate further, and to identify a novel source for anti-colon cancer drug candidates in near future.

Lung nodule pre-diagnosis and insertion path planning for chest CT images.

Medical image processing has proven to be effective and feasible for assisting oncologists in diagnosing lung, thyroid, and other cancers, especially at early stage. However, there is no reliable method for the recognition, screening, classification, and detection of nodules, and even deep learning-based methods have limitations. In this study, we mainly explored the automatic pre-diagnosis of lung nodules with the aim of accurately identifying nodules in chest CT images, regardless of the benign and malignant nodules, and the insertion path planning of suspected malignant nodules, used for further diagnosis by robotic-based biopsy puncture. The overall process included lung parenchyma segmentation, classification and pre-diagnosis, 3-D reconstruction and path planning, and experimental verification. First, accurate lung parenchyma segmentation in chest CT images was achieved using digital image processing technologies, such as adaptive gray threshold, connected area labeling, and mathematical morphological boundary repair. Multi-feature weight assignment was then adopted to establish a multi-level classification criterion to complete the classification and pre-diagnosis of pulmonary nodules. Next, 3-D reconstruction of lung regions was performed using voxelization, and on its basis, a feasible local optimal insertion path with an insertion point could be found by avoiding sternums andor key tissues in terms of the needle-inserting path. Finally, CT images of 900 patients from Lung Image Database Consortium and Image Database Resource Initiative were chosen to verify the validity of pulmonary nodule diagnosis. Our previously designed surgical robotic system and a custom thoracic model were used to validate the effectiveness of the insertion path. This work can not only assist doctors in completing the pre-diagnosis of pulmonary nodules but also provide a reference for clinical biopsy puncture of suspected malignant nodules considered by doctors.

Gut microbial signature in lung cancer patients highlights specific taxa as predictors for durable clinical benefit.

We aimed to determine microbial signature linked with lung cancer (LC) diagnosis and to define taxa linked with durable clinical benefit (DCB) of advanced LC patients. Stool samples for microbial 16S amplicon sequencing and clinical data were collected from 75 LC patients (50 of which were treated with checkpoint inhibitors) and 31 matched healthy volunteers. We compared LC to healthy controls and patients with DCB to those without. LC patients had lower α-diversity and higher between-subject diversity. Random Forests model to differentiate LC cases from controls ROC-AUC was 0.74. Clostridiales, Lachnospiraceae, and Faecalibacterium prausnitzii taxa abundance was decreased in LC compared to controls. High Akkermansia muciniphila correlated with DCB (HR 4.26, 95% CI 1.98-9.16), not only for the immunotherapy-treated patients. In addition, high Alistipes onderdonkii (HR 3.08, 95% CI 1.34-7.06) and high Ruminococcus (HR 7.76, 95% CI 3.23-18.65) correlated with DCB.Our results support the importance of gut microbiome in LC. We have validated the apparent predictive value of Akkermansia muciniphila, and highlighted Alistipes onderdonkii and Ruminococcus taxa correlation with DCB. Upon additional validations those can be used as biomarkers or as targets for future therapeutic interventions.

Inhalant cannabidiol impedes tumor growth through decreased tumor stemness and impaired angiogenic switch in NCI-H1437-induced human lung cancer model.

Lung cancer remains the most chronic form of cancer and the leading cause of cancer mortality in the world. Despite significant improvements in the treatment of lung cancer, the current therapeutic interventions are only partially effective, necessitating the continued search for better, novel alternative treatments. Angiogenesis and cancer stem cells play a central role in the initiation and propagation of cancers. Tumor angiogenesis is triggered by an angiogenic switch when pro-angiogenic factors exceed anti-angiogenic components. Although many anti-angiogenic agents are used in cancer treatment, there are therapeutic limitations with significant side effects. In recent years, cannabinoids have been investigated extensively for their potential anti-neoplastic effects. Our previous findings showed that cannabidiol (CBD) could impede tumor growth in mouse models of melanoma and glioblastoma. Importantly, CBD has been suggested to possess anti-angiogenic activity. In this study, we tested, for the first time, inhalant CBD in the treatment of heterotopic lung cancer and whether such potential effects could reduce cancer stem cell numbers and inhibit tumor angiogenesis. We implanted NCI H1437 human lung cancer cells in nude mice and treated the mice with inhalant CBD or placebo. The outcomes were measured by tumor size and imaging, as well as by immunohistochemistry and flow cytometric analysis for CD44, VEGF, and P-selectin. Our findings showed that CBD decreased tumor growth rate and suppressed expression of CD44 and the angiogenic factors VEGF and P-selectin. These results suggest, for the first time, that inhalant CBD can impede lung cancer growth by suppressing CD44 and angiogenesis.

CDCA4 interacts with IGF2BP1 to regulate lung adenocarcinoma proliferation via the PI3KAKT pathway.

