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MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis is still unclear. The present study aimed to investigate the role of The expression of (I)

The diagnostic challenge of small cell lung cancer with anti-gamma-aminobutyric-acid B receptor encephalitis a case report.

Anti-gamma-aminobutyric-acid B receptor (anti-GABA A 62-year-old man with a history of anti-GABA SCLC is the most common pulmonary neuroendocrine tumor. It secretes onconeural antibodies and is closely associated with paraneoplastic neurologic syndromes (PNSs). Lung tumors, especially SCLC, should be a concern in patients presenting with AE or neurological symptoms, even if they have not any abnormal sign in respiratory system. The early diagnosis and intervention for underlying tumors will improve the clinical outcomes of patients significantly. Thus, the close follow-up is helpful and it is imperative to select and combine the most appropriate examinations for proper diagnosis.

M2-TAMs promote immunoresistance in lung adenocarcinoma by enhancing

Immunotherapy has become the first-line treatment for advanced non-small-cell lung cancer (NSCLC), but most patients still fail to benefit or have disease progression following treatment. M2 phenotype tumor-associated macrophages (M2-TAMs) are important cellular components in the immunosuppressive microenvironment of NSCLC, but how they contribute to immunoresistance remains unclear. This study was conducted to investigate the role and mechanism of M2-TAMs in NSCLC immunoresistance. We collected postoperative tumor samples for detection of M2-TAMs and other immune cells infiltration by immunofluorescence detection and flow cytometry. We then constructed a non-contact cell co-culture system using Transwell chambers. CCK-8, colony formation, wound healing and invasion assays were performed to evaluated the effect of M2-TAMs on the proliferation, migration and invasion abilities of lung adenocarcinoma (LUAD) cells M2-TAMs were greatly increased in the tumor tissue of patients with immunoresistant LUAD. They could significantly promote the proliferation, invasion, and migration of LUAD cells, and improve their resistance to cytotoxic T lymphocytes (CTL) cytotoxicity. Further research showed M2-TAMs could considerably enhance the expression of In conclusion, M2-TAMs could promote LUAD immunoresistance by enhancing

Efficacy and safety of original EGFR-TKI combined with bevacizumab in advanced lung adenocarcinoma patients harboring EGFR-mutation experiencing gradual progression after EGFR-TKI treatment a single-arm study.

Keeping on original epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment is the standard treatment for gradual progression EGFR-positive metastatic non-small cell lung cancer (NSCLC). Angiogenic pathway can lead to EGFR-TKI resistance, but the effectiveness of combination strategies in this group is still controversial. This study aimed to assess the efficacy and safety of the original EGFR-TKI combined with bevacizumab in advanced and metastatic lung adenocarcinoma patients harboring EGFR-mutation who experience gradual progression in a real-world setting. From June 2019 to December 2021, a total of 35 metastatic EGFR positive NSCLC patients experienced gradual progression after EGFR-TKI treatments and received original TKI combined with bevacizumab were identified at Chongqing University Cancer Hospital, China. All patients were confirmed EGFR positive by rebiopsy before treatment. Patients were treated with EGFR-TKI and bevacizumab (15 mgkg Q3W) after gradual progression until rapid progression or intolerable toxicity. The overall survival (OS), progression-free survival 1 (PFS1, period from the beginning of EGFR-TKI treatment to the rapid progression of the disease), PFS2 (period from the beginning of EGFR-TKI combined with bevacizumab treatment to the rapid progression of the disease), disease control rate (DCR), and adverse events of the combined treatment were collected and analyzed. A total of 33 patients could participate the efficacy evaluation. Median PFS1 and PFS2 were 20.5 and 8 months, respectively DCR was 93.94% median OS was immature. Multivariate Cox proportional hazards model showed that smoking status hazard ratio (HR) 3.692, 95% confidence interval (CI) 1.450-9.404, P0.006, combined EGFR T790M mutation or rare mutation (HR 2.480, 95% CI 1.073-5.729, P0.034), and malignant pleural effusion (HR 3.707, 95% CI 1.460-9.414, P0.006) were independent risk factors for PFS2. The most common treatment-related adverse events greater than grade 3 included hypertension (23.7%), proteinuria (8.3%), and increased alanine aminotransferase (ALT 4.1%) and aspartate aminotransferase (AST 2.9%). Continuous original TKI combined with bevacizumab showed partly favorable efficacy and safety and may represent a therapeutic option for metastatic EGFR-mutation NSCLC patients experiencing gradual progression after EGFR-TKI treatment.

Tumor cell-derived exosomal microRNA-146a promotes non-small cell lung cancer cell invasion and proliferation by inhibiting M1 macrophage polarization.

Tumor-associated macrophages (TAMs) affects the outcomes of non-small cell lung cancer (NSCLC). NSCLC cells released exosomes to suppress the antitumor activity of TAMs. MiR-146a is a critical regulator in TAM polarization. We hypothesized that NSCLC cells released exosomal miR-146a to regulate TAM polarization and thus affected its antitumor activity. We used H1299 cells-derived exosomes to stimulate THP-1 cells that was pretreated with phorbol 12-myristate 13-acetate (M0 macrophage). Flow cytometry and reverse transcription-quantitative polymerase chain reaction (PCR) were used to determine the polarization of macrophages. The conditioned medium of exosome-treated M0 cells was used to culture H1299 cells, and the Cell Counting Kit-8, Ki67, transwell and scratch wound assays were used to determine the biological behavior of H1299 cells. To investigate whether exosomal miR-146a regulates TAM macrophages through targeting tumor necrosis factor receptor-associated factor 6 (TRAF-6) and interleukin-1 receptor-associated kinase 1 (IRAK-1), we used small interfering RNA to knockdown the expressions of them. Upregulation of miR-146a inhibited M1 polarization and thus impaired the antitumor activity of TAMs. Exosomes released by H1299 cells can be taken by M0 macrophage, and they upregulated the expression of miR-146a in M0 macrophage. The exosome suppresses M1 polarization by exosomal miR-146a. TRAF-6 and IRAK-1 mediated the inhibitive effects of exosomal miR-146a on M1 polarization. NSCLC cells released exosomal miR-146a to inhibit the expressions of TRAF-6 and IRAK-1 in TAMs, resulting in the impaired antitumor activity of TAMs. NSCLC cell-derived exosomal miR-146a represents a novel therapeutic target for NSCLC treatment.

Adverse skin reactions induced by sintilimab in advanced lung squamous carcinoma a case report and review of the literature.

Sintilimab is an immune checkpoint inhibitor (ICI). It can induce immune-related Adverse Events (irAEs). Severe adverse skin reactions are rare, but the mortality rate is high. We report the first case of successful treatment of adverse skin reactions using traditional Chinese medicine (TCM). Here we present the case of a 67-year-old male with advanced lung squamous carcinoma. After 8 cycles of chemotherapy, the patients disease progressed and the treatment regimen was adjusted to sintilimab combined with albumin paclitaxel and cisplatin. Thirty-two days after this cycle, the patient reported a sporadic rash with pruritus on the face, front chest, and both upper limbs. The area of rash was 40%, and the adverse reaction was grade 3. The level of interleukin-related indicators was above normal. The patients skin symptoms disappeared after treatment with hormones, TCM, and other drugs. The patients adverse skin reaction was due to an immune-related toxicity caused by sintilimab, so treatment with sintilimab was suspended. The albumin-paclitaxel plus cisplatin regimen was continued to treat lung cancer. Although rare, case of fatal adverse reaction caused by sintilimab have been reported. We recommend early monitoring and recognition of symptoms. During management, high-dose hormones combined TCM may be helpful.

Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.

Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success. In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells. The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity. Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Tumor-infiltrating lymphocyte enrichment predicted by CT radiomics analysis is associated with clinical outcomes of non-small cell lung cancer patients receiving immune checkpoint inhibitors.

Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through computed tomography (CT) radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we assess TIL enrichment objectively using an artificial intelligence-powered TIL analysis in hematoxylin and eosin (HE) image and analyze its association with quantitative radiomic features (RFs). Clinical significance of the selected RFs is then validated in the independent NSCLC patients who received ICI. In the training cohort containing both tumor tissue samples and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. The TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density divided by the whole TME area, as measured on an HE slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was applied to CT images from the validation cohort, which included NSCLC patients who received ICI monotherapy. A total of 220 NSCLC samples were included in the training cohort. After filtering the RFs, two features, gray level variance (coefficient 1.71 x 10 In this CT radiomics model, predicted TILes was significantly associated with ICI outcomes in NSCLC patients. Analyzing TME through radiomics may overcome the limitations of tissue-based analysis and assist clinical decisions regarding ICI.

Incidental, Solitary, and Unilateral Adrenal Metastasis as the Initial Manifestation of Lung Adenocarcinoma.

An adrenal incidentaloma is an adrenal mass ≥ 1 cm in size discovered on imaging performed for indications other than suspected adrenal disease. It has variable etiologies, which can be benign or malignant, including primary or metastatic disease. We present a rare case of metastatic lung adenocarcinoma with isolated unilateral adrenal metastases, presenting as an adrenal incidentaloma in an asymptomatic patient with no known history of malignancy. A 76-year-old man with a past medical history of chronic obstructive pulmonary disease (COPD) and heavy tobacco use was admitted for the evaluation and treatment of pneumonia. He was found to have an incidental 4.6 cm unilateral adrenal mass on his CT chest. He underwent a workup for the mass, including further imaging studies that were indeterminate and a hormonal workup that concluded that the mass was nonfunctional. Due to the patients comorbidities, it was determined that he was not a surgical candidate. A multidisciplinary team recommended a biopsy, which revealed metastatic lung adenocarcinoma. The primary lung cancer was located using positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose combined with computed tomography (F-FDG-PETCT). The patient was evaluated by an oncology service and started on chemotherapy. In this case report, we discuss the approach for evaluating adrenal incidentalomas as well as the role the biopsy has in this process based on a literature review. In addition, we draw a comparison between our case and similar cases in the literature while highlighting the differences that make this case unique.

Paclitaxel Has a Reduced Toxicity Profile in Healthy Rats After Polymeric Micellar Nanoparticle Delivery.

Nanocarrier platforms have been indicated to have great potential in clinical practice to treat non-small cell lung cancer (NSCLC). Our previous Phase III clinical study revealed that polymeric micellar paclitaxel (Pm-Pac) is safe and efficacious in advanced NSCLC patients. However, the histopathological-toxicological profile of Pm-Pac in mammals remains unclear. We examined the Pm-Pac-induced antitumour effect in both A549H226 cells and A549H226-derived xenograft tumour models.. And then, we evaluated the short-term and long-term toxicity induced by Pm-Pac in healthy Sprague‒Dawley (SD) rats. The changes in body weight, survival, peripheral neuropathy, haematology, and histopathology were studied in SD rats administered Pm-Pac at different dosages. In the A549-derived xenograft tumour model, better therapeutic efficacy was observed in the Pm-Pac group than in the solvent-based paclitaxel (Sb-Pac) group when an equal dosage of paclitaxel was administered. Toxicity assessments in healthy SD rats indicated that Pm-Pac caused toxicity at an approximately 2- to 3-fold greater dose than Sb-Pac when examining animal body weight, survival, peripheral neuropathy, haematology, and histopathology. Interestingly, based on histopathological examinations, we found that Pm-Pac could significantly decrease the incidences of paclitaxel-induced brain and liver injury but could potentially increase the prevalence of paclitaxel-induced male genital system toxicity. This study introduces the toxicological profile of the engineered nanoparticle Pm-Pac and provides a novel perspective on the Pm-Pac-induced histopathological-toxicological profile in a rat model.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country.

Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method. There were 1581 NSCLC patients in the NCTSD. Based on Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Intraluminal Small Bowel Metastasis From Primary Lung Cancer.

Lung cancer is the leading cause of cancer-related death worldwide, with frequent metastases to the brain, liver, adrenal glands, and bone. The incidence of intraluminal small bowel metastases of the lung is extremely rare and poorly documented within the literature. Few case studies have been published since the late 1980s and early 1990s. However, little is known about this rare form of metastasis. Small bowel metastatic disease has atypical symptoms that mimic a variety of other diseases as a result, signs and symptoms may be overlooked until the disease has progressed to a late stage. Signs of small bowel obstruction, symptomatic anemia, abdominal pain, and peritonitis are commonly reported signs and symptoms. Various modalities can be utilized for the workup of suspected small bowel metastasis, including positron emission tomography, computed tomography, and various forms of endoscopy. The prognosis for lung cancer patients with intestinal metastases is poor, with many only surviving months to a few years after diagnosis. Therefore, it is critical to consider small bowel masses as a differential diagnosis in a patient with primary lung cancer who demonstrates clinical signs consistent with symptomatic anemia secondary to gastrointestinal (GI) bleeding, peritonitis, or small bowel obstruction. We report an unusual case of intraluminal and fungating small bowel masses in a patient who had previously undergone lung resections and chemo-immunotherapy. She was diagnosed with non-small undifferentiated carcinoma with tumor necrosis over 12 years before disease recurrence in the bilateral lungs, right adrenal gland, bone, and small bowel. The discovery of the small bowel metastases occurred while undergoing treatment for advanced-stage disease. At this time, she completed chemo-immunotherapy and remained on maintenance immunotherapy. The patient also underwent a partial right adrenalectomy and radiotherapy to the right adrenal gland. Given that she was experiencing symptomatic anemia and further workup indicated that the GI masses were causing her anemia, she underwent palliative small bowel resection of the masses. The pathology results demonstrated that the masses originated from her primary lung cancer, confirming metastatic disease to the small bowel.

