Small Cell Lung Carcinoma Research Articles

Gastric metastasis of small cell lung carcinoma: A rare but noteworthy entity to consider.

Small cell lung carcinoma (SCLC) is an aggressive malignancy known for its propensity for early and extensive metastatic spread. Gastric metastasis, where cancer cells disseminate from the lung to the stomach, is a rare but increasingly recognized complication of SCLC. This review provides a comprehensive overview of gastric metastasis in SCLC, addressing its clinical significance, diagnostic challenges, management strategies, and prognosis. Additionally, it examines the broader metastatic patterns of SCLC and compares them with other malignancies known for gastric metastasis. Gastric metastasis in SCLC, though infrequent, is clinically significant and often indicates advanced disease with a poor prognosis. SCLC typically metastasizes to the liver, brain, bones, and adrenal glands, with the stomach being an unusual site. The incidence of gastric metastasis ranges from 1% to 5% in autopsy studies, although this may be underestimated due to diagnostic difficulties and asymptomatic early lesions. Diagnosing gastric metastasis presents several challenges, including the asymptomatic nature of many cases, limitations of conventional imaging techniques, and difficulties in distinguishing metastatic lesions from primary gastric cancer via endoscopy. Histopathological diagnosis requires careful examination to identify SCLC cells through their characteristic small cell morphology and neuroendocrine markers. Management of gastric metastasis in SCLC typically involves a multidisciplinary approach. Systemic therapy, primarily chemotherapy, remains the cornerstone of treatment, with palliative care addressing symptoms and complications. Surgical intervention is usually reserved for specific cases requiring symptomatic relief. The prognosis for patients with gastric metastasis from SCLC is generally poor, reflecting the advanced stage of the disease. Median survival is significantly reduced compared to patients without gastric metastasis. This review emphasizes the need for enhanced awareness and early detection to improve patient outcomes and highlights the importance of ongoing research into better diagnostic and therapeutic strategies.

Homology modelling, molecular docking studies and synthesis of aminopyrimidines as inhibitors for deoxynucleoside kinase analogues in cancer chemoprevention

The development of alternative anticancer agents with minimal side effects has become more critical due to the rising recurrence of mammalian malignancies and the severe side effects of chemotherapeutic treatments. Kinases are an essential target for neostatic impact as they play an important role in the modulation of growth factor signalling. Our work aims to screen novel nine-series of thiazole-based aminopyrimidines and sulphaminopyrimidines against the enzymes mitochondrial thymidine kinase 2, deoxyguanosine kinase (2OCP), deoxycytidine kinase (2QRN) and thymidylate kinase (1E2Q) by molecular docking, synthesise and to study their in vitro inhibitory studies. The synthesised compounds were characterised by Infrared, Nuclear magnetic resonance and Mass spectroscopy. In silico studies, compound 4c stands out among the series, with a reported docking score ranging from −6 to −8 Kcal/mol against all the analogue kinases. The in vitro cytotoxicity assay against human small-cell lung carcinoma (A-549) has shown that 5c (IC50 = 53.9 µM) has an excellent cytotoxic effect over 4c (IC50= 68.68 µM). The reason might be the presence of the benzene sulphonamide group, which enhances their anticancer action. To conclude, the compounds 4c and 5c were found to be potent inhibitors of the deoxynucleoside kinases. In vivo studies must further verify these to prove their potent neostatic effect.

ARAF Amplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors

Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

Clinico-Epidemiological Profile and Treatment Outcome of Small Cell Lung Carcinoma: A Retrospective Study from a Tertiary Cancer Centre in Northeast India