Lung adenocarcinomas (LUAD) remain the leading cause of death in many countries. In this study, we investigated the role of division cycle-associated 4 (CDCA4) in the carcinogenesis of LUADs. Real-time fluorescent quantitative polymerase chain reaction and western blot were performed to detect the messenger RNA and protein levels of CDCA4 in cells. Cell counting kit 8, real-time cell analysis, clone formation, EdU assays, and cell-cycle assays were used to preliminarily investigate the proliferation and cell-cycle-related functions of CDCA4 in lung adenocarcinoma. Immunoprecipitation assays were used to identify possible targets of CDCA4. A xenograft model was used to examine how CDCA4 knockdown affects LUAD cells growth in vivo. We found that the expression of CDCA4 was upregulated in LUAD cell lines. When CDCA4 was knocked out, the ability of LUAD cells to proliferate was dramatically reduced, and the cell cycle was stalled in the S phase. Meanwhile, boosting the CDCA4 expression had the opposite effect. The critical protein levels of phosphatidylinositol 3 kinase (PI3K)protein kinase B (AKT) signaling pathway were subsequently examined. The findings demonstrated that elevated CDCA4 lowered the phosphate and tensin homolog expression and increased the p-PI3K and p-AKT levels. Moreover, we demonstrated that CDCA4 favorably regulated IGF2BP1, a downstream target. The downregulation of the IGF2BP1 expression could reverse the proliferation promotion effect induced by the CDCA4 overexpression. CDCA4 can operate as an oncogenic factor to control the growth of lung adenocarcinoma via the PI3KAKT pathway.

Argentine consensus recommendations for lung cancer screening programmes a RANDUCLA-modified Delphi study.

Lung cancer (LC) screening improves LC survival the best screening method in terms of improving survival is low-dose CT (LDCT), outpacing chest X-ray and sputum cytology. A consensus of experts in Argentina was carried out to review the literature and generate recommendations for LC screening programmes. A mixed-method study was used with three phases (1) review of the literature (2) modified Delphi consensus panel and (3) development of the recommendations. The Evidence to Decision (EtD) framework was used to generate 13 evaluation criteria. Nineteen experts participated in four voting rounds. Consensus among participants was defined using the RANDUCLA method. A total of 16 recommendations scored ≥7 points with no disagreement on any criteria. Screening for LC should be performed with LDCT annually in the population at high-risk, aged between 55 and 74 years, regardless of sex, without comorbidities with a risk of death higher than the risk of death from LC, smoking ≥30 pack-years or former smokers who quit smoking within 15 years. Screening will be considered positive when finding a solid nodule ≥6 mm in diameter (or ≥113 mm The recommendations provide a basis for minimum requirements from which local institutions can develop their own protocols adapted to their needs and resources.

Rare case of anti-CV2 paraneoplastic polyneuropathy associated with lung adenocarcinoma.

We describe the first case of anti-CV2 paraneoplastic polyneuropathy associated with lung adenocarcinoma. Our patient presented with progressive unsteadiness and numbness involving bilateral upper and lower limbs. He had symmetrical length-dependent lower motor neuron pattern of weakness and numbness involving both small and large fibres with prominent sensory ataxia. An extended workup for the polyneuropathy involving a serum paraneoplastic antineuronal antibody panel showed a positive reaction for anti-CV2 antibody. CT scan of the thorax, abdomen and pelvis revealed a right upper lung nodule and histopathological examination of the nodule revealed lung adenocarcinoma. He was scheduled for chemotherapy following his discharge and there was improvement of his sensorimotor polyneuropathy following his chemotherapy.

Airway mucus in pulmonary diseases Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers.

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction andor adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.

Benzoapyrene treatment modulates Nrf2Keap1 axis and changes the metabolic profile in rat lung cancer.

Lung cancer is an aggressive malignancy and the leading cause of cancer-related deaths. Benzoapyrene (BaP), a polycyclic hydrocarbon, plays a pivotal role in lung carcinogenesis. Uncovering the molecular mechanism underlying the pathophysiology of BaP induced malignancy is crucial. Male Sprague Dawley rats were induced with BaP to generate a lung cancer model. The BaP administered rats show increased body and lung weight, loss of normal pulmonary architecture, and decreased survival. This study demonstrated that BaP upregulates activating transcription factor-6 (ATF6) and CEBP Homologous Protein (CHOP) and induces endoplasmic reticulum (ER) stress. BaP also dysregulated mitochondrial homeostasis by upregulating, PTEN-induced putative kinase-1 (PINK1) and Parkin. BaP affected the levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and increased oxidative stress. BaP exposure downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1(HO1). The metabolomic study identified that biosynthesis of nucleotide, amino acids, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and glutathione metabolism were up-accumulated. On the other hand, lower accumulation of fatty acids e.g., palmitic acid, stearic acid, and oleic acid were reported in the BaP induced group. Overall, the results of this study indicate that BaP treatment affects several signaling and metabolic pathways, whose dysregulation might be involved in lung cancer induction.

Comparison of digital PCR systems for the analysis of liquid biopsy samples of patients affected by lung and colorectal cancer.