Will Patients With Liver Metastasis From Aggressives Cancers Benefit From Surgical Resection

We aimed to evaluate the outcomes of resections for liver metastases (LMs) originating from pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and esophagusgastric cancers (EGCs), which we label as major killers (MKs overall survival (OS) under 10%). We hypothesized that LM resection must provide the patient with almost a year of OS postoperatively that is considered beneficial. From January 2005 to December 2020, 23 patients underwent resection for isolated LM from MKs. These patients underwent surgery after a multidisciplinary discussion about their performance status, disease evolution during prolonged medical treatment, and the existence or absence of extrahepatic metastases. LM originated from an PDAC, EGC, or NSCLC in 10 patients (43%), nine patients (39%), and four patients (18%), respectively. The median delay between primary cancer and LM diagnoses was 12 months, and the median delay between LM diagnosis and liver resection was 10 months. Most patients, who had objectively responded to medical treatment (57%), had a solitary (61%) and unilobar (70%) LM. Severe morbidity and 90-day mortality rates were 13% and 4.3%, respectively. Margin-free resection was achieved in 16 patients (70%). After liver resection, the median OS was 24 months without a statistical difference when considering the primary tumor site 1, 3-, and 5-year OS were 70%, 23%, and 23%, respectively. Selection based on criteria such as good clinical condition, response to treatment, and long observation period helped identify patients with LM of MKs who seemed to benefit from resection.

Cerebral Infarction Caused by Trousseaus Syndrome Associated With Lung Cancer.

Lung cancer is one of the common cancers that can cause Trousseaus syndrome. However, there are few reports of cerebral infarction due to Trousseaus syndrome associated with lung cancer. The aim of this study is to investigate the clinical features of lung cancer-related cerebral infarction and effective management practice. Japanese patients diagnosed with Trousseaus syndrome-related cerebral infarction associated with lung cancer between August 2012 and November 2021 in our hospital were retrospectively enrolled. Clinical data, treatment, and outcomes of the patients were collected. Ten patients were enrolled. The median age was 65 years (range 43 - 84 years). All patients had advanced lung cancer. The histological types were adenocarcinoma (n 8), pleomorphic carcinoma (n 1), and small cell lung cancer (n 1). Recurrent cerebral infarction occurred in six patients. Among four patients who had continued heparin since the initial infarction, recurrence occurred in one. D-dimer was high in all 10 patients at the initial cerebral infarction. D-dimer level at the time of recurrent cerebral infarctions was higher than that at the first cerebral infarctions. Since performance status declined in nine patients, one patient continued anticancer drugs after cerebral infarction. Four patients died within 100 days of the onset of cerebral infarction. Cerebral infarction of lung cancer-related Trousseaus syndrome has poor prognosis. Heparin may be effective in controlling the condition. In addition, D-dimer may serve as a marker of cancer-related thrombosis.

Thyroid transcription factor-1 expression in rectal adenocarcinoma metastatic to the lung.

Distinguishing metastatic lung tumors from primary lung cancer is essential for planning the appropriate treatment strategy. Thyroid transcription factor-1 (TTF-1) is a reliable immunohistochemistry (IHC) marker for differentiating between primary lung adenocarcinomas and metastatic lung tumors originating from colorectal adenocarcinomas. Herein, we report a rare case of TTF-1 expression in both the metastatic lung tumor and primary rectal adenocarcinoma. Aside from the similar histological characteristics of both tumors when stained with hematoxylin-eosin, the IHC patterns, including negative results for alveolar epithelium markers (napsin A and CK7) and positive results for intestinal markers (CK20, CDX2, SATB2, and β-catenin), of the lung tumor and the primary rectal adenocarcinoma strongly supported the final diagnosis. Considering the non-negligible frequency of TTF-1 positivity in colorectal adenocarcinomas, applying the IHC panel including multiple markers for alveolar epithelium and intestinal differentiation, would be helpful to support the diagnosis of metastatic lung tumor from a rectal adenocarcinoma.

Erratum to lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2.

This corrects the article DOI 10.1515med-2022-0538..

Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues.

Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGFVEGFR therapy however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGFVEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.

Corrigendum to Surface-guided radiotherapy for lung cancer can reduce the number of close patient contacts without compromising initial setup accuracy Tech. Innov. Patient Support Radiat. Oncol. 20 (2021) 61-63.

This corrects the article DOI 10.1016j.tipsro.2021.11.005..

Development and Validation of Coding Algorithms to Identify Patients with Incident Non-Small Cell Lung Cancer in United States Healthcare Claims Data.

We sought to develop and validate an incident non-small cell lung cancer (NSCLC) algorithm for United States (US) healthcare claims data. Diagnoses and procedures, but not medications, were incorporated to support longer-term relevance and reliability. Patients with newly diagnosed NSCLC per Surveillance, Epidemiology, and End Results (SEER) served as cases. Controls included newly diagnosed small-cell lung cancer and other lung cancers, and two 5% random samples for other cancer and without cancer. Algorithms derived from logistic regression and machine learning methods used the entire sample (Approach A) or started with a previous algorithm for those with lung cancer (Approach B). Sensitivity, specificity, positive predictive values (PPV), negative predictive values, and F-scores (compared for 1000 bootstrap samples) were calculated. Misclassification was evaluated by calculating the odds of selection by the algorithm among true positives and true negatives. The best performing algorithm utilized neural networks (Approach B). A 10-variable point-score algorithm was derived from logistic regression (Approach B) sensitivity was 77.69% and PPV 67.61% (F-score 72.30%). This algorithm was less sensitive for patients ≥80 years old, with Medicare follow-up time <3 months, or missing SEER data on stage, laterality, or site and less specific for patients with SEER primary site of main bronchus, SEER summary stage 2000 regional by direct extension only, or pre-index chronic pulmonary disease. Our study developed and validated a practical, 10-variable, point-based algorithm for identifying incident NSCLC cases in a US claims database based on a previously validated incident lung cancer algorithm.

HOXB7 induces STAT3-mediated transformation and lung metastasis in immortalized mammary gland NMuMG cells.

The homeobox family genes are often dysregulated in various cancer types. Particularly HOXB7 amplification and overexpression correlate with poor prognosis in various cancer such as gastric, pancreatic, and lung cancers. Moreover, HOXB7 is known to contribute to cancer progression by promoting epithelial to mesenchymal transition, anticancer drug resistance, and angiogenesis. In this study, we show that HOXB7 is coamplified with ERBB2 in a subset of breast cancer patients and HOXB7 expression correlates with poor prognosis in HER2-positive breast cancer patients. This clinical observation is supported by the following results-HOXB7 overexpression in an immortalized murine mammary gland epithelial cell line NMuMG induces cellular transformation in vitro, tumorigenesis, and lung metastasis through the activation of JAK-STAT signaling.

A 3D Ex Vivo Tumor-Immune Coculture System Mimicking In Vivo Tumor Environmental Stress on CD8 T Cells Exhaustion.

Dissection of exhaustion trajectories of immune cells under tumor selection pressure in the tumor microenvironment (TME) elucidates the underlying machinery in anti-tumor immunity, which still lacks easy-to-use models to decipher. Herein, gelatin methacryloyl (GelMA)-poly (ethylene oxide) (PEO) based 3D hydrogel microspheroids are constructed with non-immunogenicity and controllable macroporous structure to establish a tumor-immune cell coculture (3D-HyGTIC) system. In 3D-HyGTIC system, when immune cells embarked, stepwise up-regulation of main immune checkpoints (ICs) molecules is observed with compromised cytokine production in CD8

Bioengineering and Clinical Translation of Human Lung and its Components.

Clinical lung transplantation has rapidly established itself as the gold standard of treatment for end-stage lung diseases in a restricted group of patients since the first successful lung transplant occurred. Although significant progress has been made in lung transplantation, there are still numerous obstacles on the path to clinical success. The development of bioartificial lung grafts using patient-derived cells may serve as an alternative treatment modality however, challenges include developing appropriate scaffold materials, advanced culture strategies for lung-specific multiple cell populations, and fully matured constructs to ensure increased transplant lifetime following implantation. This review highlights the development of tissue-engineered tracheal and lung equivalents over the past two decades, key problems in lung transplantation in a clinical environment, the advancements made in scaffolds, bioprinting technologies, bioreactors, organoids, and organ-on-a-chip technologies. The review aims to fill the lacuna in existing literature toward a holistic bioartificial lung tissue, including trachea, capillaries, airways, bifurcating bronchioles, lung disease models, and their clinical translation. Herein, the efforts are on bridging the application of lung tissue engineering methods in a clinical environment as it is thought that tissue engineering holds enormous promise for overcoming the challenges associated with the clinical translation of bioengineered human lung and its components.

Value of dual-source CT dual-energy parameters combined with serum detection of VEGF and CEA in the diagnosis of early lung cancer.

To discuss the value of dual-source CT dual-energy parameters combined with serum detection of vascular endothelial growth factor (VEGF) and carcinoembryonic antigen (CEA) in the diagnosis of early lung cancer (LC). In total, 100 patients with lung lesions in our hospital from January 2020 to January 2022 were selected for retrospective study, and were divided into the lung cancer group (group A) and benign lung disease group (group B) according to the final results of pathological diagnosis, using dual-source CT dual-energy scanning combined with serum detection of VEGF and CEA to analyze the diagnostic values of single detection and combined detection. Among the 100 patients with lung lesions, there were 58 patients with LC and 42 patients with benign lung diseases after pathological examination, with no statistical difference in normalized iodine concentration (NIC) and the increased value of iodine at arterial phase between the two groups (P > 0.05). The NIC value of group A was higher than group B at venous phase (P < 0.05). The serum levels of VEGF and CEA in group A were higher than group B (P < 0.05). The area under the curve, specificity, sensitivity, Youden index and 95% CI of combined diagnosis were higher than single detection of NIC, VEGF and CEA at venous phase. The combined application of dual-source CT dual-energy parameters and serum detection of VEGF and CEA has higher diagnostic value in patients with early LC, which can provide effective reference for clinical diagnosis and treatment, with higher application value in clinic.

Construction and validation of a novel tumor necrosis factor-related apoptosis-inducing ligand mutant MuR5S4-TR.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells but has no significant effect on normal cells. However, the use of TRAIL is limited for resistance by more than 50% of the tumor cell lines. Its very important to develop a more efficient form of TRAIL for cancer treatment. The N-terminal in soluble fragments (114-281aa) of TRAIL was redesigned to construct a novel TRAIL mutant-MuR5S4-TR. The Cell Counting Kit-8 method to explore the antitumor effects. The potential mechanisms were also explored. Novel TRAIL mutant with cell-penetrating peptides (CPP) like and Second mitochondria-derived activator of caspases (Smac) like structure-MuR5S4-TR was successfully constructed. The prokaryotic expression system was successfully built, and the MuR5S4-TR was purified and reconfirmed by western blot. MuR5S4-TR could enhance the antitumor effects of TRAIL in most of the cancer cell lines significantly, NCI-H460 lung cancer cell line, for instance. After MuR5S4-TR treatment, the expressions of death receptor 4 (DR4), DR5, Caspase-8, and cleaved Caspase-3 were remarkably increased, however, there was no significant difference in X-linked inhibitor of apoptosis expression. We constructed a novel TRAIL mutant with CPP-like and Smac-like structure-MuR5S4-TR. The MuR5S4-TR showed significantly stronger antitumor effects than TRAIL in many tumor cell lines. The MuR5S4-TR showed strong antitumor effects both in vitro and in vivo. This preliminary study implies that MuR5S4-TR may be a more efficient form of TRAIL for cancer therapy.

In Situ Reprogramming of Tumor-Associated Macrophages with Internally and Externally Engineered Exosomes.

The reprogramming of tumor-associated macrophages (TAMs) has emerged as an efficient strategy for immunotherapy. However, most of the approaches did not allow the in situ reprogramming of TAM because their low efficiency, non-specificity, or potential side effects. Herein, we produced exosomes with the clustered regularly interspaced short palindromic repeats interference (CRISPRi) internally engineered and the TAM specific peptide externally engineered onto the exosome membrane. The internally and externally engineered exosomes (IEEE, also named as I3E) allowed the selective homing to tumor tissue and targeted to M2-like TAMs, which nearly repressed the expression of PI-3 kinase gamma (PI3Kγ) completely, and induced the TAMs polarizing to M1 both in vitro and in vivo. The polarized M1 macrophages awakened the hot tumor-immunity, causing the increase of T lymphocyte infiltration and the decrease of myeloid-derived suppressor cells, and inhibiting the tumor growth significantly. I3E reprogramed TAMs in situ precisely and efficiently.

Patterns of staging, treatment, and mortality in gastric, colorectal, and lung cancer among older adults with and without preexisting dementia a Japanese multicentre cohort study.

Little is known about dementias impact on patterns of diagnosis, treatment, and outcomes in cancer patients. This study aimed to elucidate the differences in cancer staging, treatment, and mortality in older cancer patients with and without preexisting dementia. Using cancer registry data and administrative data from 30 hospitals in Japan, this multicentre retrospective cohort study examined patients aged 65-99 years who were newly diagnosed with gastric, colorectal, or lung cancer in 2014-2015. Dementia status (none, mild, and moderate-to-severe) at the time of cancer diagnosis was extracted from clinical summaries in administrative data, and set as the exposure of interest. We constructed multivariable logistic regression models to analyse cancer staging and treatment, and multivariable Cox regression models to analyse three-year survival. Among gastric (n 6016), colorectal (n 7257), and lung (n 4502) cancer patients, 5.1%, 5.8%, and 6.4% had dementia, respectively. Patients with dementia were more likely to receive unstaged and advanced-stage cancer diagnoses less likely to undergo tumour resection for stage I, II, and III gastric cancer and for stage I and II lung cancer less likely to receive pharmacotherapy for stage III and IV lung cancer more likely to undergo tumour resection for all-stage colorectal cancer and more likely to die within three years of cancer diagnosis. The effects of moderate-to-severe dementia were greater than those of mild dementia, with the exception of tumour resection for colorectal cancer. Older cancer patients with preexisting dementia are less likely to receive standard cancer treatment and more likely to experience poorer outcomes. Clinicians should be aware of these risks, and would benefit from standardised guidelines to aid their decision-making in diagnosing and treating these patients.