Background: Small cell lung cancer (SCLC) accounts for 12-15% of all lung cancers and is associated with poor outcomes. This study aimed to understand the clinico-epidemiological profile and outcomes of SCLC in the North-East Indian population. Methods: A retrospective analysis was performed on medical records of patients with SCLC who were diagnosed, treated, and followed up at the Department of Medical Oncology, Dr. B. Borooah Cancer Institute, during the period from January 2016 to December 2021. Results: A total of 70 patients were evaluated, with a median age of 62 years, and 82.8% were male. The majority of patients (72.8%) were diagnosed with extensive-stage (ES) disease. Common symptoms included cough (61.4%), chest pain (45.7%), and breathing difficulty (44.2%). The most commonly used chemotherapy regimen was etoposide-platinum. Overall survival (OS) for all patients was 6.1 months. Three-year OS was significantly better in patients with limited-stage (LS) disease (16.4 months vs. 4.3 months in LS vs. ES disease, p<0.05). Median progression-free survival (mPFS) for all patients was 4 months. Survival rates at 6, 12, 24, and 36 months were 45.7%, 18.5%, 5.7%, and 1.4%, respectively. Median OS was significantly correlated with the number of metastatic sites (8.6 months with <3 organ involvement vs. 1.9 months with ≥3 organ involvement; p<0.0001). Patients who received combined modality treatment had better survival than those treated with chemotherapy alone (10.7 months in chemo-radiotherapy vs. 3 months in chemotherapy alone, p<0.001). Conclusion: SCLC remains a highly aggressive disease with poor survival. Advanced-stage presentation with distant organ metastasis is the most important factor associated with poor survival in patients with SCLC1

Nontuberculous mycobacterial pulmonary disease caused by Mycobacterium seoulense.

Mycobacterium seoulense was first isolated and reported in Korea in 2007. We report a rare case of nontuberculous mycobacterial (NTM) pulmonary disease caused by M. seoulense. A woman in her mid-90s was referred to our hospital due to bloody sputum. She had medical histories of chronic heart failure and chemoradiotherapy for right small cell lung carcinoma. Chest computed tomography showed a consolidation on the mediastinal side of the right lung following radiotherapy and nodules with bronchiectasis of the right upper and middle lobes. Acid-fast culture tests of sputum were positive for M. seoulense. We are currently treating her with tranexamic acid and carbazochrome sodium sulfonate and conducting careful follow-up. M. seoulense infection may need to be recognized as one of the notable NTM pulmonary diseases presenting with respiratory symptoms and radiological findings.

Aberrant positivity for BCOR immunohistochemistry in merkel cell carcinoma - a potential diagnostic pitfall

BackrgoundMerkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma, frequently associated with clonal Merkel cell polyomavirus integration. MCC can pose significant diagnostic challenges due to its diverse clinical presentation and its broad histological differential diagnosis. Histologically, MCC presents as a small-round-blue cell neoplasm, where the differential diagnosis includes basal cell carcinoma, melanoma, hematologic malignancies, round cell sarcoma and metastatic small cell carcinoma of any site. We here report strong aberrant immunoreactivity for BCOR in MCC, a marker commonly used to identify round cell sarcomas and other neoplasms with BCOR alterations.MethodsBased on strong BCOR expression in three index cases of MCC, clinically mistaken as sarcoma, a retrospective analysis of three patient cohorts, comprising 31 MCC, 19 small cell lung carcinoma (SCLC) and 5 cases of neoplasms with molecularly confirmed BCOR alteration was conducted. Immunohistochemical staining intensity and localization for BCOR was semi-quantitatively analyzed.ResultsThree cases, clinically and radiologically mimicking a sarcoma were analyzed in our soft tissue and bone pathology service. Histologically, the cases showed sheets of a small round blue cell neoplasm. A broad panel of immunohistochemistry was used for lineage classification. Positivity for synaptophysin, CK20 and Merkel cell polyoma virus large T-antigen lead to the diagnosis of a MCC. Interestingly, all cases showed strong positive nuclear staining for BCOR, which was included for the initial work-up with the clinical differential of a round cell sarcoma. We analyzed a larger retrospective MCC cohort and found aberrant weak to strong BCOR positivity (nuclear and/or cytoplasmic) in up to 90% of the cases. As a positive control, we compared the expression to a small group of BCOR-altered neoplasms. Furthermore, we investigated a cohort of SCLC as another neuroendocrine neoplasm and found in all cases a diffuse moderate to strong BCOR positivity.ConclusionsThis study demonstrates that neuroendocrine neoplasms, such as MCC and SCLC can express strong aberrant BCOR. This might represent a diagnostic challenge or pitfall, in particular when MCC is clinically mistaken as a soft tissue or a bone sarcoma.