Highly sensitive technologies are available for the molecular characterization of solid tumors, including digital PCR (dPCR). Liquid biopsy, based on the analysis of cell-free DNA (cfDNA), is often used to assess EGFR or RAS alterations in lung and colorectal cancers. Our study aimed to compare the results of two different dPCR platforms for the detection of mutations in cfDNA. Plasma samples from lung and colorectal cancer patients collected as per routine procedures have been tested. cfDNA Was extracted from plasma, and samples were screened on the droplet digital PCR (ddPCR, BioRad) and solid dPCR QIAcuity (Qiagen). A total of 42 samples were analyzed, obtained from 20 Non-Small Cell Lung Cancer (NSCLC) patients carrying an EGFR or a KRAS mutation on tissue at diagnosis, and from 22 samples of colorectal cancer (CRC) patients, 10 of which presenting a KRAS mutation. EGFR mutation detection was 58.8% for ddPCR and 100% for dPCR (κ 0.54 95% CI, 0.37-0.71), compared to tissue results. The detection rate for RAS mutations was 72.7% for ddPCR and 86.4% for dPCR (κ 0.34 95% CI, 0.01-0.68), compared to tissue results. This study showed moderate agreement between dPCR and ddPCR. Sampling effect or threshold settings may potentially explain the differences in the cfDNA data between the two different platforms.

Antigen-specific memory TH17 cells promote cross-protection against Nontypeable Haemophilus influenzae following mild influenza A virus infection.

Secondary bacterial pneumonia following influenza A virus (IAV) infection is the leading cause of hospitalization and death associated with IAV infection worldwide. Nontypeable Haemophilus influenzae (NTHi) is one of the most common causes of secondary bacterial pneumonia. Current efforts to develop vaccines against NTHi infection focus on inducing antibodies but are hindered by antigenic diversity among NTHi strains. Therefore, we interrogated the contribution of the memory T-helper type 17 (T

An Integrated Physical Optimization framework for proton SBRT FLASH treatment planning allows dose, dose rate, and LET optimization using patient-specific ridge filters.

Patient-specific ridge filters provide a passive means to modulate proton energy to obtain a conformal dose. Here we describe a new framework for optimization of filter design and spot maps to meet the unique demands of ultra-high dose rate (FLASH) radiotherapy. We demonstrate an Integrated Physical Optimization IMPT (IPO-IMPT) approach for optimization of dose, dose-averaged dose rate (DADR), and dose-averaged LET (LET We developed an inverse planning software to design patient-specific ridge filters that spread the Bragg peak from a fixed-energy, 250 MeV beam to a proximal beam-specific planning target volume (BSPTV). The software defines patient-specific ridge filter pin shapes and uses a Monte Carlo calculation engine, based on Geant4, to provide dose and LET influence matrices. Plan optimization, using matRAD, accommodates the IPO-IMPT objective function considering dose, dose rate, and LET simultaneously with minimum MU constraints. The framework enables design of both regularly spaced and sparse-optimized ridge filters, from which some pins are omitted to allow faster delivery and selective LET optimization. To demonstrate the framework, we designed ridge filters for three example lung cancer patients and optimized the plans using IPO-IMPT. The IPO-IMPT framework selectively spared the OARs by reducing LET and increasing dose rate, relative to IMPT planning. Sparse-optimized ridge filters were superior to regularly spaced ridge filters in dose rate. Depending on which parameter is prioritized, volume distributions and histograms for dose, DADR, and LET This proof-of-concept study demonstrates the feasibility of using an IPO-IMPT framework to accomplish proton FLASH stereotactic body proton therapy, accounting for dose, DADR, and LET

Long-term exposure to fine particulate matter and site-specific cancer mortality A difference-in-differences analysis in Jiangsu province, China.

Accumulating studies have reported that chronic exposure to ambient fine particulate matter (PM To explore the causal effect of long-term PM For each of 53 county-based spatial units in Jiangsu province, we calculated annual death counts for all-site cancer and 23 site-specific cancers. Using a validated high-resolution PM During the study period, we identified 947,337 adult cancer deaths in Jiangsu province. Each 1 μgm Long-term exposure to ambient PM

Immune-related interstitial lung disease induced by different immune checkpoint inhibitors regimens A real-world study from 2014 to 2022 based on FAERS databases.

This study further approaches immune-related interstitial lung disease adverse event in patients undergoing immune checkpoint inhibitor (ICI) monotherapy, ICI plus chemotherapy and ICI plus anti-VEGF therapy in the postmarketing period. Reports for ICI-related interstitial lung disease adverse event from the FDA Adverse Event Reporting System (FAERS) database between 2014 and 2022 were analysed in this study. The reporting odds ratio (ROR) and Bayesian confidence propagation neural networks of information components (IC) were computed to identify disproportionate reporting of ICI-related interstitial lung disease. 44,964,609 records were extracted from the FAERS database, with 9150 records for interstitial lung disease after ICI treatment. Men had a slightly higher reporting frequency than women (63.07% vs. 25.69%). The morbidity rate (2.05%) of acute respiratory distress syndrome was low, the fatality rate (67.55%) was the highest, the time to onset was relatively short. Within 3 months, the cumulative proportion of ICI-related interstitial lung disease records was 75.03%. The ICI plus anti-VEGF therapy group had the lowest frequency of interstitial lung disease adverse events compared to the ICI monotherapy group and the ICI plus chemotherapy group (IC

Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma A systematic scoping review.