Biotin-dependent cell envelope remodelling is required for Mycobacterium abscessus survival in lung infection.

Mycobacterium abscessus is an emerging pathogen causing lung infection predominantly in patients with underlying structural abnormalities or lung disease and is resistant to most frontline antibiotics. As the pathogenic mechanisms of M. abscessus in the context of the lung are not well-understood, we developed an infection model using air-liquid interface culture and performed a transposon mutagenesis and sequencing screen to identify genes differentially required for bacterial survival in the lung. Biotin cofactor synthesis was required for M. abscessus growth due to increased intracellular biotin demand, while pharmacological inhibition of biotin synthesis prevented bacterial proliferation. Biotin was required for fatty acid remodelling, which increased cell envelope fluidity and promoted M. abscessus survival in the alkaline lung environment. Together, these results indicate that biotin-dependent fatty acid remodelling plays a critical role in pathogenic adaptation to the lung niche, suggesting that biotin synthesis and fatty acid metabolism might provide therapeutic targets for treatment of M. abscessus infection.

Artificial intelligence-based radiomics for the prediction of nodal metastasis in early-stage lung cancer.

We aimed to investigate the value of computed tomography (CT)-based radiomics with artificial intelligence (AI) in predicting pathological lymph node metastasis (pN) in patients with clinical stage 0-IA non-small cell lung cancer (c-stage 0-IA NSCLC). This study enrolled 720 patients who underwent complete surgical resection for c-stage 0-IA NSCLC, and were assigned to the derivation and validation cohorts. Using the AI software Beta Version (Fujifilm Corporation, Japan), 39 AI imaging factors, including 17 factors from the AI ground-glass nodule analysis and 22 radiomics features from nodule characterization analysis, were extracted to identify factors associated with pN. Multivariate analysis showed that clinical stage IA3 (p 0.028), solid-part size (p < 0.001), and average solid CT value (p 0.033) were independently associated with pN. The receiver operating characteristic analysis showed that the area under the curve and optimal cut-off values of the average solid CT value relevant to pN were 0.761 and -103 Hounsfield units, and the threshold provided sensitivity, specificity, and negative predictive values of 69%, 65%, and 94% in the entire cohort, respectively. Measuring the average solid-CT value of tumors for pN may have broad applications such as guiding individualized surgical approaches and postoperative treatment.

Symptom Trajectories Informing Patient Care After Lung Cancer Surgery A Longitudinal Patient-Reported Outcome Study.

Application of patient-reported outcomes (PROs) in surgical oncology has been limited because of patient heterogeneity. We analyzed symptom trajectories and their associations with recovery outcomes after lung cancer surgery, aiming to profile the heterogeneity of patients experiences and to identify patients needing extensive care. Symptoms were assessed with the MDASI-LC before surgery, daily after surgery in hospital and weekly within 1 month after discharge. Patients were clustered based on symptoms from post-operative day 1 (POD1) to POD5, using the latent-class-trajectory-model. Functional recovery was compared across the trajectories. Logistic regression was used to explore risk factors for trajectories of more severe symptoms. Based on the five most severe post-surgery symptoms (pain, fatigue, coughing, shortness of breath, and disturbed sleep), we identified three distinct symptom trajectories among 424 patients mild, N 225 (53.07%) severe-to-mild, N 86 (20.28%) severe, N 104 (24.53%). At discharge, more severe patients (73.96%) did not achieve a functional recovery compared with those in mild (32.54%, P < 0.0001) or severe-to-mild (56.96%, P 0.0274) groups. Factors of significant symptom increase on POD1 were younger-than-55 (OR 1.94 95% CI 1.30-2.93, P 0.001), undergoing open or multi-port video-assisted thoracoscopic surgery (OR 1.59 95% CI 1.05-2.41, P 0.03), and using two chest tubes (OR 1.72 95% CI 1.12-2.65, P 0.01). For patients experiencing dramatic symptom increase on POD1, older age (OR 2.51 95% CI 1.40-4.59, P 0.002) was associated with severe trajectory. This study demonstrated that PRO measures were capable of profiling heterogeneous symptom trajectories after lung cancer surgery. Those in-hospital trajectories were able to differentiate patients responses to treatments and signal the needs for extensive post-discharge care.

Com probe implemented STexS II greatly enhances specificity in SARS-CoV-2 variant detection.

The initial introduction of utilizing double helix structural oligonucleotides known as SNP typing with excellent specificity (STexS) in a standard PCR greatly improved the detection of single nucleotide polymorphisms (SNP) by enhancing amplification rates of primer-matching strands and interrupting mismatched strands by constant instability of kinetics regarding alignment attaching and detaching. The model was beneficial overall in detecting SNP variants consisting of large amounts of wildtype strands such as EGFR mutation genotyping for early detection of non-small cell lung cancer. While the STexS PCR is advantageous in detecting SNPs and biomarkers, limitations were yet observed. Despite the ability to detect variants 10 times more effective than a typical amplification-refractory mutation system PCR, it could only perform optimally in DNA concentrations around 101 105. To further enhance STexS specificity to perform detecting viral-RNA variants such as the infamous SARS-CoV-2, a novel improvement of the regular TaqMan Probe using Com-probes to inhibit high copy wild targets and amplify low copy mutant targets. By introducing the novel STexS II, omicron variants of SARS-CoV-2 were able to be successfully detected in high concentrations of normal genes.

Impact of thyroid cancer on the cancer risk in patients with non-alcoholic fatty liver disease or dyslipidemia.

The raised prevalence of obesity has increased the incidence of obesity-related metabolic diseases such as dyslipidemia (DL) and non-alcoholic fatty liver disease (NAFLD), along with the development and progression of various types of cancer, including thyroid cancer. In this study, we investigated whether thyroid cancer in patients with DL and NAFLD could be a risk factor for other cancers. To achieve our goal, we generated two independent cohorts from our institution and from the National Health Insurance System in South Korea. Based on the ICD-10 code, we conducted exact matching (15 matching) and estimated the overall risk of thyroid cancer for other cancers in patients with DL or NAFLD. Univariate and multivariate analyses showed that the hazard ratio (HR) of thyroid cancer was 2.007 (95% Confidence Interval CI, 1.597-2.522) and 2.092 (95% CI, 1.546-2.829), respectively in the institutional cohort and 1.329 (95% CI, 1.153-1.533) and 1.301 (95% CI, 1.115-1.517), respectively in the nationwide cohort. Risk analysis revealed a significant increase in the HR in lip, tongue, mouth, lung, bone, joint, soft tissue, skin, brain, male cancers and lymphoma after thyroid cancer occurred. Thyroid cancer in patients with DL or NAFLD might be a valuable factor for predicting the development of other cancers.

Association of CT findings with invasive subtypes and the new grading system of lung adenocarcinoma.

To predict the differentiation between invasive growth patterns and new grades of lung adenocarcinoma (LAC) using computed tomography (CT). The CT features of 180 surgically treated LAC patients were compared retrospectively to pathological invasive subtypes and tumour grades as defined by the new grading system published in 2021 by the World Health Organization. Two radiologists reviewed the images semi-quantitatively and independently. Univariable and multivariable regression models were built from the statistical means of their assessments to predict invasive subtypes and grades. The area under the curve (AUC) calculation was used to select the best models. The Youden index was applied to determine the cut-off values for radiological parameters. The acinarpapillary patterns were associated with ill-defined margins, lower consolidationtumour ratio and air bronchogram. The solid growth pattern was associated with a well-defined margin and hypodensity, and the micropapillary (MP) subtype with spiculation. From Grades 1 to 3, the amount of air bronchogram decreased and the consolidationtumour ratio increased. In the sub-analyses, the best model for differentiating Grade 2 from Grade 1 had the following CT features solidsubsolid type, consolidationtumour ratio, well-defined margin, and air bronchogram (AUC 0.783) and Grade 3 from Grade 2 size of the consolidation partwhole tumour ratio, size of the consolidation part, and well-defined margin (AUC 0.759). The interobserver agreements between the two radiologists varied between 0.67 and 0.98. Air bronchogram, consolidationtumour ratio, and well-defined margin are among the best imaging findings to discriminate between both invasive subtypes and the new grades in LAC.

Venous thromboembolism incidence and risk factors associated with immune checkpoint inhibitors among patients with advanced non-small cell lung cancer.

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with lung cancer. Systemic therapies, such as chemotherapy (chemo), are associated with increased risk of VTE. Immune checkpoint inhibitors (ICIs) are a new standard of care for the treatment of lung cancer, but their association with VTE is not fully understood. We evaluated the incidence of VTE and risk factors for patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line ICI-based, chemo-based, or ICIchemo regimens. This retrospective cohort study used HealthCore Integrated Research Environment - Oncology data, an integrated database of administrative claims, coupled with clinical data from a cancer-care quality program. Patients with first-line treatment of stage IV non-small cell lung cancer from July 2014 to August 2020 were grouped based on three treatment types ICI-based, chemo-based, or ICIchemo. Patients with VTE before initiation of systemic treatment were excluded. Newly diagnosed VTE events were identified via inpatient and outpatient diagnosis codes. Cox proportional hazards models were used to investigate the factors associated with VTE risk. Among 2299 eligible patients (ICI-based, n605 chemo-based, n1092 ICIchemo, n602) with a median follow-up of 9.1 months, the VTE incidence rates (95% CI) per 100 person-years were 17.8 (95% CI 16.0 to 19.5) overall, 13.5 (95% CI 10.6 to 16.5) for ICI-based, 18.0 (95% CI 15.5 to 20.5) for chemo-based, and 22.4 (95% CI 20.2 to 24.5) for ICIchemo. The 6-month cumulative incidence of VTE was 8.1% for ICI-based, 10.9% for chemo-based, and 12.8% for ICIchemo. Pulmonary embolism was most common, accounting for 63% of the VTE events. After controlling for baseline patient characteristics, the risk of VTE was 26% lower for ICI-based regimens than for chemo-based regimens (HR 0.74, p0.03). There was no meaningful difference in the risk between ICIchemo and chemo-based regimens (HR 1.12, p0.36). Previous radiation and severe obesity (body mass index ≥40) were associated with VTE. VTE incidence rate per 100 person-years was common across regimens in patients with aNSCLC, but numerically lower for patients receiving ICI-based regimens compared with those receiving chemo-based and ICIchemo regimens. VTE is a common complication of lung cancer, and there is a continued need for awareness of VTE as a comorbidity in this population.

Clinicopathological and predictive value of MAIT cells in non-small cell lung cancer for immunotherapy.

Immune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment. To investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing. MAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients. MAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy.

Longitudinal patient-reported outcomes 1 year after thoracoscopic segmentectomy versus lobectomy for early-stage lung cancer a multicentre, prospective cohort study protocol.

Segmentectomy and lobectomy are the main surgical procedures for early-stage lung cancer. However, few studies have analysed patient-reported outcomes after segmentectomy versus lobectomy. This study aims to compare patient-reported outcomes-such as symptoms, daily functioning and quality of life-between thoracoscopic segmentectomy and lobectomy for early-stage lung cancer during the 1 year after surgery. Overall, 788 newly diagnosed patients with early-stage lung cancer (tumour size ≤2 cm), who are scheduled to undergo thoracoscopic segmentectomy or lobectomy, will be recruited in this multicentre, prospective cohort study. The patients will receive standardised care after surgery. The Perioperative Symptom Assessment for Lung Surgery-a validated lung cancer surgery-specific scale-will be used to assess the symptoms and functions at baseline, at discharge and monthly after discharge for 1 year. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Lung Cancer module 29 will be used to assess the patients quality of life at the same time points. The primary outcome will be the shortness of breath scores during the first year after thoracoscopic segmentectomy and lobectomy and will be compared using mixed-effects models. The secondary outcomes will include other symptoms, indicators of daily functioning, quality of life scores and traditional clinical outcomes. These will be compared using mixed-effects models and the Students t-test, non-parametric test or Χ The Ethics Committee for Medical Research and New Medical Technology of Sichuan Cancer Hospital approved this study (approval number SCCHEC-02-2022-002). All participants will be instructed to provide informed consent. The manuscript is based on protocol version 3.0. The study results will be presented at medical conferences and published in peer-reviewed journals. ChiCTR2200060753.

The c-Myc targeting hnRNPAB promotes lung adenocarcinoma cell proliferation via stabilization of CDK4 mRNA.

The c-Myc oncoprotein plays a pivotal role in tumorigenesis. The deregulated expression of c-Myc has been linked to a variety of human cancers including lung adenocarcinoma. The oncogenic function of c-Myc has been largely attributed to its intrinsic nature as a transcription factor. Here we reported the RNA binding protein hnRNPAB as a direct transcriptional target of c-Myc by performing quantitative real-time polymerase chain reaction (qRT-PCR), western blot, chromatin immunoprecipitation (ChIP), and luciferase reporter analyses. Flow cytometry, colony formation, and RNA immunoprecipitation (RIP) assays were used to investigate the role of hnRNPAB in lung adenocarcinoma cell proliferation, as well as the underlying mechanism. HnRNPAB was functionally shown to promote lung adenocarcinoma cell proliferation by accelerating G1S cell cycle progression. Mechanistically, hnRNPAB interacted with and stabilized CDK4 mRNA, thereby increasing CDK4 expression. Moreover, hnRNPAB was able to promote G1S cell cycle progression and cell proliferation via the regulation of CDK4. HnRNPAB was also revealed as a mediator of the promoting effect of c-Myc on cell proliferation. Together, these findings demonstrate that hnRNPAB is an important regulator of lung adenocarcinoma cell proliferation. They also add new insights into the mechanisms of how c-Myc promotes tumorigenesis.