Detection of SEZ6, a therapeutic target, in medullary thyroid carcinoma.

Seizure-related 6 homolog (SEZ6) is a cDNA that strongly associated with neuroendocrine differentiation. Recently, SEZ6 expression was found in a subset of small cell lung carcinoma (SCLC). Furthermore, ABBV-011, a novel antibody drug conjugate targeting SEZ6 has been developed and is currently in clinical trial in treating SCLC and neuroendocrine neoplasms, including medullary thyroid carcinoma (MTC). We herein presented the first evidence that SEZ6 was highly expressed in MTC. SEZ6 immunoexpression was studied in 78 MTCs and correlated with clinicopathologic characteristics, outcome, and molecular profile. SEZ6 was highly expressed in primary tumors, regional recurrence, and distant metastasis. Using two different SEZ6 antibody clones SC17.14 and 14E5, SEZ6 immunopositivity was seen in 91% to 93% of primary MTCs, 100% of regional recurrence, and 75% to 83% of distant metastasis. High level of SEZ6 immunoexpression determined using H score was associated with male sex, advance stage, and extrathyroidal thyroidal extension. There was no correlation between SEZ6 expression and outcome or RET/RAS mutation status in MTC. The frequency of SEZ6 positivity in MTC without RET/RAS mutations were 83%. SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targetted antibody-drug conjugate therapy a promising targeted therapy for MTCs.

Expression of POU2F3 Transcription Factor and POU2AF2, POU2F3 Coactivator, in Tuft Cell-like Carcinoma and Other Tumors.

Epithelial chemosensory cells in hollow organs, also known as tuft cells, were implicated in tumorigenesis, including a tuft cell-like small cell lung carcinoma. Expression of the POU2F3 transcription factor is a marker of tuft cell lineage. However, tuft cell development, differentiation, and proliferation are controlled by the expression of the complex formed by POU2F3 and POU2AF2 or POU2AF3 transcriptional coactivators. A cohort of epithelial (n=6064) and mesenchymal/neuroectodermal (n=2730) tumors was screened for POU2F3 expression by immunohistochemistry. Variable immunoreactivity ranging from diffuse to scattered positive cells was found in ∼12.4% of epithelial and 4.6% of mesenchymal/neuroectodermal tumors. Cases with predominantly diffuse or patchy POU2F3 positivity representing various types of malignant tumors (n=43) were selected for further study, including POU2AF2 immunohistochemistry. Thirteen of 15 tumors with neuroendocrine differentiation originating from the lung, colon, head and neck, skin, and bladder revealed diffuse POU2F3 positivity. Most of those tumors (n=9) co-expressed POU2AF2, usually extensively. Seven squamous and basal cell carcinomas from the oral cavity, skin, lung, and thymus with diffuse POU2F3 immunostaining except one, lacked POU2AF2 expression. Other variably POU2F3-positive carcinomas (n=13) from the colon, pancreas, liver, kidney, testis, endometrium, ovary, and breast lacked POU2AF2 immunoreactivity. All POU2F3-positive mesenchymal and neuroectodermal tumors (n=8), including synovial sarcoma, solitary fibrous tumor, glioblastoma, Wilms tumor, and melanoma were POU2AF2-negative. POU2F3 expression is a highly sensitive but nonspecific indicator of tuft cell differentiation. Co-expression of POU2F3 and POU2AF2 appears to be a more specific marker, although it may not pinpoint tumors driven by the POU2F3-POU2AF3 complex.

Application of the 5th WHO Guidelines for the Diagnosis of Lung Carcinoma in Small Lung Biopsies in a Tertiary Care Center: Is Insecurity of Pathologists for the Accurate Diagnosis Justified?