This systematic scoping review compares the toxicities experienced by patients receiving immune checkpoint inhibitors (ICIs) or targeted therapy (TT) for stage III (resected and unresectable) and stage IV melanoma. OVID Medline, Embase, and PsycInfo were searched to identify Phase III trials reporting toxicities of FDA-approved ICIs and TT for advanced melanoma. AEs that were reported by ≥ 10% of patients in the evaluated trials were included. Toxicity profiles of 11208 patients from 24 studies were reviewed. The rate of AEs was lower with ICIs compared to TT. However, ICIs were associated with higher rates of long-term or permanent AEs compared to TT, where toxicities generally were shortterm and reversible with treatment discontinuation. The toxicity profiles of ICIs and TT vary substantially. Whilst the rate of AEs was lower with ICIs than during TT, it was also associated with higher rates of potentially chronic AEs.

The prognostic gene CRABP2 affects drug sensitivity by regulating docetaxel-induced apoptosis in breast invasive carcinoma A pan-cancer analysis.

Cellular retinoic acid-binding protein 2 (CRABP2), a specific transporter of retinoic acid, has been shown to have an important biological role in human cancers. However, due to the substantial variability among different tumors, the role of CRABP2 remains uncertain and has not yet been subjected to systematic analysis. Utilizing The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Kaplan-Meier Plotter, Biomarker Exploration of Solid Tumors (BEST), Cancer Cell Line Encyclopedia (CCLE), Receiver Operating Characteristic plotter (ROC plotter), and other online public tools, expression levels of CRABP2 in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and ovarian serous cystadenocarcinoma (OV) were found to be significantly greater than those in adjacent normal tissues, suggesting a correlation to poor prognosis. Among the three, CRABP2 expression in BRCA was most closely associated with clinical prognosis. In a study of docetaxel-treated BRCA patients, CRABP2 expression was significantly higher in the drug-resistant group. Colony formation and flow cytometry analysis were used to further investigate the relationship between CRABP2 and docetaxel sensitivity in BRCA cells MDA-MB-231and BT549. The knockdown of CRABP2 expression significantly reduced cell growth and increased sensitivity to the chemotherapeutic agent docetaxel in BRCA cells. Furthermore, CRABP2 knockdown augmented docetaxel-induced apoptosis. Molecular docking using SwissDock tool revealed that CRABP2 had a greater binding affinity to docetaxel than docetaxel-targeted proteins. This research provides an insight into the expression and prognostic potential of CRABP2 in cancers and suggests that CRABP2 may control docetaxel sensitivity in BRCA cells through apoptosis, warranting further investigation.

Pulmonary Vein Stump Thrombosis and Cerebral Infarction after Left Upper Lobectomy.

Pulmonary vein stump thrombosis may occur after left upper lobectomy (LUL) and is a potential risk factor for cerebral infarction. However, there are few reports on the role of pulmonary vein stump thrombosis in the development of cerebral infarction. We aimed to clarify the correlation between pulmonary vein stump thrombosis and cerebral infarction following LUL. We evaluated 296 patients who underwent contrast-enhanced computed tomography (CT) after LUL for lung cancer at the Shizuoka Cancer Center Hospital in Shizuoka, Japan, between September 2002 and December 2015. The cerebral infarction in patients with pulmonary vein stump thrombosis was examined, and the risk factors for cerebral infarction were identified via a univariate analysis of the clinicopathological and surgical variables. Overall, 179 men and 117 women (median age 68 years range 36-88 years) were included. The median observation period was 68 months. Pulmonary vein stump thrombosis occurred in 21 (7%) patients and cerebral infarction occurred in 15 (5%) patients. None of the 21 patients with pulmonary vein stump thrombosis developed cerebral infarction. Most cerebral infarctions (1215) were diagnosed in the late phase (> 3 months). The pathological stage of cancer was found to be the only significant risk factor for cerebral infarction by the univariate analysis. Pulmonary vein stump thrombosis following LUL was not necessarily associated with cerebral infarction, including the late phase. A prospective observational study with contrast-enhanced chest CT would be required to investigate the risk factors for cerebral infarction in each phase of the postoperative period.

Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer.

Local environmental factors influence CD8

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-αβ-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-αβ immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-αβ. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-αβ-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-αβ-dependent antiviral immunity.

Platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds induces mitophagy-mediated apoptosis in A549DDP cancer cells.

For the first time, two new mononuclear platinum(II) coordination compounds, Pt(L1)(DMSO)Cl (PtL1) and Pt(L2)(DMSO)Cl (PtL2) with the 5-(ethoxymethyl)-8-hydroxyquinoline hydrochloride (H-L1) and 5-bromo-8-hydroxyquinoline (H-L2) have been synthesized and characterized. The cytotoxic activity of PtL1 and PtL2 were screened in both healthy HL-7702 cell line and cancer cell lines, human lung adenocarcinoma A549 cancer cells and cisplatin-resistant lung adenocarcinoma A549DDP cancer cells (A549R), and were compared to that of the H-L1, H-L2, H-L3 ligands and 8-hydroxyquinoline (H-L3) platinum(II) complex Pt(L3)(DMSO)Cl (PtL3). MTT results showed that PtL1 bearing one deprotonated L1 ligand against A549R was more potent by 8.8-48.6 fold than that of PtL2 and PtL3 complexes but was more selective toward healthy HL-7702 cells. In addition, PtL1 and PtL3 overcomes tumour drug resistance by significantly inducing mitophagy and causing the change of the related proteins expression, which leads to cell apoptosis. Moreover, the inhibitory effect of PtL1 on A549 xenograft tumour was 68.2%, which was much higher than that of cisplatin (cisPt, ca. 50.0%), without significantly changing nude mice weight in comparison with the untreated group. This study helps to explore the potential of the platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds for the new Pt-resistant cancer therapy.