Central Nervous System Disease in Patients With RET Fusion-Positive NSCLC Treated With Selpercatinib.

Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases. A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest systemic progression of disease and death were considered competing risks. The median age was 65 years, and the most common 5 fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval CI 0%-10%), 10% (95% CI 0%-22%), 17% (3%-30%), 17% (3%-30%), and 20% (5%-35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI 0%-0%). CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role.

Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression.

Exosome is an important way for tumor cells to communicate with other cells and plays an important role in tumor progression. Previous studies revealed that miR-195-5p acts as a tumor suppressor in lung cancer. However, the role and molecular mechanism of exosomal transferred miR-195-5p in lung adenocarcinoma (LAC) remains unknown. Here, we found that miR-195-5p expression in circulating exosomes of LAC patients was lower than that of healthy controls. Meanwhile, the expression of exosomal miR-195-5p from normal bronchial epithelial cell line BEAS-2B cells was significantly higher than that of lung cancer cell lines. The exosome labeling assay confirmed that BEAS-2B cells-derived exosomes could be captured by lung cancer cells. Furthermore, exosomal miR-195-5p derived from BEAS-2B cells remarkably inhibited the proliferation, migration, invasion of lung cancer cells, and tumor growth in vivo. In addition, exosomal miR-195-5p from BEAS-2B cells also suppressed the tube-forming ability of vascular endothelial cells. Moreover, we verified that miR-195-5p decreased apelin (APLN) expression to inactivate the Wnt signaling pathway, thereby inhibiting tumor invasiveness and angiogenesis. In conclusion, our research shows that exosomal miR-195-5p from normal bronchial epithelial cells hinders the progression of LAC, suggesting that regulation of exosomal miR-195-5p provides a novel strategy for LAC treatment.

Novel EGFR-mutant mouse models of lung adenocarcinoma reveal adaptive immunity requirement for durable osimertinib response.

Lung cancers bearing oncogenically-mutated EGFR represent a significant fraction of lung adenocarcinomas (LUADs) for which EGFR-targeting tyrosine kinase inhibitors (TKIs) provide a highly effective therapeutic approach. However, these lung cancers eventually acquire resistance and undergo progression within a characteristically broad treatment duration range. Our previous study of EGFR mutant lung cancer patient biopsies highlighted the positive association of a TKI-induced interferon γ transcriptional response with increased time to treatment progression. To test the hypothesis that host immunity contributes to the TKI response, we developed novel genetically-engineered mouse models of EGFR mutant lung cancer bearing exon 19 deletions (del19) or the L860R missense mutation. Both oncogenic EGFR mouse models developed multifocal LUADs from which transplantable cancer cell lines sensitive to the EGFR-specific TKIs, gefitinib and osimertinib, were derived. When propagated orthotopically in the left lungs of syngeneic C57BL6 mice, deep and durable shrinkage of the cell line-derived tumors was observed in response to daily treatment with osimertinib. By contrast, orthotopic tumors propagated in immune deficient nunu or Rag1

Dose Limiting Pulmonary Toxicity in a Phase 12 Study of Radiation and Chemotherapy with Ipilimumab Followed by Nivolumab for Patients With Stage 3 Unresectable Non-Small Cell Lung Cancer.

We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial. Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mgkg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests. The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3) possible treatment-related toxicity, most commonly pulmonary AEs (n 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n 12, 63%) or patient choice (n 2, 11%). Eleven patients (58%) experienced G2 pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached NR), and 12-month freedom from G2 pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumoniachronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method. Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonatecholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.

Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response A real-world study.

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.

One-off low-dose CT screening of positive nodules in lung cancer A prospective community-based cohort study.

To improve the early stage diagnosis and reduce the lung cancer (LC) mortality for positive nodule (PN) population, data on effectiveness of PN detection using one-off low-dose spiral computed tomography (LDCT) screening are needed to improve the PN management protocol. We evaluate the effectiveness of PN detection and developed a nomogram to predict LC risk for PNs. A prospective, community-based cohort study was conducted. We recruited 292,531 eligible candidates during 2012-2018. Individuals at high risk of LC based on risk assessment underwent LDCT screening and were divided into PN and non-PN groups. The effectiveness of PN detection was evaluated in LC incidence, mortality, and all-cause mortality. We performed subgroup analysis of characteristic variables for the association between PN and LC risk. A competing risk model was used to develop the nomogram. Participants (n 14901) underwent LDCT screening PNs were detected in 1193 cases (8·0%). After a median follow-up of 6·1 years, 193 were diagnosed with LC (1·3%). Of these, 94 were in the PN group (8·0%). LC incidence, mortality, and all-cause mortality were significantly higher in the PN group (adjusted hazard ratios 10.60 (7.91-14.20), 7.97 (5.20-12.20), and 1.94 (1.51-2.50), respectively). Additionally, various PN characteristics were associated with an increased probability of developing LC. The C-index value of the nomogram for predicting LC risk of PN individuals was 0·847. The protocol of PNs management for improvement could focus on specific characteristic population and high-risk PN individuals by nomogram assessment.

Pan-cancer antagonistic inhibition pattern of ATM-driven G2M checkpoint pathway vs other DNA repair pathways.

DNA repair mechanisms keep genome integrity and limit tumor-associated alterations and heterogeneity, but on the other hand they promote tumor survival after radiation and genotoxic chemotherapies. We screened pathway activation levels of 38 DNA repair pathways in nine human cancer types (gliomas, breast, colorectal, lung, thyroid, cervical, kidney, gastric, and pancreatic cancers). We took RNAseq profiles of the experimental 51 normal and 408 tumor samples, and from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases - of 500407 normal and 5752646 tumor samples, and also 573 normal and 984 tumor proteomic profiles from Proteomic Data Commons portal. For all the samplings we observed a congruent trend that all cancer types showed inhibition of G2M arrest checkpoint pathway compared to the normal samples, and relatively low activities of p53-mediated pathways. In contrast, other DNA repair pathways were upregulated in most of the cancer types. The G2M checkpoint pathway was statistically significantly downregulated compared to the other DNA repair pathways, and this inhibition was strongly impacted by antagonistic regulation of (i) promitotic genes CCNB and CDK1, and (ii) GADD45 genes promoting G2M arrest. At the DNA level, we found that ATM, TP53, and CDKN1A genes accumulated loss of function mutations, and cyclin B complex genes - transforming mutations. These findings suggest importance of activation for most of DNA repair pathways in cancer progression, with remarkable exceptions of G2M checkpoint and p53-related pathways which are downregulated and neutrally activated, respectively.

Liver angiocrine factors.

Endothelial cells secrete growth factors, chemokines, and extracellular matrix components, including angiocrine factors or angiokines, involved in the regulation of organ morphogenesis, homeostasis, and regeneration. The concepts of angiocrine signaling have been demonstrated in the liver, pancreas, brain, lung, heart, kidney, skin, bone marrow, as well as in pathological conditions, including cancer. The aim of this review article is to analyze the role of angiocrine factors in the liver in physiological as well as in pathological conditions.

Enrolment of older adults with advanced or metastatic non-small cell lung cancer in first-line clinical trials in the multicentre ESME cohort.

There is a great need for data based on clinical trials for the older population in order to improve treatment. Historically, the inclusion rate of older adults in clinical trials has been low, but the rate specific to lung cancer is unknown, as are the factors associated with enrolment. We used the national Epidemio-Strategy and Medical Economics Advanced or Metastatic Lung Cancer (AMLC) Data Platform, a multicentre real-life database. Inclusion criteria were patients with advanced or metastatic non-small cell lung cancer (AMNSCLC) aged 70 years or older, with at least one line of systemic treatment from 01 January 2015 to 31 December 2018. The primary objective was to evaluate the proportion of older adults enrolled in clinical trials. Secondary objectives were to identify factors associated with enrolment in clinical trials for older patients and to compare the overall survival of older adults included in trials versus those not included. There were 3488 patients aged ≥70 years (median age at AMNSCLC 75 years). Among older patients, 234 (6.7%) were enrolled in a clinical trial in the first-line setting. Significant factors associated with enrolment in the multivariable analysis in older patients were good Eastern Cooperative Oncology Group (ECOG) Performance Status (PS 0) (p < 0.001), de novo versus recurrent presentation at diagnosis (p < 0.001), and non-central nervous system (CNS) metastases versus advanced setting or CNS metastases (p < 0.001). Medical history was associated with fewer inclusions (odds ratio OR 0.74, 95% confidence interval CI 0.56 0.99). Among older patients, being enrolled in a trial in the first-line setting was not associated with better overall survival (OS) (hazard ratio HR 1.03 95%CI 0.86-1.22) in the multivariable analysis. In this large database, few older AMNSCLC patients were enrolled in a trial. Factors associated with enrolment were good ECOG PS, absence of medical history, de novo AMNSCLC, and presentation with non-CNS metastases.

Fatal Stent-Associated Respiratory Tract Infection Caused by K64-ST11 KPC-2-Producing Carbapenem-Resistant Hypervirulent

BAP1 is a novel regulator of HIF-1α.

Single-cell transcriptomic analyses provide insights into the cellular origins and drivers of brain metastasis from lung adenocarcinoma.

Brain metastasis (BM) is the most common intracranial malignancy causing significant mortality, and lung cancer is the most common origin of BM. However, the cellular origins and drivers of BM from lung adenocarcinoma (LUAD) have yet to be defined. The cellular constitutions were characterized by single-cell transcriptomic profiles of 11 LUAD primary tumor (PT) and 10 BM samples (GSE131907). Copy number variation (CNV) and clonality analysis were applied to illustrate cellular origins of BM tumors. Brain metastasis-associated epithelial cells (BMAECs) were identified by pseudotime trajectory analysis. By using machine-learning algorithms, we developed the BM-index representing the relative abundance of BMAECs in the bulk RNA-seq data, indicating high risk of BM. Therapeutic drugs targeting BMAECs were predicted based on the drug sensitivity data of cancer cell lines. Differences in macrophages and T cells between PTs and BMs were investigated by single-cell RNA (scRNA) and immunohistochemistry and immunofluorescence data. CNV analysis demonstrated BM was derived from subclones of PT with a gain of chromosome 7. We then identified BMAECs and its biomarker, S100A9. Immunofluorescence indicated strong correlations of BMAECs with metastasis and prognosis evaluated by the paired PT and BM samples from Peking Union Medical College Hospital (PUMCH). We further evaluated the clinical significance of BM-index and identified 7 drugs that potentially target BMAECs. This study clarified possible cellular origins and drivers of metastatic LUAD at single cell level, and laid a foundation for early detections of LUAD patients with a high risk of BM.

FOXO3 Activation Prevents Cellular Senescence in Emphysema Induced by Cigarette Smoke.

Because cigarette smoke can induce COPDemphysema through accelerating senescence with or without an incomplete repair system. However, the pathogenesis of COPD following lung senescence induced by CS is not fully understood. Airspace enlargement and airway epithelial cell senescence are common finding during the COPD development. We investigated the lung tress response to CS and demonstrated that a stress-responsive transcription factor, FOXO3, was regulated by deacetylase. SIRT1 inhibited FOXO3 acetylation and FOXO3 degradation, leading to FOXO3 accumulation and activation in airway epithelial cells. CS exposure activated SIRT1 contributed to FOXO3 activation and functioned to protect lungs, as deletion of SIRT1 decreased CS-induced FOXO3 activation and resulted in more severe airway epithelial cells senescence airspace enlargement. Strikingly, deletion of FOXO3 during the development of COPD aggravated lung structural and functional damage, leading to a much more profound COPD phenotype. We show that deletion of FOXO3 resulted in decreased autophagic response and increased senescence, which may explain lung protection by FOXO3. Our study indicates that in the COPD, stress-responsive transcription factors can be activated for adaptions to counteract senescence insults, thus attenuating COPD development.

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls. Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls. This prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Womens Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n 45 358) on ageyear of enrollment and study arm. Cancer diagnosis (site, stage, and treatment) via Medicare and medical records. Trajectories of self-reported physical function (RAND Short Form 36 RAND-36 scale range 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis. This study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, -5.3 95% CI, -6.4 to -4.3 points per year in regional vs -2.8 95% CI, -3.4 to -2.3 for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, -7.9 95% CI, -12.2 to -3.6 points per year with any chemotherapy -3.1 95% CI, -6.0 to -0.3 with radiation therapy alone and -2.6 95% CI, -4.2 to -1.0 with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined -4.3 95% CI, -5.9 to -2.6 points per year in the year following diagnosis vs -1.4 95% CI, -1.7 to -1.0 points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis. In this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

Trends in real-world biomarker testing and overall survival in US patients with advanced non-small-cell lung cancer.

Molecular diagnostics play a critical role in precision medicine. Treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend that patients newly diagnosed with advanced non-small-cell lung cancer (aNSCLC) undergo molecular testing for PD-L1 and genomic aberrations to guide treatment choices. Based on the results of such biomarker testing, physicians can select optimal treatments for individual patients. The aim of this study was to describe the latest trends and disparities in real-world biomarker testing with a focus on PD-L1 and to explore the impact of biomarker testing on outcomes in first-line treatment of aNSCLC in the United States. Patients initiating first-line aNSCLC treatment were identified in the Flatiron Health database (112015–10312021 N 30,631). Annual trends in pre-first-line biomarker testing (PD-L1, major genomic aberrations), demographic and clinical factors associated with PD-L1 testing, and associations between PD-L1 andor ≥1 genomic aberration testing and outcomes (e.g., overall survival OS, time-to-next treatment TTNT) were assessed. Biomarker testing in patients receiving first-line treatment for aNSCLC increased between 2015 and 2017 and plateaued between 2018 and 2021. By 2021, approximately 20% of patients did not receive PD-L1 testing before first-line treatment and not all patients had equal access to testing. Both PD-L1 and genomic aberration testing were associated with improved OS and TTNT. This is likely due to enhanced treatment decisions leading to optimal treatment selection. Future research is warranted to understand interventions to improve biomarker testing and reduce disparities between different patient populations to improve treatment outcomes.