The diagnosis of lung carcinoma (LC) is currently performed in small biopsies and according to the WHO classification by using limited stains to spare tissue for molecular testing. This procedure, however, often causes diagnostic uncertainty among pathologists. In this retrospective analysis, we compared the diagnosis made by these guidelines in 288 lung biopsies with that using more stains, as retrieved from our archive. We also compared the results of p63 and p40 immunoexpression and investigated the diagnostic role of p53/Rb1. In our investigation, we reached a definite diagnosis with a mean number of one stain compared with six stains in the original diagnostic procedure, with a 97.3% concordance rate. Only in the case of metastases, a clear advantage is proven in the use of more stains, especially in the absence of clinical information. We also found a comparable utility of p40 and p63 for the diagnosis of squamous cell carcinoma, despite the higher p63 expression in other histological types. Moreover, normal p53/Rb1 expression could be utilized for the exclusion of small-cell LC. Our study confirms the diagnostic certainty achieved by the suggestions of the WHO classification and justifies the potential insecurity in the absence of adequate communication with the treating clinician.

The rare case of synchronous bilateral breast metastasis from a lung neuroendocrine tumor (small cell lung carcinoma): a case report and literature review

BackgroundBreast metastasis from small cell neuroendocrine carcinoma (SNEC) is very rare. In the present report, we describe a case of a female patient who was initially diagnosed with triple negative primary bilateral breast cancer, but during systemic examination, the diagnosis was bilateral breast metastasis from SNEC.Case presentationA 62-year-old woman with no history of smoking presented to the Department of General Medicine with left-sided chest pain, and computed tomography revealed masses in both breasts and left pleural thickening that was further confirmed by mammography and ultrasound of the breasts. A needle biopsy was performed, and triple negative primary bilateral breast cancer was diagnosed. Because progastrin-releasing peptide (ProGRP) 37,300 pg/ml (normal range, 0–81.0 pg/ml) and neuron-specific enolase 35.0 ng/ml (normal range, 0–16.3 ng/ml) levels were elevated, thoracoscopic biopsy was performed, and SNEC was diagnosed. Pathological examinations showed that the bilateral breast masses were also positive for immunohistochemical staining of chromogranin A, synaptophysin, and CD56, leading to a diagnosis of bilateral breast metastasis of neuroendocrine tumor.ConclusionAlthough very rare, the possibility of breast metastasis should be considered when malignancy is suspected in other organs.

Comparison of clinical, hormonal, pathological and treatment outcomes of ectopic Cushing's syndrome by sex: results of a multicenter study.

To compare clinical and hormonal data, neuroendocrine neoplasia (NEN) localization, treatment, and survival outcomes in ectopic Cushing's syndrome (ECS) by sex. Eleven experienced centers from our country participated in this retrospective study. The clinical and hormonal features, tumor imaging, pathological results, treatment modalities, and disease courses of the patients were evaluated. 28 female and 26 male patients with ECS were compared. The mean age at diagnosis, clinical characteristics, and hormonal evaluation results were similar. However, insulin-requiring diabetes mellitus (p = 0.04) and osteoporosis with fractures were more common in males (p = 0.03). While more patients with increased DHEA-S levels than the upper limit of normal were found to be higher in females, central hypothyroidism were higher in males (p = 0.02). At the diagnosis, 36 NENs (68% of females and 69% of males) were localized. Small cell lung carcinoma was higher in males (p = 0.02), and the frequency of other NENs was not different. Curative surgery was performed on 61% of females and 46% of males. Tumor size, Ki-67 labeling index, positive ACTH immunostaining, local lymph node and distant metastasis rates were similar in both sexes. In the follow-up, the tumor became visible in 7 of 10 females and 4 of 8 males after medical treatment and/or bilateral adrenalectomy. The remission rates (65% of females, 62% of males) and NEN-related death rates (14% of females, 30% of males) were similar. While ECS has a similar disease course in many aspects in males and females, hyperglycemia and osteoporosis are more severe in males.