Deciphering the role of Hippo pathway in lung cancer.

Hippo pathway has been initially recognized as a regulatory mechanism for modulation of organ size in fruitfly. Subsequently, its involvement in the regulation of homeostasis and tumorigenesis has been identified. This pathway contains some tumor suppressor genes such as hippo (hpo) and warts (wts), as well as a number of oncogenic ones such as yorkie (yki). Recent studies have shown participation of Hippo pathway in the lung carcinogenesis. This pathway can affect lung cancer via different mechanisms. The interaction between some miRNAs and Hippo pathway is a possible mechanism for carcinogenic processes. Moreover, some other types of non-coding RNAs including PVT1, SFTA1P, NSCLCAT1 and circ0067741 are implicated in this process. Besides, anti-cancer effects of gallic acid, icotinib hydrochloride, curcumin, ginsenoside Rg3, cryptotanshinone, nitidine chloride, cucurbitacin E, erlotinib, verteporfin, sophoridine, cisplatin and verteporfin in lung cancer are mediated through modulation of Hippo pathway. Here, we summarize the results of recent studies that investigated the role of Hippo signaling in the progression of lung cancer, the impact of non-coding RNAs on this pathway and the effects of anti-cancer agents on Hippo signaling in the context of lung cancer.

Primary endpoints to assess the efficacy of novel therapeutic approaches in epidermal growth factor receptor-mutated, surgically resectable non-small cell lung cancer A review.

While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options.

Impact of surgery and adjuvant chemotherapy on the survival of stage I lung adenocarcinoma patients with tumor spread through air spaces.

Tumor spread through air spaces (STAS) is a unique mechanism of lung cancer metastasis however, its clinical value for stage I lung adenocarcinoma (ADC) remains unclear at present. We investigated the (1) prognosis of patients after sublobar resection compared with lobectomy for stage I lung adenocarcinoma with STAS and (2) potential benefits of adjuvant chemotherapy (ACT) for patients with stage I ADC and STAS. A total of 3328 consecutive patients with stage I ADC were retrospectively identified between 2014 and 2018 at our institution among them, 600 were diagnosed with STAS. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of STAS on overall survival (OS) and recurrence-free survival (RFS). Among stage IA patients with STAS, there was no significant difference between those who underwent sublobar resection and lobectomy in OS (P 0.919) and RFS (P 0.066). Multivariate analysis confirmed this result (sublobar resection versus lobectomy, OS HR 0.523, 95 % CI, 0.056-18.458, P 0.714 RFS, HR 0.360, 95 % CI, 0.115-1.565, P 0.897). ACT did not improve the prognosis of stage IA patients but did improve the RFS of stage IB patients with high-risk recurrence factors, including poorly differentiated tumors, lymphovascular invasion and visceral pleural invasion (P 0.046). Sublobar and lobectomy resection provided a comparable prognosis for stage IA ADC patients with STAS. When STAS was confirmed postoperatively, ACT should be considered for patients with stage IB with high-risk recurrence factors but not for those with stage IA disease.

Real-world comparison of survival outcomes with cisplatin versus carboplatin in patients with limited-stage small-cell lung cancer.

Limited-stage small-cell lung cancer (LS-SCLC) is potentially curable with concurrent chemoradiation (CRT). Cisplatin is the preferred platinum for the chemotherapy backbone in national guidelines. Unfortunately, many LS-SCLC patients are elderly, with comorbidities and poor performance status (PS), which preclude the use of cisplatin. Carboplatin may be a suitable alternative. This analysis evaluates the overall survival (OS) and time to next treatment (TTNT) in LS-SCLC patients receiving concurrent CRT by platinum use. The study included LS-SCLC patients in the Flatiron Health nationwide de-identified electronic health record-derived database who received CRT in 2013-2019 with follow-up through May 2020. TTNT and OS were compared using both unadjusted and inverse propensity-weighted Cox proportional hazards models. This study included patients treated with carboplatin (n 600) or cisplatin (n 572) in combination with etoposide and radiation. Cisplatin patients were younger, had a shorter time from diagnosis to radiation, and had less kidney disease. In an unadjusted analysis, median overall survival (mOS) was greater in the cisplatin group than the carboplatin group with mOS of 22.3 months vs. 19.2 months and Hazard Ratio (HR) of 0.83 (p 0.01). In the inverse propensity-weighted analysis, this difference was no longer significant (HR 0.93, p 0.37). No differences were seen in TTNT. When balancing on key clinical factors, we observed no statistical difference in OS or TTNT by platinum choice in real-world LS-SCLC patients treated with CRT. Although observational, the results from this large data set are consistent with the hypothesis that either cisplatin or carboplatin is an appropriate therapy regardless of health status.

Forskolin affects proliferation, migration and Paclitaxel-mediated cytotoxicity in non-small-cell lung cancer cell lines via adenylyl cyclasecAMP axis.