Cathelicidin LL-37 promotes EMT, migration and metastasis of hepatocellular carcinoma cells in vitro and mouse model.

The effect of cathelicidin hCAP18LL-37 in hepatocellular carcinoma (HCC) metastasis remains unclear. Here, we confirmed that LL-37 expression enhanced endothelial-mesenchymal transition (EMT), migration and invasion in HCC cells. And the HER2EGFR-MAPKERK signal participated in the process above. More frequent lung metastases were observed in an LL-37-overexpressing hematogenous metastasis model. Interestingly, 1,25(OH)

A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC the final ASTRIS data.

Osimertinib is a drug that blocks the activity of a protein called EGFR on cancer cells, reducing their growth and spread. ASTRIS is the largest real-world study that evaluated the outcomes with osimertinib treatment for patients with advanced non-small-cell lung cancer (NSCLC), and the EGFR T790M mutation, who had received previous treatment for their cancer. There were 3014 patients included in this study. The main aim of this study was to measure the time at which half of the patients were still alive after starting osimertinib treatment, this was 22.8 months. The study also measured the time at which half of the patients had experienced worsening (progression) of their cancer (11.1 months) and the time when half of the patients had stopped receiving osimertinib treatment (13.5 months). None of the patients experienced any unexpected side effects of the treatment. These data are consistent with those observed in comparable clinical trials with osimertinib, supporting the use of osimertinib treatment for patients with advanced NSCLC and the EGFR T790M mutation after their initial cancer treatment has stopped working.

Automated Coronary Artery Calcium and Quantitative Emphysema in Lung Cancer Screening Association With Mortality, Lung Cancer Incidence, and Airflow Obstruction.

To assess automated coronary artery calcium (CAC) and quantitative emphysema (percentage of low attenuation areas %LAA) for predicting mortality and lung cancer (LC) incidence in LC screening. To explore correlations between %LAA, CAC, and forced expiratory value in 1 second (FEV1) and the discriminative ability of %LAA for airflow obstruction. Baseline low-dose computed tomography scans of the BioMILD trial were analyzed using an artificial intelligence software. Univariate and multivariate analyses were performed to estimate the predictive value of %LAA and CAC. Harrell C-statistic and time-dependent area under the curve (AUC) were reported for 3 nested models (Modelsurvey age, sex, pack-years Modelsurvey-LDCT Modelsurvey plus %LAA plus CAC Modelfinal Modelsurvey-LDCT plus selected confounders). The correlations between %LAA, CAC, and FEV1 and the discriminative ability of %LAA for airflow obstruction were tested using the Pearson correlation coefficient and AUC-receiver operating characteristic curve, respectively. A total of 4098 volunteers were enrolled. %LAA and CAC independently predicted 6-year all-cause (Modelfinal hazard ratio HR, 1.14 per %LAA interquartile range IQR increase 95% CI, 1.05-1.23, 2.13 for CAC ≥400 95% CI, 1.36-3.28), noncancer (Modelfinal HR, 1.25 per %LAA IQR increase 95% CI, 1.11-1.37, 3.22 for CAC ≥400 95%CI, 1.62-6.39), and cardiovascular (Modelfinal HR, 1.25 per %LAA IQR increase 95% CI, 1.00-1.46, 4.66 for CAC ≥400, 95% CI, 1.80-12.58) mortality, with an increase in concordance probability in Modelsurvey-LDCT compared with Modelsurvey (P<0.05). No significant association with LC incidence was found after adjustments. Both biomarkers negatively correlated with FEV1 (P<0.01). %LAA identified airflow obstruction with a moderate discriminative ability (AUC, 0.738). Automated CAC and %LAA added prognostic information to age, sex, and pack-years for predicting mortality but not LC incidence in an LC screening setting. Both biomarkers negatively correlated with FEV1, with %LAA enabling the identification of airflow obstruction with moderate discriminative ability.

Study on the hepatotoxicity and potential mechanism of gefitinib based on CYP450 in mice and AML12 cells.

Gefitinib is mainly used for the treatment of non-small-cell lung cancer. Hepatotoxicity is one of the main side effects of gefitinib, and seriously affects the treatment process of the disease. However, the hepatotoxicity mechanism of gefitinib remains unclear. The hepatotoxicity of different doses of gefitinib was investigated in mice and AML-12 cells, and the possible correlation of hepatotoxicity with CYP450 was analysed. The toxic effects of gefitinib were confirmed by the increased liver index, decreased body weight and survival rate, injured liver function and histopathology followed 16 days of oral administration. Gefitinib (400 mgkg) upregulated the hepatic mRNA expression of CYP1A1 and downregulated the CYP2D9 and CYP2D10 in mice. Furthermore, we verified that gefitinib produced cytotoxicity on AML-12 cells in a dose and time-dependent manner, and confirmed that gefitinib (20 μM) induced cell apoptosis, upregulated mRNA expression of CYP1A1 and downregulated CYP2D9 and CYP2D10. Pearson correlation analysis also showed that the hepatotoxicity of gefitinib was positively correlated with CYP1A1 and negatively correlated with CYP2D9 and CYP2D10. Our results suggested that the hepatotoxicity gefitinib may be associated with CYP1A1, CYP2D9 and CYP2D10. These findings will contribute to a better understanding of the mechanism of gefitinib hepatotoxicity.

RNA-Binding Proteins as a Molecular Link between COPD and Lung Cancer.

Chronic obstructive pulmonary disease (COPD) represents an independent risk factor for lung cancer development. Accelerated cell senescence, induced by oxidative stress and inflammation, is a common pathogenic determinant of both COPD and lung cancer. The post transcriptional regulation of genes involved in these processes is finely regulated by RNA-binding proteins (RBPs), which regulate mRNA turnover, subcellular localization, splicing and translation. Multiple pro-inflammatory mediators (including cytokines, chemokines, proteins, growth factors and others), responsible of lung microenvironment alteration, are regulated by RBPs. Several mouse models have shown the implication of RBPs in multiple mechanisms that sustain chronic inflammation and neoplastic transformation. However, further studies are required to clarify the role of RBPs in the pathogenic mechanisms shared by lung cancer and COPD, in order to identify novel biomarkers and therapeutic targets. This review will therefore focus on the studies collectively indicating the role of RBPs in oxidative stress and chronic inflammation as common pathogenic mechanisms shared by lung cancer and COPD.

Radiation-induced lung injury (RILI) is one of the most prominent complications of thoracic radiotherapy for which effective therapy is still lacking. This study investigates the nutraceutical potential of the culinary spice

Immunotherapy-based therapy as a promising treatment for EGFR-mutant advanced non-small cell lung cancer patients after EGFR-TKI resistance.

Traditionally, epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has been regarded as a cold tumor based on the immunosuppressive tumor immune microenvironment (TIME). However, recent studies have found that EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment could shift host immunity from immunosuppressive to immunosupportive TIME, which has renewed hopes of immunotherapy. In this review, we highlight five main immunotherapy-based therapies for patients after EGFR-TKI failure, including safety and efficacy data from prospective and retrospective clinical studies. The efficacy of immunotherapy alone is extremely limited. Immunotherapy plus chemotherapy show an ORR of 29.5%-59.3% and an mPFS of about 7 months. There is still scarce evidence for immunotherapy plus antiangiogenesis therapy. A combination of immunotherapy with EGFR-TKIs exhibits higher treatment-related adverse events and lower clinical outcomes compared to EGFR-TKI alone. Importantly, immunotherapy plus antiangiogenesis and chemotherapy achieves an mPFS of 6.9-10.2 months. In general, the strategy of combining immunotherapy with chemotherapy andor an antiangiogenic drug is a novel and promising method for treating advanced NSCLC after EGFR-TKI failure. Therefore, the dominant population of EGFR-TKI resistant patients were characterized by EGFR uncommon mutation, EGFR L858R mutation, PD-L1 ≥ 50%, prior antiangiogenic drugs, and negative T790 M mutation for immunotherapy-based therapy.

Nighttime continuous contactless smartphone-based cough monitoring for the ward A validation study.

Clinical deterioration can go unnoticed in hospital wards for hours. Mobile technologies such as wearables and smartphones enable automated, continuous, non-invasive ward monitoring and allow the detection of subtle changes in vital signs. Cough holds great potential for monitoring through mobile technologies on the ward as it is not only a symptom of prevalent respiratory diseases such as asthma, lung cancer, and COVID-19 but also a predictor of acute health deterioration. In past decades, many efforts have been made to develop an automatic cough counting tool. To date, however, there is neither a standardized, sufficiently validated method nor a scalable cough monitor that can be deployed on a consumer-centric device that reports cough counts continuously. These shortcomings limit the tracking of coughing and, consequently, hinder the monitoring of disease progression in prevalent respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19 in the ward. This exploratory study involves the validation of an automated smartphone-based monitoring system for continuous cough counting in two different modes in the ward. Unlike previous studies that focused on evaluating cough detection models on unseen data, the focus of this work is to validate a holistic smartphone-based cough detection system operating in near real-time. Automated cough counts are measured consistently on-device and on-computer, and compared with cough and non-cough sounds counted manually over eight hours long nocturnal recordings in nine patients with pneumonia in the ward. The proposed cough detection system consists primarily of an Android app running on a smartphone that detects coughs and records sounds, and secondarily of a backend that continuously receives the cough detection information and displays the hourly cough counts. Cough detection is based on an ensemble Convolutional Neural Network developed and trained on asthmatic cough data. In this validation study, a total of 72 hours of recording from nine participants with pneumonia, four of whom were infected with SARS-CoV-2, were analyzed. All recordings were subjected to manual analysis by two blinded raters. The proposed system yielded sensitivity and specificity of 72% and 99% on-device and 82% and 99% on-computer, respectively, for detecting coughs. The mean difference between the automated and human rater cough counts were -1.0, CI 95% -12.3, 10.2 and -0.9, CI 95% -6.5, 4.8 coughs per hour within-subject for the on-device and on-computer mode, respectively. The proposed system thus represents a smartphone cough counter that can be used for continuous hourly assessment of cough frequency in the ward.

Development of a new minimally invasive phototherapy for lung cancer using antibody-toxin conjugate.

Photodynamic therapy (PDT) is a cancer-targeted treatment that uses a photosensitizer (PS) and laser irradiation. The effectiveness of current PDT using red light for advanced cancers is limited, because red light can only reach depths within a few millimeters. To enhance the antitumor effect for lung cancers, we developed a new phototherapy, intelligent targeted antibody phototherapy (iTAP). This treatment uses a combination of immunotoxin and a PS, mono-L-aspartyl chlorin e6 (NPe6). We examined whether cetuximab encapsulated in endosomes was released into the cytosol by PS in PDT under light irradiation. A431 cells were treated with fluorescein isothiocyanate-labeled cetuximab, NPe6, and light irradiation and were observed with fluorescence microscopy. We analyzed the cytotoxicity of saporin-conjugated cetuximab (IT-cetuximab) in A431, A549, and MCF7 cells and the antitumor effect in model A549-bearing mice in vivo using the iTAP method. Fluorescent microscopy analysis showed that the photodynamic effect of NPe6 (20 μM) and light irradiation (37.6 Jcm Our study is the first report of the iTAP method using NPe6 for lung cancer cells. The iTAP method may become a new, minimally invasive treatment superior to current PDT methods.

Pulmonary Hydatid Cyst in Children and Adults Diagnosis and Management.

Hydatid cyst disease induced by Echinococcus granulosus is a parasitic disease known since ancient times. Today, it continues to be seen in many countries and creates serious problems. The lung is the second most frequently affected organ by hydatid cysts after the liver. Lung involvement is more prevalent in children than adults, and the growth of the cyst is faster in children. Hydatid cysts are mostly seen in the right lower lobe of the lung. Common symptoms are chest pain, cough, and shortness of breath, with the most diagnostic symptom being the expectoration of cyst fluid or membranes. In endemic areas, the diagnosis of hydatid cysts can usually be made easily by clinical findings, serology tests, and radiological findings. When the hydatid cyst ruptures and becomes complicated, it is clinically and radiologically confused with many diseases, especially lung cancer. Surgery is accepted as primary treatment of lung hydatid cysts all over the world. The surgical approach is related to several factors such as the size of the cyst, whether it is intact or complicated, unilateral or bilateral, solitary or multiple, and the presence of destruction of the lung parenchyma. Although it is stated by some surgeons that capitonnage is not required, the most frequently applied surgical technique is cystotomy and capitonnage. Pulmonary resection should be avoided as much as possible, particularly in children. Albendazole or mebendazole treatment in pulmonary hydatid cyst is generally used after surgery and to prevent recurrences.

Cost-effectiveness analysis of atezolizumab plus chemotherapy as first-line treatment for patients with advanced nonsquamous non-small-cell lung cancer in China.