Metabolomic Profiling of Pulmonary Neuroendocrine Neoplasms.

Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs.

Prognostic impact of interstitial lung disease on pulmonary high-grade neuroendocrine carcinoma

Pulmonary high-grade neuroendocrine carcinomas (HGNECs) have poor prognoses and require multimodal treatment, and interstitial lung disease (ILD) restricts sufficient treatment of patients with lung cancer. We aimed to clarify ILD’s prognostic impact on pulmonary HGNEC, which has previously gone unreported. We retrospectively analyzed 53 patients with HGNEC who underwent resections at our department between 2006 and 2021 and evaluated the clinicopathological prognostic features, including ILD. The patients’ mean age was 70 years; 46 (87%) were male, and all were smokers. Large-cell neuroendocrine and small-cell lung carcinomas were diagnosed in 36 (68%) and 17 (32%) patients, respectively. The pathological stages were stage I, II, and III in 31 (58%), 11 (21%), and 11 (21%) patients, respectively. Nine patients (17%) had ILD, which was a significant overall survival prognostic factor in a multivariate Cox proportional hazards regression analysis (p = 0.048), along with lymph node metastasis (p = 0.004) and non-administration of platinum-based adjuvant chemotherapy (p = 0.003). The 5 year survival rate of the ILD patients was 0%, significantly worse than that of patients without ILD (58.7%; p = 0.003). Patients with HGNEC and ILD had a poor prognosis owing to adjuvant therapy’s limited availability for recurrence and the development of acute exacerbations associated with ILD.

Occipital condyle syndrome due to small-cell lung carcinoma: A case report.

Skull base metastases, including those from small-cell lung carcinoma (SCLC), can present with various syndromes depending on the site of involvement, such as orbital syndrome, parasellar syndrome, middle fossa syndrome, jugular foramen syndrome, and occipital condyle syndrome (OCS). One such example is OCS, which consists of unilateral occipital headache accompanied with ipsilateral hypoglossal palsy. This case report describes a 51-year-old man initially diagnosed with OCS, which led to the discovery of systemic bone metastases from SCLC. Magnetic resonance imaging showed lesions in the occipital condyle and hypoglossal canal, while positron emission tomography-computed tomography identified a lung mass and widespread metastases. SCLC is highly aggressive and metastatic, with the bone being a common site of spread. In this case, the OCS preceded the diagnosis of the underlying malignancy. Prompt diagnosis and treatment are crucial, as patients with OCS often have advanced disease. This case highlights the importance of considering SCLC as a potential etiology for OCS, given the propensity for bone metastases. Early recognition and evaluation of OCS is essential to initiate appropriate management.

The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma.

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component-by-component next-generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double-positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1-dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3-dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic-like expression. Among the combined SCLCs with component-specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic-like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'.

POU4F3 Is a Sensitive and Specific Marker of Merkel Cell Carcinoma

Although of therapeutic importance, a single sensitive and specific immunostain to distinguish Merkel cell carcinoma (MCC) from mimics is not currently available. In addition, single tumor cells are difficult to detect in sentinel lymph node biopsy. Leveraging publicly available data sets of 9264 solid tumors and >600,000 single-cell transcriptomes, we identified POU4F3 to be a specific marker of MCC. Analyses of Pan-Cancer RNA bulk sequencing data of 24 tumor types from Tumor Cancer Genomic Atlas data sets as well as non-Tumor Cancer Genomic Atlas small cell lung carcinoma and MCC data sets confirmed POU4F3 specificity for MCC. Single-cell RNA-sequencing analyses also confirmed the lack of POU4F3 expression in lung small cell carcinoma as well as a variety of normal tissues. Nuclear POU4F3 immunohistochemical expression was noted in 98.7% of 153 MCCs and in only 1.7% of mimics (3 of 180 cases, including 95 small cell carcinomas, of which 55 were from lungs and the remainder from other sites). Three POU4F3-positive non-MCC cases were from lungs (2 cases) and vagina (1 case). All 153 tested MCC cases were negative for ASCL1, a key transcriptional regulator highly expressed in small cell lung carcinoma. NeuroD1 was seen in a subset of MCC cases (20.9%, 32/153). POU4F3 immunostain was performed on 29 sentinel lymph nodes, and strong POU4F3 nuclear expression facilitated the ease of metastasis detection, even single tumor cells. Our study built on prior works shows that POU4F3 is a sensitive and specific clinical marker of MCC.