Non-Small-Cell Lung Cancer (NSCLC) is considered one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. Despite the undoubted therapeutic advances that have occurred in clinical practice over time, due to its high degree in both heterogeneity and resistance, NSCLC remains largely incurable. As a natural cAMP elevating agent, Forskolin has shown anti-cancer properties in different tumor types, thus supposing its possible usage in treating malignancies. In this study, we investigated the Forskolin outcome in H1299 and A549 NSCLC cell lines, either alone or in combination with Paclitaxel. We proved that Forskolin impairs cell growth and migration ability of these cells, concurrently. Albeit with a different extent between H1299 and A549, changes in cell-cycle progression and epithelial-mesenchymal markers were observed in response to Forskolin administration. Interestingly, comparable cell growth impairment was also obtained with the cAMP phosphodiesterase inhibitor IBMX, while the employment of adenylyl cyclase inhibitor SQ22536 counteracted, at least in part, the Forskolin-mediated anticancer effects. Besides as a single agent, we also demonstrated that Forskolin strongly enhances Paclitaxel-induced cytotoxicity, affecting cell death mainly via apoptosis induction. Notably, H89-mediated protein kinase A (PKA) inhibition further deteriorated the combination outcome. Altogether, our data designate Forskolin as a possible anticancer molecule in NSCLC, and recognize the adenylyl cyclasecAMP axis as one of the pathways involved in. Although achieved at preclinical stage, our findings encourage the design of future studies aimed at further exploring the Forskolin employment in NSCLC treatment.

Specific detection of n-propanol gas via terahertz metasurface sensor modified by molecularly imprinted polymer.

As an organic substance, n-propanol gas has been paid attention to in environmental monitoring and exhalation of lung cancer patient. In this paper a rapid detection method for n-propanol gas is developed based on molecularly imprinted polymers (MIP) and terahertz (THz) metasurface sensors. We first prepared a MIP suitable for detecting the n-propanol gas. And then the n-propanol MIP was modified to the THz metasurface sensor for detecting the n-propanol gas. Since the MIP adsorbed with n-propanol changes the dielectric environment of the sensor, the resonance frequency of the sensor also change. So we based on the n-propanol concentration was analyzed according to the change in resonance frequency. The experimental results showed that the sensor can effectively detect the n-propanol concentration in the range of 50-500 ppm (parts per million). In addition, we also verified the specificity and repeatability of the sensor. This work provides a new idea and method for the sensitive and specific detection of n-propanol gas.

Machine intelligence for radiation science summary of the Radiation Research Society 67th annual meeting symposium.

The era of high-throughput techniques created big data in the medical field and research disciplines. Machine intelligence (MI) approaches can overcome critical limitations on how those large-scale data sets are processed, analyzed, and interpreted. The 67

Room-Temperature Phosphorescence and Cellular Phototoxicity Activated by Triplet Dynamics in Aggregates of Push-Pull Phenothiazine-Based Isomers.

In this study, we report a comprehensive time-resolved spectroscopic investigation of the excited-state deactivation mechanism in three push-pull isomers characterized by a phenothiazine electron donor, a benzothiazole electron acceptor, and a phenyl π-bridge where the connection is realized at the relative

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors--by inhibition of deoxyhypusine synthase--abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34 progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.

Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer 5-Year Update of the Phase III KEYNOTE-407 Study.

Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer.

Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non-small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8

Quantitation of Ten Urinary Nicotine Metabolites, Including 4-Hydroxy-4-(3-pyridyl) Butanoic Acid, a Product of Nicotine 2-Oxidation, and CYP2A6 Activity in Japanese Americans, Native Hawaiians, and Whites.

Smoking intensity varies across smokers and is influenced by individual variability in the metabolism of nicotine, the major addictive agent in tobacco. Therefore, lung cancer risk, which varies by racial ethnic group, is influenced by the primary catalyst of nicotine metabolism, cytochrome P450 2A6 (CYP2A6). In smokers, CYP2A6 catalyzes nicotine 5-oxidation.

Phantom-Less Nonlinear Magnetic Resonance Imaging Calibration With Multiple Input Blood Flow Model.

Previous work used phantoms to calibrate the nonlinear relationship between the gadolinium contrast concentration and the intensity of the magnetic resonance imaging signal. This work proposes a new nonlinear calibration procedure without phantoms and considers the variation of contrast agent mass minimum combined with the multiple input blood flow system. This also proposes a new single-input method with meaningful variables that is not influenced by reperfusion or noise generated by aliasing. The reperfusion in the lung is usually neglected and is not considered by the indicator dilution method. However, in cases of lung cancer, reperfusion cannot be neglected. A new multiple input method is formulated, and the contribution of the pulmonary artery and bronchial artery to lung perfusion can be considered and evaluated separately. The calibration procedure applies the minimum variation of contrast agent mass in 3 different regions (1) pulmonary artery, (2) left atrium, and (3) aorta. It was compared with four dimensional computerized tomography with iodine, which has a very high proportional relationship between contrast agent concentration and signal intensity. Nonlinear calibration was performed without phantoms, and it is in the range of phantom calibration. It successfully separated the contributions of the pulmonary and bronchial arteries. The proposed multiple input method was verified in 6 subjects with lung cancer, and perfusion from the bronchial artery, rich in oxygen, was identified as very high in the cancer region. Nonlinear calibration of the contrast agent without phantoms is possible. Separate contributions of the pulmonary artery and aorta can be determined.