The aim of the study was to evaluate the cost-effectiveness of adding atezolizumab to first-line chemotherapy for advanced nonsquamous non-small-cell lung cancer (NSCLC) from Chinese healthcare system. A partitioned survival model (PSM) was established to simulate 3-week patients transition in a 20-year time horizon to estimate the health and economic outcomes of adding atezolizumab to first-line chemotherapy for advanced nonsquamous NSCLC. Costs and utility values were obtained from the local charges and published studies. Sensitivity analyses were conducted to confirm the robustness of the model results. Atezolizumab plus chemotherapy yielded additional 0.36 life years (LYs) and 0.23 quality-adjusted life-years (QALYs), and the marginal cost was $60,154.48, resulting in an ICER of atezolizumab plus chemotherapy versus chemotherapy was $267,264.85QALY. One-way sensitivity analyses revealed that the cost of atezolizumab was the main driver of the model outcomes, and the probabilistic sensitivity analyses suggested that atezolizumab plus chemotherapy had 0% probability of being cost-effective first-line option at the willingness-to-pay (WTP) threshold of $37,652QALY in China. Atezolizumab plus chemotherapy could not be considered cost-effective compared with chemotherapy alone as the first-line strategy for patients with advanced nonsquamous NSCLC in China. And appropriately reduce the price of atezolizumab is necessary.

Survival outcome of upfront surgery for clinical single-station N2 non-small cell lung cancer.

Pathological N2 (pN2) non-small cell lung cancer (NSCLC) is diverse its treatment depends on the clinical N (cN) status. We aimed to determine the efficacy of upfront surgery for cN2pN2 NSCLC. The study included 43 cN2pN2 NSCLC patients who underwent upfront surgery at the Shizuoka Cancer Center between 2002 and 2017. Survival outcome, focusing on cN2 status, was retrospectively investigated. Mediastinal lymph nodes were pre-operatively evaluated using computed tomography and positron emission tomography. Surgical eligibility criteria included single-station cN2. N2 with N1 and skip N2 were defined as N2 with and without ipsilateral hilar lymph node metastasis, respectively. A platinum-doublet regimen was used for adjuvant chemotherapy. Survival curves were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model. Clinical-skip N2 and cN2 with N1 cases included 22 and 21 patients, respectively. Twenty-three patients received adjuvant chemotherapy. The median follow-up duration was 73 months. Clinical-skip N2 had a significantly better 5-year recurrence-free survival (RFS) than cN2 with N1 (58.3 vs 28.6%, P 0.038) and was an independent favorable RFS predictor. Recurrence within 18 months occurred in 71% of cN2 with N1 cases. Five-year overall survival and RFS rates in patients receiving adjuvant chemotherapy vs those without adjuvant chemotherapy were 82.2 vs 41.9% (P 0.019) and 56.5 vs 28.0% (P 0.049), respectively. Clinical-skip N2 had an excellent prognosis, and upfront surgery was acceptable. Conversely, upfront surgery followed by chemotherapy is not recommended for cN2 with N1 patients because of early recurrence.

Association between socioeconomic status and net survival after primary lung cancer surgery a tertiary university hospital retrospective observational study in Japan.

Inequalities in opportunities for primary lung cancer surgery due to socioeconomic status exist. We investigated whether socioeconomic inequalities exist in net survival after curative intent surgery at a tertiary university hospital, in Japan. Data from the hospital-based cancer registry on primary lung cancer patients who received lung resection between 2010 and 2018 were linked to the surgical dataset. An area deprivation index, calculated from small area statistics and ranked into tertiles based on Japan-wide distribution, was linked with the patients address as a proxy measure for individual socioeconomic status. We estimated net survival of up to 5 years by deprivation tertiles. Socioeconomic inequalities in cancer survival were analyzed using an excess hazard model. Of the 1039 patient-sample, advanced stage (Stage IIIA) was more prevalent in the most deprived group (28.1%) than the least deprived group (18.0%). The 5-year net survival rates (95% confidence interval) from the least to the most deprived tertiles were 82.1% (76.2-86.6), 77.6% (70.8-83.0) and 71.4% (62.7-78.4), respectively. The sex- and age-adjusted excess hazard ratio of 5-year death was significantly higher in the most deprived group than the least deprived (excess hazard ratio 1.64, 95% confidence interval 1.09-2.47). The hazard ratio reduced toward null after additionally accounting for disease stage, suggesting that the advanced stage may explain the poor prognosis among the deprived group. There was socioeconomic inequality in the net survival of patients who received curative intent surgery for primary lung cancer. The lower socioeconomic status group might be less likely to receive early curative surgery.

Pharmacotherapy for lung cancer with comorbid interstitial pneumonia limited evidence requires appropriate evaluation.

Reply to Pharmacotherapy for lung cancer with comorbid interstitial pneumonia limited evidence requires appropriate evaluation.

Patient-specific respiratory motion management using lung tumors vs fiducial markers for real-time tumor-tracking stereotactic body radiotherapy.

In real-time lung tumor-tracking stereotactic body radiotherapy (SBRT), tracking accuracy is related to radiotherapy efficacy. This study aimed to evaluate the respiratory movement relationship between a lung tumor and a fiducial marker position in each direction using four-dimensional (4D) computed tomography (CT) images. A series of 31 patients with a fiducial marker for lung SBRT was retrospectively analyzed using 4DCT. In the upper (UG) and middle and lower lobe groups (MLG), the cross-correlation coefficients of respiratory movement between the lung tumor and fiducial marker position in four directions (anterior-posterior, left-right, superior-inferior SI, and three-dimensional 3D) were calculated for each gating window (≤1, ≤2, and ≤ 3 mm). Subsequently, the proportions of phase numbers in unplanned irradiation (with lung tumors outside the gating window and fiducial markers inside the gating window) were calculated for each gating window. In the SI and 3D directions, the cross-correlation coefficients were significantly different between UG (mean r 0.59, 0.63, respectively) and MLG (mean r 0.95, 0.97, respectively). In both the groups, the proportions of phase numbers in unplanned irradiation were 11 %, 28 %, and 63 % for the ≤ 1-, ≤2-, and ≤ 3-mm gating windows, respectively. Compared with MLG, fiducial markers for UG have low cross-correlation coefficients between the lung tumor and the fiducial marker position. Using 4DCT to assess the risk of unplanned irradiation in a gating window setting and selecting a high cross-correlation coefficient fiducial marker in advance are important for accurate treatment using lung SBRT.

Antibody Correlates of Protection From Severe Respiratory Syncytial Virus Disease in a Vaccine Efficacy Trial.

Respiratory syncytial virus (RSV) can cause serious lung infections in young children and there is currently no available vaccine. We used complementary statistical frameworks to analyze 4 RSV serology measurements in mothers and their infants in South Africa who participated in a phase 3 maternal immunization trial of an RSV F protein nanoparticle vaccine as correlates of risk and of protection against different RSV disease endpoints. We found evidence to support each antibody measurement-encompassing RSV-neutralizing antibodies and F surface glycoprotein-binding antibodies-as an inverse correlate of risk of RSV-associated acute lower respiratory tract infection with severe hypoxia in at least 1 framework, with vaccine-induced fold-rise from the maternal enrollment to day 14 samples of anti-F immunoglobulin G (IgG) binding antibodies having the most consistent evidence. This evidence includes a significant association of fold-rise anti-F IgG with vaccine efficacy (VE) achieving a baseline covariate-adjusted VE of 75% requires a vaccine-induced maternal anti-F IgG fold-rise of around 16. Neither multivariable logistic regression nor superlearning analyses showed benefit to including multiple time points or assays in the same model, suggesting a parsimonious correlate. Post hoc exploratory analyses supported adherence of vaccine-induced maternal anti-F IgG fold-rise to the Prentice criteria for a valid surrogate endpoint. Our results suggest that the vaccine induced protective anti-F antibody responses. If this finding is confirmed, VE could potentially be augmented by increasing these responses.

The Influence of Adopting New Reference Breathing Parameters on ICRP66 Model on the Regional Deposition of the Inhaled Attached Radon-222 Daughters Within the Human Airways.

The radiation dose from internal radiation exposure is difficult to measure directly and hence different lung models were developed. The dose on the lung is the result of the regional deposition of aerosols carrying radon daughters in the respiratory tract. Deposition of aerosols can be take place during inhalation and exhalation in the 5 regions of the respiratory tract due to variation of aerosol sizes and other biological factors such as breathing rate. In this paper, a modified breathing rate is instead applied on the assumptions developed by the ICRP66 model to analyze the regional deposition of radioactive aerosols and a comparison has been made with the result of ICRP66 model deposition. According to the result, as the diameter of aerosols increases from 1 to 10 μm, the percentage deposition fraction in extrathoracic regions, in ET1 region increases from 6.53% to 48.43% and in ET2 region increases from 7.3% to 50.33%. The aerodynamic deposition of the attached fraction of radon aerosols along the bronchial regions (bronchi (BB), and bronchiolar (bb) region) is found small and almost constant. For 1 μm diameter aerosols, the percentage deposition is found 0.82%, for 5 μm diameter aerosols, the deposition is predicted 2.56% and at 10 μm the deposition is predicted about 1.93% in bronchi (BB) region. In the bronchiolar region (bb) for 1 μm aerosols, the deposition predicted is 1.5% and at 10 μm about 0.88% is predicted. The deposition of small size attached fraction of radon aerosols is found maximum in the alveolar region as compared to other regions of the respiratory tract and the deposition becomes almost negligible for large size aerosols in this region.

Two cases report of secretory carcinoma of the salivary gland in the lung one primary and one metastatic after many years.

Secretory carcinoma of the salivary gland (SCSG) is a recently discovered salivary gland tumor that occurs mostly in the major salivary glands and occasionally in the skin, cervix, trachea, etc. Secretory carcinoma of the lung is extremely rare. To our knowledge, this is the third report of SCSG arising as a primary pulmonary tumor. The two SCSG cases reported in this paper are unique in that one was primary and the other was metastasized to the lung. Case 1 is a primary endobronchial tumor in a 66-year-old man. He went to the doctor complaining of fever, cough and yellow phlegm, and his body weight was significantly reduced by 3 kg. The bronchoscope showed the growth of new organisms in the right upper lobe of the lung. Immunohistochemistry of his biopsy specimen was positive for AE1AE3, Keratin7 (CK7), S-100, mammaglobin, and pan-TRK, but negative for thyroid transcription factor-1 (TTF-1), napsin-A, synaptophysin (SYN), chromogranin A (CGA), and discovered on GIST-1 (Dog-1), and the MKI-67 (Ki-67) proliferation index was 2%. This case lacked the typical By examining these two cases, we have a better understanding of the clinicopathological features of secretory carcinoma, which will help to improve the accuracy of pathological diagnosis.

Clinical Profile, Practice Pattern, and Outcomes With First-Line Therapy in ALK-Positive Lung Cancer Real-World Data From Resource-Constrained Settings.

ALK inhibitors are one of the success stories in precision medicine for treating patients with advanced ALK-positive NSCLC. Nevertheless, developing countries have substantial constraints in using ALK inhibitors, with limited data from India. An audit of a prospectively collected database of patients with advanced ALK-positive NSCLC treated from January 2013 to March 2018 was conducted. The SPSS version 20.0 was used for statistical analysis. A total of 441 patients were available for analysis 62.5% were males, median age was 50 (range 19-75) years, and 78.3% had Eastern Cooperative Oncology Group performance status of 0 to 1. When all the lines of therapies were included in the analysis, ALK inhibitors could be used in 379 (85.9%) of the total ALK-positive patients and 292 patients (66.2%) received ALK inhibitors in the first line in any strategy. The major reason for not starting ALK inhibitors upfront was financial constraints in 69% of the patients. The median progression-free survival on first-line therapy for the entire cohort was 14.1 months (95% confidence interval CI 12.2-15.9), with a significant difference between patients receiving ALK inhibitor in first line in any strategy versus not in first line (17.2 mo 95% CI 14.5-19.9 versus 5.9 mo 95% CI 4.2-7.6, Most of our patients with ALK-positive NSCLC were exposed to ALK inhibitors through various support mechanisms. Those patients who could receive ALK inhibitors in the first line had a significant survival advantage as compared with others.

A Mechanism Exploration for the Yi-Fei-San-Jie Formula against Non-Small-Cell Lung Cancer Based on UPLC-MSMS, Network Pharmacology, and

Non-small-cell lung cancer (NSCLC) is one of the most prevalent cancers worldwide. A Yi-Fei-San-Jie formula (YFSJF), widely used in NSCLC treatment in south China, has been validated in clinical studies. However, the pharmacological mechanism behind it remains unclear. In this study, 73 compounds were identified using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MSMS), with 58 enrolled in network pharmacology. The protein-protein interaction network, functional enrichment analysis, and compound-target-pathway network were constructed using 74 overlapping targets from 58 drugs and NSCLC. YFSJF has many targets and pathways in the fight against NSCLC. PIK3R1, PIK3CA, and AKT1 were identified as key targets, and the PI3KAKT pathway was identified as the key pathway. According to the Human Protein Atlas (THPA) database and the Kaplan-Meier Online website, the three key targets had varying expression levels in normal and abnormal tissues and were linked to prognosis. Molecular docking and dynamics simulations verified that hub compounds have a strong affinity with three critical targets. This study revealed multiple compounds, targets, and pathways for YFSJF against NSCLC and suggested that YFSJF might inhibit PIK3R1, PIK3CA, and AKT1 to suppress the PI3KAKT pathway and play its pharmacological role.

TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer.