The oral PI3Kδ inhibitor linperlisib for the treatment of relapsed andor refractory follicular lymphoma A phase 2, single-arm, open-label clinical trial.

To investigate the efficacy and safety of the novel orally active phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor in relapsed andor refractory follicular lymphoma (FL) patients who had received at least two prior systemic treatments. Histologically confirmed relapsed andor refractory FL patients with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg qd, po in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression free survival (PFS), overall survival (OS), disease control rate and drug safety profile. Of 114 screened relapsed andor refractory FL patients, 84 were enrolled in the full analysis set (FAS). The ORR of 84 FAS patients was 79.8% (95%CI 69.6-87.8, 67 patients), with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (range 9.3-15.9). The median PFS was 13.4 months (95%CI 11.1-16.7). The 12-month OS rate was 91.4% (95%CI 82.7-95.8. and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%) and interstitial lung disease (3.6%). Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed andor refractory FL patients who had received at least two prior systemic therapies.

Breast and Lung Cancer Screening Among Medicare Enrollees During the COVID-19 Pandemic.

Several studies reported sharp decreases in screening mammography for breast cancer and low-dose computed tomographic screening for lung cancer in the early months of the COVID-19 pandemic, followed by a return to normal or near-normal levels in the summer of 2020. To determine the observed vs expected mammography and low-dose computed tomographic scan rates from the beginning of the pandemic through April 2022. In this retrospective cohort study assessing mammography and low-dose computed tomography rates from January 2017 through April 2022, data for January 2016 to February 2020 were used to generate expected rates for the period March 2020 to April 2022. The study included a 20% national sample of Medicare fee-for-service enrollees among women aged 50 to 74 years for mammography, and men and women aged 55 to 79 years for low-dose computed tomographic scan. Receipt of screening mammography or low-dose computed tomographic scan. The yearly cohorts for the mammography rates included more than 1 600 000 women aged 50 to 74 years, and the cohorts for the low-dose computed tomographic scan rates included more than 3 700 000 men and women aged 55 to 79 years. From January 2017 through February 2020, monthly mammography rates were flat, whereas there was a monotonic increase in low-dose computed tomographic scan rates, from approximately 500 per million per month in early 2017 to 1100 per million per month by January 2020. Over the period from March 2020 to April 2022, there were episodic drops in both mammography and low-dose computed tomographic scan rates, coincident with increases in national COVID-19 infection rates. For the periods from March 2020 to February 2020 and March 2021 to February 2022, the observed low-dose computed tomographic scan rates were 24% (95% CI, 23%-24%) and 14% (95% CI, 13%-15%) below expected rates, whereas mammography rates were 17% (95% CI, 17%-18%) and 4% (95% CI, 4%-3%) below expected. In this cohort study, the decreases in cancer screening during the early phases of the COVID-19 pandemic did not resolve after the initial pandemic surges. Successful interventions to improve screening rates should address pandemic-specific reasons for low screening participation.

Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010.

Anthracyclines increase the risk for congestive heart failure (CHF) however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies. To compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community. This retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022. Cancer treatment and CHF risk factors. The main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history. A total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 95% CI, 1.90-4.32 P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 95% CI, 2.11-5.00 P < .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 95% CI, 0.83-3.81 P .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P < .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mgm2 compared with those at a dose of 180 to 250 mgm2 (HR, 0.54 95% CI, 0.19-1.51) or at a dose of more than 250 mgm2 (HR, 1.23 95% CI, 0.52-2.91). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 95% CI, 1.99-3.86 P < .001). In this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Recent Developments and Challenges in Molecular-Targeted Therapy of Non-Small-Cell Lung Cancer.

Treatment of lung cancer with conventional therapies, which include radiation, surgery, and chemotherapy results in multiple undesirable adverse or side effects. The major clinical challenge in developing new drug therapies for lung cancer is resistance, which involves mutations and disturbance in various signaling pathways. Molecular abnormalities related to epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) Kirsten rat sarcoma virus (KRAS) mutations, translocation of the anaplastic lymphoma kinase (ALK) gene, mesenchymal-epithelial transition factor (MET) amplification have been studied to overcome the resistance and to develop new therapies for non-small cell lung cancer (NSCLC). But, inevitable development of resistance presents limits the clinical benefits of various new drugs. Here, we review current progress in the development of molecularly targeted therapies, concerning six clinical biomarkers EGFR, ALK, MET, ROS-1, KRAS, and B-RAF for NSCLC treatment.

Exploring the Mechanical Perspective of a New Anti-Tumor Agent Melatonin.

Melatonin is a serotonin-derived pineal gland hormone with many biological functions like regulating the sleep-wake cycle, circadian rhythm, menstrual cycle, aging, immunity, and antioxidants. Melatonin synthesis and release are more pronounced during the night, whereas exposure to light decreases it. Evidence is mounting in favor of the therapeutic effects of melatonin in cancer prevention, treatment and delayed onset in various cancer subtypes. Melatonin exerts its anticancer effect through modification of its receptors such as melatonin 1 (MT1), melatonin 2 (MT2), and inhibition of cancer cell proliferation, epigenetic alterations (DNA methylationdemethylation, histone acetylationdeacetylation), metastasis, angiogenesis, altered cellular energetics, and immune evasion. Melatonin performs a significant function in immune modulation and enhances innate and cellular immunity. In addition, melatonin has a remarkable impact on epigenetic modulation of gene expression and alters the transcription of genes. As an adjuvant to cancer therapies, it acts by decreasing the side effects and boosting the therapeutic effects of chemotherapy. Since current treatments produce drug-induced unwanted toxicities and side effects, they require alternate therapies. A recent review article attempts to summarize the mechanistic perspective of melatonin in different cancer subtypes like skin cancer, breast cancer, hepatic cancer, renal cell cancer, non-small cell lung cancer (NSCLC), colon oral, neck, and head cancer. The various studies described in this review will give a firm basis for the future evolution of anticancer drugs.

Oncology Clinical Trials in Greece Progress in the Past Decade.

Cancer is established as a major contributor to global burden as millions of deaths are reported every year. Advances in molecular, epidemiologic and clinical research have led to significant improvements in prevention, screening and treatment of tumors. The purpose of the study is to describe the progress of oncology clinical trials performed in Greece during the past decade and the obstacles that still need to be addressed in cancer research. A search was conducted in the public database EU Clinical Trials Register using the algorithm cancer AND Greece. Results included relevant trials approved between 2010 and 2020. A total of 480 trials were approved for conduct in Greece from 2010 to 2020. The majority are multinational, phase III trials, exploring the efficacy and safety of agents in the management of lung cancer and multiple myeloma. A variety of small-molecules and monoclonal antibodies has and is being tested against key binding targets. Based on their promising effects on patients responses and outcomes, many have been marketed for the treatment of several cancer types and are considered milestones in cancer discovery. It goes without saying that oncology research has made tremendous steps towards the development of potent and tolerable anticancer agents, with Greece having an active role. Current efforts focus on the use of alternative designs and tools aiming at further improving patients survival and quality of life, while globalization of clinical research is also a matter of high importance.

LINC00312 Inhibits Lung Cancer Progression through the miR-3175SEMA6A Axis.

This study aims to clarify molecular mechanisms and tumor-associated functions of LINC00312 in lung cancer. GEO database was used to acquire lung cancer-related expression microarrays. Then, relevant databases were applied to predict the downstream miRNA for LINC00312 and the target mRNA for the potential miRNA, with their associations deeply confirmed through dual-luciferase and RIP assays. The expression levels of epithelial-mesenchymal transition -related proteins (N-cadherin, Vimentin, MMP-2, and MMP-9) were examined by Western blot. The proliferation, migration, and invasion were evaluated through in vitro experiments including CCK-8 and Transwell assays and further validated by nude mouse xenograft tumor experiment. LINC00312, serving as a tumor suppressor, was down-regulated in lung cancer cells. RIP assay proved that miR-3175 bound LINC00312 and SEMA6A. The dual-luciferase assay showed that miR-3175 specifically targeted SEMA6A, suppressing the expression of SEMA6A. Overexpressing LINC00312 remarkably inhibited the binding between miR-3175 and SEMA6A. Overexpressing miR-3175 or silencing SEMA6A could hamper the effects of LINC00312 on lung cancer cells. LINC00312 inhibits lung cancer occurrence and progression via the miR-3175SEMA6A axis.

IncRNA EPB41L4A-AS1 Mitigates the Proliferation of Non-Small-Cell Lung Cancer Cells through the miR-105-5pGIMAP6 Axis.

Non-small-cell lung cancer (NSCLC) is the major subtype of lung cancer, with a series of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and proteins involved in its pathogenesis. This study sought to investigate the functionality of lncRNA EPB41L4A antisense RNA 1 (lncRNA EPB41L4A-AS1) in the proliferation of NSCLC cells and provide a novel theoretical reference for NSCLC treatment. Levels of lncRNA EPB41L4A-AS1, miR-105-5p, and GTPase, IMAP family member 6 (GIMAP6) in tissues and cells were measured by RT-qPCR and the correlation between lncRNA EPB41L4A-AS1 and clinicopathological characteristics was analyzed. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. The subcellular localization of lncRNA EPB41L4A-AS1 was analyzed by the subcellular fractionation assay and the binding of miR-105-5p to lncRNA EPB41L4A-AS1 or GIMAP6 was analyzed by dual-luciferase and RNA pull-down assays. Functional rescue experiments were performed to analyze the role of miR-105-5pGIMAP6 in NSCLC cell proliferation. lncRNA EPB41L4A-AS1 and GIMAP6 were downregulated while miR-105-5p was upregulated in NSCLC tissues and cells. lncRNA EPB41L4A-AS1 was correlated with tumor size and clinical staging and its overexpression reduced NSCLC cell proliferation. lncRNA EPB41L4A-AS1 was negatively correlated with miR-105-5p and positively correlated with GIMAP6 in NSCLC tissues, and lncRNA EPB41L4A-AS1 sponged miR-105-5p to promote GIMAP6 transcription in NSCLC cells. Overexpression of miR-105-5p or knockdown of GIMAP6 reversed the inhibition of lncRNA EPB41L4A-AS1 overexpression on NSCLC cell proliferation. lncRNA EPB41L4A-AS1 was downregulated in NSCLC and mitigated NSCLC cell proliferation through the miR-105-5pGI-MAP6 axis.