Ferroptosis, a newly identified form of cell death, plays critical roles in the development and chemoresistance of lung cancer. Tripartite motif 6 (TRIM6) acts as an E3-ubiquitin ligase and can promote the progression of human colorectal cancer. The present study is aimed at investigating its role and potential mechanisms in lung cancer. Lentiviral vectors were used to overexpress or knock down TRIM6 in human lung cancer cells. Cell survival, colony formation, lipid peroxidation, intracellular iron levels, and other ferroptotic markers were examined. The role of TRIM6 on ferroptosis and chemosensitivity was further tested in mouse tumor xenograft models. TRIM6 was highly expressed in human lung cancer tissues and cells, and its expression in the lung cancer cells was further increased by ferroptotic stimulation. TRIM6 overexpression inhibited, while TRIM6 silence promoted erastin- and RSL3-induced glutaminolysis and ferroptosis in the lung cancer cells. Mechanistically, TRIM6 directly interacted with solute carrier family 1 member 5 to promote its ubiquitination and degradation, thereby inhibiting glutamine import, glutaminolysis, lipid peroxidation, and ferroptotic cell death. Moreover, we observed that TRIM6 overexpression reduced the chemotherapeutic effects of cisplatin and paclitaxel. In contrast, TRIM6 silence sensitized human lung cancer cells to cisplatin and paclitaxel in vivo and in vitro. Our findings for the first time define TRIM6 as a negative regulator of ferroptosis in the lung cancer cells, and TRIM6 overexpression enhances the resistance of human lung cancer cells to chemotherapeutic drugs. Overall, targeting TRIM6 may help to establish novel strategies to treat lung cancer.

Exploratory Analysis of Survival and Mortality Rates among Older Lung Cancer Patients Utilizing Different Treatment Modalities.

A Complete Sustained Response of Advanced Non-Small-Cell Lung Cancer After Immune Checkpoint Inhibitor, Radiotherapy, and Chemotherapy.

Lung cancer is the leading cause of cancer-related mortality worldwide. The treatment of advanced lung cancer is improving with the development of new treatments like immune checkpoint inhibitors (ICIs) and various molecular targeted agents, which have extended overall survival (OS). However, complete remissions remain rare. The efficacy of chemotherapy is modest, which makes a complete sustained response very unlikely, especially when compared with more recent options. In this article, we report a stage IV non-small-cell lung cancer (SCLC) that achieved a complete response in 2018 with chemotherapy (cisplatin and paclitaxel) after pembrolizumab and after the patient had received radiotherapy for superior vena cava syndrome (SVCS). The patient remains in complete response as of October 2022. We hypothesized that the overlap between circulating anti-PD-1, radiotherapy, and cytotoxic agents could explain this outcome.

The Curious Case of the Black Buboes.

Anthracosis is an environmental lung disease caused by carbon deposition and pigmentation in the airways. However, in rare instances, it can also have systemic involvement. We present a patient with B-symptoms and diffuse lymphadenopathy who was diagnosed with the infrequently described nodal anthracosis. A 64-year-old Vietnamese gentleman with a 50-pack-year smoking history who was recently diagnosed with prostate cancer post-radical prostatectomy and awaiting radiation therapy presented with generalized weakness, low-grade fever, night sweats, and unquantifiable weight loss for a month. He was hemodynamically stable, and examination revealed bilateral inguinal and axillary lymphadenopathy. Computed tomography (CT) showed diffuse lymphadenopathy involving the mediastinum, hilar, axillary, mesenteric, retroperitoneal, and bilateral iliac chains with multiple diffuse pulmonary nodules. Laboratories disclosed anemia, thrombocytopenia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), albumin-globulin (A-G) reversal, and sterile blood cultures. The disseminated intravascular coagulation panel was negative with normal fibrinogen and mildly elevated D-dimer. Autoimmune workup, including antinuclear antibody (ANA), was negative. Infectious workup included

Asymptomatic Intraosseous Meningioma of the Humerus A Case Report and Review of the Literature.

Meningiomas are the most common central nervous system tumor. They are typically benign neoplasms but may produce neurological symptoms due to mass effect. Meningiomas may also extend to extradural locations however, these account for only a small percentage of all meningiomas. Most extradural meningiomas arise in intraosseous locations, usually within the cranial bones or vertebrae. However, this is a rare case of extradural extension of an asymptomatic intracranial meningioma to the proximal humerus in the absence of any musculoskeletal symptoms. To the best of our knowledge, this presentation of an extradural intraosseous meningioma has not previously been reported in the literature. We present a case of an incidental intraosseous meningioma in a 66-year-old man. This patient was initially being screened for metastasis of stage IA1 adenocarcinoma of the lung, and a positron emission tomography (PET) scan revealed a focus of activity in the proximal diaphysis of the right humerus suspicious for malignancy. The upper extremity magnetic resonance imaging (MRI) demonstrated an indeterminate lesion. Curettage of the humeral lesion revealed an intraosseous psammomatous meningioma without evidence of metastatic lung carcinoma. Our case report aims to illustrate the importance of considering alternative metastatic sources, such as intracranial meningioma, during the investigation of an indeterminate bony lesion. This is the first case to illustrate asymptomatic intraosseous meningioma in an appendicular skeletal location, highlighting the need for thorough source investigation.

Alcoholic liver disease in relation to cancer incidence and mortality Findings from a large, matched cohort study in South Korea.

To estimate the risk of cancer incidence and mortality among patients with alcoholic liver disease in South Korea. A matched cohort study was conducted, including 1,042,185 men (alcoholic liver disease cases 208,437 controls 833,748) and 100,400 women (alcoholic liver disease cases 20,080 controls 80,320), matched for sex, age, smoking, alcohol consumption, and body mass index at a 14 ratio. The risk of cancer incidence and mortality in the alcoholic liver disease group was assessed using Cox proportional hazards regression models. Both men and women with alcoholic liver disease had an elevated risk of all-cancer and liver cancer incidence and mortality in comparison with the control group. In men, alcoholic liver disease was associated with a significantly higher risk of development of 10 cancer types, including lip, oral cavity, and pharynx esophagus liver gallbladder and biliary tract pancreas larynx lung kidney thyroid gland and leukemia. Subgroup analysis by hepatitis B and C infection showed increased hazard ratios of all cancer incidences and mortality in the alcoholic liver disease group, regardless of hepatitis B or C infection status. In both sexes, a higher number and more years of hospital or clinic visits for alcoholic liver disease were associated with an increased risk of incidence and mortality from all cancers and liver cancer. A more profound dose-response relationship between alcoholic liver disease and alcohol consumption was observed in women than in men. Our findings emphasize the need for a clinical surveillance program and the early detection of cancer in patients with alcoholic liver disease.

Cost-effectiveness of first-line immunotherapies for advanced non-small cell lung cancer.

Researchers have not simultaneously compared the cost-effectiveness of six immunotherapies with chemotherapy for advanced non-small cell lung cancer. This study evaluated the cost-effectiveness across different programmed death-ligand 1 (PD-L1) levels. A Markov model with lifetime horizon was created for seven regimens pembrolizumab plus chemotherapy (pembro-chemo), nivolumab plus ipilimumab (nivo-ipi), nivolumab, ipilimumab plus chemotherapy (nivo-ipi-chemo), atezolizumab plus chemotherapy (atezo-chemo), atezolizumab, bevacizumab plus chemotherapy (atezo-beva-chemo), single-agent pembrolizumab, and chemotherapy alone. Input parameters were derived from trial data, a network meta-analysis, and other literature. We conducted the analysis from the perspective of US health care sector. For all patients without considering PD-L1 expression, the incremental cost-effectiveness ratio (ICER) of pembro-chemo versus chemotherapy was $183,299 per quality-adjusted life year (QALY). The preferred regimens based on ICERs differed by PD-L1 levels. For patients with PD-L1 ≥50%, pembrolizumab versus chemotherapy and pembro-chemo versus pembrolizumab resulted in ICERs of $96,189 and $198,913 per QALY, respectively. The other strategies were dominated. For patients with PD-L1 of 1%-49%, the ICER of pembro-chemo comparing to chemotherapy was $218,159 per QALY. The other regimens were dominated by pembro-chemo. For patients with PD-L1 <1%, nivo-ipi versus chemotherapy and nivo-ipi-chemo versus nivo-ipi resulted in ICERs of $161,277 and $881,975 per QALY, and the other regimens were dominated strategies. At the willingness-to-pay threshold of $150,000 per QALY, pembrolizumab had 87% and pembro-chemo had 1% probabilities being cost-effective in patients with PD-L1 ≥50% and 1%-49%, respectively. Nivo-ipi had a 34% probability being cost-effective in patients with PD-L1 <1%. The PD-L1 level should be incorporated into treatment decision-making. Our findings suggest that first-line pembrolizumab, pembro-chemo, and nivo-ipi are the preferred strategies for patients with PD-L1 ≥50%, 1%-49%, and <1%, respectively.

Reducing tobacco-associated lung cancer risk a study protocol for a randomized clinical trial of AB-free kava.

Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers. A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 11 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit. Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kavas benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases. ClinicalTrials.gov with the identifier NCT05081882. Registered on October 18, 2021.

Cyanoacrylate glue foreign body after CT-guided localization of a pulmonary nodule during video-assisted thoracoscopic surgery a case report.

A tracheal foreign body is a common airway aspiration that creates an emergency, which often causes unobserved respiratory problems and requires management. Iatrogenic tracheal foreign bodies are rarely observed, which results in tracheal obstruction. If the foreign body were removed from the tracheobronchial system, it would save lives. A similar case of a tracheal foreign body was focused on, which was caused by medical glue used during preoperative computed tomography localization of pulmonary nodules. The foreign body was deposited in the right upper bronchi, accidentally discovered after anesthesia when a double-lumen tube was located by fiber bronchoscopy. Following a video-assisted thoracoscopic surgery, the foreign body was removed using a respiratory endoscopy without subsequent adverse consequences for the patient. There is a risk of complications from iatrogenic airway foreign bodies for preoperative localization of pulmonary nodules by injecting cyanoacrylate glue.

Endobronchial metastasis secondary to occulting renal cell carcinoma literature review and a rare case report.

Endobronchial Metastasis from extrathoracic tumors is a rare neoplasm that accounts for approximately 1.1% of total endobronchial malignancies. The most common primary tumors associated with EBM are from the colorectal, breast, and kidney regions. Although it represents a late manifestation in the context of tumor progression, it can rarely antedate the diagnosis of the primary tumor. A 67-years-old male was referred from another city hospital to our thoracic surgery department due to a 4-months history of hemoptysis and productive cough. A chest X-ray and computed tomography scan showed a soft-tissue mass within the left main bronchus and atelectasis of the anterior segment of the left upper lobe. Furthermore, a flexible bronchoscopy revealed a hypervascular lesion occluding completely the left upper lobe bronchus. The patient underwent lobectomy and pathological examination suggested endobronchial metastasis from clear cell renal cell carcinoma. A second computed tomography scan of the abdomen and pelvis showed a well-defined mass arising from the lateral aspect of the right kidney therefore, the patient underwent right radical nephrectomy three weeks later and pathology confirmed the diagnosis of clear renal cell carcinoma with endobronchial metastasis. Despite its rarity, physicians should consider the possibility of endobronchial metastases in the setting of endobronchial lesions. Proper diagnostic approaches should also be considered to rule out the potential of asymptomatic extrathoracic neoplasms. In this manuscript, we aimed to report a rare case -the first from Syria to our knowledge- of an endobronchial metastasis that preceded the diagnosis of renal cell carcinoma. Importantly, we reviewed the existing literature and discussed the diagnostic and treatment approaches.

NEMO- and RelA-dependent NF-κB signaling promotes small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKKNF-κB signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMOIKKγ, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-κB signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-κB family member p65RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKKNF-κB signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-κB levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKKNF-κB signaling plays an important role in promoting SCLC, identifying the IKKNF-κB pathway as a promising therapeutic target.

Influence of Tyrosyl-DNA Phosphodiesterase 1 Inhibitor on the Proapoptotic and Genotoxic Effects of Anticancer Agent Topotecan.

To date, various strategies have been proposed to increase the efficiency of cancer therapy. It is known that the action of DNA repair system can determine the resistance of cancer cells to DNA-damaging chemotherapy and radiotherapy, and one of these ways to increase therapeutic efficiency is the search for inhibitors of enzymes of the DNA repair system. Inhibition of the DNA repair enzyme tyrosyl-DNA phosphodiesterase1 (Tdp1) leads to an increase in the effectiveness of the topoisomerase 1 (Top1) inhibitor, the anticancer drug topotecan. Covalent complexes Top1-DNA, which are normally short-lived and are not a threat to the cell, are stabilized under the influence of topotecan and lead to cell death. Tdp1 eliminates such stabilized complexes and thus weaken the effect of topotecan therapy. We have previously shown that the use of the usnic acid hydrazonothiazole derivative OL9-119 in combination with topotecan increased the antitumor and antimetastatic efficacy of the latter in a mouse model of Lewis lung carcinoma. In this work, it was shown that the combined use of topotecan and Tdp1 inhibitor, the hydrazonothiazole derivative of usnic acid OL9-119, leads to an increase in the DNA-damaging effect of topotecan which is used in the clinic for the treatment of cancer. The study of the proapoptotic effect of the compound OL9-119 showed that the compound itself does not induce apoptosis, but increases the proapoptotic effect of topotecan. The results of the study could be used to improve the effectiveness of anticancer therapy andor to reduce the therapeutic dose of topotecan and, therefore, the severity of side effects.

Application of PLGA as a Biodegradable and Biocompatible Polymer for Pulmonary Delivery of Drugs.

Pulmonary administration of biodegradable polymeric formulation is beneficial in the treatment of various respiratory diseases. For respiratory delivery, the polymer must be non-toxic, biodegradable, biocompatible, and stable. Poly D, L-lactic-co-glycolic acid (PLGA) is a widely used polymer for inhalable formulations because of its attractive mechanical and processing characteristics which give great opportunities to pharmaceutical industries to formulate novel inhalable products. PLGA has many pharmaceutical applications and its biocompatible nature produces non-toxic degradation products. The degradation of PLGA takes place through the non-enzymatic hydrolytic breakdown of ester bonds to produce free lactic acid and glycolic acid. The biodegradation products of PLGA are eliminated in the form of carbon dioxide (CO

Genetic trajectory and clonal evolution of multiple primary lung cancer with lymph node metastasis.

Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis havent been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.

Human lung carcinomas synthesize immunoregulatory glucocorticoids.

The need for new options in lung cancer treatment inevitably leads back to basic research. The tumor itself and the tumor environment especially the interaction with the immune system need to be better understood to develop targeted therapies. In the context of lung cancer glucocorticoids (GC) are mainly known as a combination drug to attenuate side-effects of chemotherapies. However, endogenous extra-adrenal GC have been shown to substantially regulate local immune responses within various tissues, including the lung. In this study we investigated whether primary lung tumors have maintained the capacity to synthesize GC and may thereby regulate anti-tumor immune responses. We show that several non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC) cell lines express key steroidogenic enzymes and synthesize bioactive GC under steady state conditions. We also show that tumor-derived GC can inhibit splenic T cell activation, thus demonstrating their immunoregulatory potential. Moreover, steroidogenic enzymes were detected by quantitative RT-PCR and immunohistochemistry in tissue sections of different human lung tumors, further strengthening the idea that human lung carcinomas regulate their microenvironment by releasing immunoregulatory GC, which potentially contributes to immune evasion and treatment resistance.

The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells.

Human cancers often re-express germline factors, yet their mechanistic role in oncogenesis and cancer progression remains unknown. Here we demonstrate that DEAD-box helicase 4 (DDX4), a germline factor and RNA helicase conserved in all multicellular organisms, contributes to increased cell motility and cisplatin-mediated drug resistance in small cell lung cancer (SCLC) cells. Proteomic analysis suggests that DDX4 expression upregulates proteins related to DNA repair and immuneinflammatory response. Consistent with these trends in cell lines, DDX4 depletion compromised in vivo tumor development while its overexpression enhanced tumor growth even after cisplatin treatment in nude mice. Further, the relatively higher DDX4 expression in SCLC patients correlates with decreased survival and shows increased expression of immuneinflammatory response markers. Taken together, we propose that DDX4 increases SCLC cell survival, by increasing the DNA damage and immune response pathways, especially under challenging conditions such as cisplatin treatment.

An epithelial-to-mesenchymal transition induced extracellular vesicle prognostic signature in non-small cell lung cancer.

Despite significant therapeutic advances, lung cancer remains the leading cause of cancer-related death worldwide

A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium.

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynureninetryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

Old age and EGFR mutation status in inoperable early-stage non-small cell lung cancer patients receiving stereotactic ablative radiotherapy A single institute experience of 71 patients in Taiwan.

Stereotactic ablative radiotherapy (SABR) is now the standard of care for patients with inoperable early-stage lung cancer. Many of these patients are elderly. EGFR (epidermal growth factor receptor) mutation is also common in the Asian population. To evaluate the effects of old age and EGFR mutation on treatment outcomes and toxicity, we reviewed the medical records of 71 consecutive patients with inoperable early-stage non-small cell lung cancer (NSCLC) who received SABR at Taipei Veterans General Hospital between 2015 and 2021. The study revealed that median age, follow-up, Charlson comorbidity index, and ECOG score were 80 years, 2.48 years, 3, and 1, respectively. Of these patients, 37 (52.1%) were 80 years or older, and 50 (70.4%) and 21 (29.6%) had T1 and T2 diseases, respectively. EGFR mutation status was available for 33 (46.5%) patients, of whom 16 (51.5%) had a mutation. The overall survival rates at 1, 3, and 5 years were 97.2, 74.9, and 58.3%, respectively. The local control rate at 1, 3, and 5 years was 97.1, 92.5, and 92.5%, respectively. Using Cox proportional hazards regression we found that male sex was a risk factor for overall survival (p 0.036, 95% CI 1.118-26.188). Two patients had grade 2 pneumonitis, but no other grade 2 or higher toxicity was observed. We did not find any significant differences in treatment outcomes or toxicity between patients aged 80 or older and those with EGFR mutations in this cohort. These findings indicate that age and EGFR mutation status do not significantly affect the effectiveness or toxicity of SABR for patients with inoperable early-stage NSCLC.

Safety and feasibility of minimally invasive lobectomy after neoadjuvant immunotherapy for non-small cell lung cancer.

The objective of this study was to evaluate the feasibility of minimally invasive surgery (MIS) and perioperative outcomes following neoadjuvant immunotherapy for resectable non-small cell lung cancer (NSCLC). Patients with stage I to III NSCLC treated with immunotherapy with or without chemotherapy or chemotherapy alone prior to lobectomy were identified in the National Cancer Database (2010-2018). The percentage of operations performed minimally invasively, conversion rates, and perioperative outcomes were evaluated using propensity-score matching. Propensity-score matching was also used to compare perioperative outcomes between patients who underwent an open lobectomy and those who underwent an MIS lobectomy after neoadjuvant immunotherapy. Of the 4229 patients identified, 218 (5%) received neoadjuvant immunotherapy and 4011 (95%) received neoadjuvant chemotherapy alone. There was no difference in the rate of MIS lobectomy among patients who received immunotherapy compared with those who received chemotherapy alone in propensity score-matched analysis (60.8% vs 51.6% P .11). There also were no significant differences in the rate of conversion from MIS to open lobectomy (14% vs 15%, P .83 odds ratio, 1.1 95% confidence interval, 0.51-2.24) or in nodal downstaging, margin positivity, 30-day readmission, and 30- and 90-day mortality between the 2 groups. In a subgroup analysis of only patients treated with neoadjuvant immunotherapy, there were no differences in pathologic or perioperative outcomes between patients who underwent open lobectomy and those who underwent MIS lobectomy. In this national analysis, neoadjuvant immunotherapy for resectable NSCLC was not associated with an increased likelihood of the need for thoracotomy, conversion from MIS to open lobectomy, or inferior perioperative outcomes.

Effects of tract embolization on pneumothorax rate after percutaneous pulmonary microwave ablation a rabbit study.

To determine the effects of tract embolization with gelatin sponge particles on the prevention of pneumothorax after percutaneous microwave ablation (MWA) in rabbit lungs. Twenty-four New Zealand white rabbits were randomly divided into Group A (MWA followed by tract embolization with gelatin sponge particles, Twenty-four animals underwent 47 sessions of MWA (24 sessions in Group A and 23 sessions in Group B). Group A had a statistically lower rate of pneumothorax than Group B (25.0 Results of the present study showed needle tract embolization with gelatin sponge particles after CT-guided pulmonary MWA can significantly reduce the incidence of pneumothorax. Gelatin sponge particles can effectively seal the needle tract after ablation and can be completely absorbed in the body with good safety.

PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection.

The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisinkexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 11 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference -30% 95% CI -53.40% to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline -56% vs -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference -37.50% 95% CI -68.20% to -6.70%). PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 IMPACT-SIRIO 5 NCT04941105).

Current situation and future directions of lung cancer risk factor awareness in Palestine a cross-sectional study.

To evaluate lung cancer (LC) risk factor awareness among Palestinians and identify factors associated with good awareness. Cross-sectional study. Participants were recruited using convenience sampling from hospitals, primary healthcare centres (PHCs) and public spaces located at 11 governorates in Palestine. Of 5174 approached, 4817 participants completed the questionnaire (response rate93.1%). A total of 4762 questionnaires were included 2742 from the West Bank and Jerusalem (WBJ) and 2020 from the Gaza Strip. Exclusion criteria were working or studying in a health-related field, having a nationality other than Palestinian and visiting oncology departments or clinics at the time of data collection. TOOL A modified version of the validated LC Awareness Measure was used for data collection. The primary outcome was LC risk factor awareness level as determined by the number of factors recognised poor (0-3), fair (4-7) and good (8-10). Secondary outcomes include the recognition of each LC risk factor. Smoking-related risk factors were more often recognised than other LC risk factors. The most recognised risk factors were smoking cigarettes (n4466, 93.8%) and smoking shisha (waterpipes) (n4337, 91.1%). The least recognised risk factors were having a close relative with LC (n2084, 43.8%) and having had treatment for any cancer in the past (n2368, 49.7%).A total of 2381 participants (50.0%) displayed good awareness of LC risk factors. Participants from the WBJ and the Gaza Strip had similar likelihood to display good awareness (50.6% vs 49.1%). Being≥45 years, having higher education and monthly income, knowing someone with cancer and visiting hospitals and PHCs seemed to have a positive impact on displaying good awareness. Half of study participants displayed good awareness of LC risk factors. Educational interventions are warranted to further improve public awareness of LC risk factors, especially those unrelated to smoking.

Novel Image-Guided Flexible-Probe Transbronchial Microwave Ablation for Stage 1 Lung Cancer.

Image-guided percutaneous thermal ablation is an established treatment option for early-stage lung cancer in medically inoperable patients but carries a high risk of pleura-related complications, particularly pneumothorax. This study aimed to determine if image-guided transbronchial microwave ablation (tMWA) is a feasible approach to treat peripheral stage 1 lung cancer. A prospective, single-arm, multicenter study sought to enroll 40 adults who were medically inoperable or declined surgery for peripheral stage 1 lung tumors (≤20 mm). Ablation was performed using navigational bronchoscopy and a flexible MWA probe, guided by cone-beam CT with augmented fluoroscopy. Follow-up at 1, 6, and 12 months included CT imaging of the ablation zone and possible tumor recurrence, adverse events (AEs), pulmonary function, and quality of life. Across 2 sites, 11 tumors (10 NSCLC, 1 carcinoid) were treated in 10 enrolled patients. Median tumor diameter was 13 × 14 mm (7-19 mm) and median minimum ablative margin was 11 mm (5-19 mm). Technical success and technique efficacy were achieved in all patients. No tumor recurrence was seen during 12-month follow-up. No pneumothorax, pleural effusion, or bronchopleural fistula were noted. Minor AEs included scant hemoptysis, pain, cough, and dyspnea. Two serious AEs occurred ≤30 days of ablation and included a COPD exacerbation (day 9) and a death of unknown cause (day 15). The death led the sponsor to halt enrollment. Pulmonary function and quality-of-life indices remained stable. Image-guided tMWA is a technically feasible approach for peripheral early-stage lung cancer but warrants further evaluation of safety and efficacy in larger cohorts.

Effect of Chemotherapy in Stage II-IV Large Cell Lung Carcinoma and Construction of its Predictive Nomograms A SEER Analysis.

Large cell lung carcinoma (LCLC) is generally poorly differentiated with a poor prognosis. This study aimed to explore the impact of chemotherapy on the prognosis of patients with stage Ⅱ-Ⅳ LCLC and to construct nomograms to predict overall survival (OS) and cancer-specific survival (CSS). Propensity score matching (PSM) analysis was used to balance the effects of baseline characteristics. The Kaplan-Meier method was used to analyze the prognostic impact of chemotherapy on LCLC patients. Cox regression analysis was used to identify prognostic risk factors, and then nomograms were constructed and validated. Overall, we identified 2532 patients with LCLC from the Surveillance, Epidemiology, and End Results (SEER) database. The chemotherapy group showed better OS and CSS compared to the non-unknown chemotherapy group for stage II-IV LCLC patients (p < 0.05). Two nomograms were plotted based on the results of Cox regression analysis. The areas under the curves (AUCs) of 1-, 3-, and 5- years OS were 0.786, 0.824, and 0.837, and the AUCs of CSS were 0.785, 0.821, and 0.836. The calibration curves showed excellent agreement between the prediction and the actual observation, and the decision curve analysis (DCA) demonstrated good clinical utility. Chemotherapy could improve the prognosis among stage II-IV LCLC patients. In addition, the nomograms showed good predictive ability, which could be useful in making clinical decisions.

Immunogenomic analysis of human brain metastases reveals diverse immune landscapes across genetically distinct tumors.

Brain metastases (BrMs) are the most common form of brain tumors in adults and frequently originate from lung and breast primary cancers. BrMs are associated with high mortality, emphasizing the need for more effective therapies. Genetic profiling of primary tumors is increasingly used as part of the effort to guide targeted therapies against BrMs, and immune-based strategies for the treatment of metastatic cancer are gaining momentum. However, the tumor immune microenvironment (TIME) of BrM is extremely heterogeneous, and whether specific genetic profiles are associated with distinct immune states remains unknown. Here, we perform an extensive characterization of the immunogenomic landscape of human BrMs by combining whole-exomewhole-genome sequencing, RNA sequencing of immune cell populations, flow cytometry, immunofluorescence staining, and tissue imaging analyses. This revealed unique TIME phenotypes in genetically distinct lung- and breast-BrMs, thereby enabling the development of personalized immunotherapies tailored by the genetic makeup of the tumors.

Current understanding of the intratumoral microbiome in various tumors.

It is estimated that in the future, the number of new cancer cases worldwide will exceed the 19.3 million recorded in 2020, and the number of deaths will exceed 10 million. Cancer remains the leading cause of human mortality and lagging socioeconomic development. Intratumoral microbes have been revealed to exist in many cancer types, including pancreatic, colorectal, liver, esophageal, breast, and lung cancers. Intratumoral microorganisms affect not only the host immune system, but also the effectiveness of tumor chemotherapy. This review concentrates on the characteristics and roles of intratumoral microbes in various tumors. In addition, the potential of therapies targeting intratumoral microbes, as well as the main challenges currently delaying these therapies, are explored. Furthermore, we briefly summarize existing technical methods used to characterize intratumoral microbes. We hope to provide ideas for exploring intratumoral microbes as potential biomarkers and targets for tumor diagnosis, treatment, and prognostication.