Association between common chronic pulmonary diseases and lung cancer: Mendelian randomization analysis

BackgroundLung cancer is a leading public health concern worldwide. Previous evidence suggests that chronic obstructive pulmonary disease (COPD) and asthma may contribute to its development. However, whether these common chronic pulmonary diseases are causal factors of lung cancer remained unclear.MethodsSummary statistics from genome-wide association studies (GWAS) were used for Mendelian randomization (MR) analysis. Genetic data for COPD were obtained from the Global Biobank Meta-Analysis Initiative, and asthma data were retrieved from the UK Biobank cohort. Suitable instrumental variables were selected based on quality control measures. GWAS summary data for lung cancer were obtained from a large study involved 85,716 participants. MR analysis was performed using various methods, and sensitivity analyses were conducted. Multivariable MR (MVMR) analysis was employed to account for potential confounding factors.ResultsOur MR analysis revealed a significant causal association between COPD and lung cancer, including its subtypes such as lung squamous cell carcinoma, lung adenocarcinoma, and small cell lung carcinoma. Genetically predicted COPD was associated with a 64% increased risk of lung cancer and a 2.3 to 2.8-fold increased risk of the different subtypes. However, in the MVMR analysis adjusting for smoking, alcohol drinking, and body mass index, the association between COPD and lung cancer became non-significant. No significant association was observed between asthma (childhood-onset and adult-onset) and lung cancer and its histological subtypes.ConclusionsOur study suggests a potential causal association between COPD and lung cancer. However, this association became non-significant after adjusting for smoking in the multivariable analysis.

Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic.

Prostate cancer (PCa) neuroendocrine tumor (NET)-like cells with low or absent androgen receptor (AR) signaling cause hormone therapy resistance and poor prognosis. Small cell lung carcinoma (SCLC), a high-grade NET, presents with metastasis early and has poor survival. ONC201/TIC10 is a first-in-class cancer therapeutic with clinical activity in diffuse gliomas and neuroendocrine tumors. We hypothesized that markers of neuroendocrine differentiation, activation of the integrated stress response (ISR) and the TRAIL pathway, as well as the expression of ClpP, contribute to neuroendocrine tumor cell death and sensitivity to ONC201. We show that PCa and SCLC cell lines (N=6) are sensitive to ONC201, regardless of the extent of neuroendocrine differentiation. Endogenous levels of some NET markers (CgA, FoxO1, ENO2, PGP9.5, SOX2) are present in a spectrum in PCa and SCLC cell lines. Overexpression of neural transcription factor BRN2 in DU145 PCa cells does not increase expression of NET differentiation markers FoxO1, ENO2, PGP9.5, and CgA at 48 hours. However, the transient BRN2 overexpression showed slight decreases in some NET markers on the spectrum while maintaining sensitivity of PCa cells to ONC201 before any phenotypic change related to NET differentiation. Our results show that ONC201 has preclinical activity against PCa including those without NET markers or in PCa cells with transient overexpression of neural transcription factor BRN2. Our results have relevance to activity of ONC201 in PCa where most castrate-resistant androgen-independent cancers are not therapy resistant due to NET differentiation. Importantly, NET differentiation does not promote resistance to ONC201 supporting further clinical investigations across the spectrum of PCa.

Chromothripsis-mediated small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis - massive, localized chromosome shattering - recurrently involving chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.

A Newly Developed Anti-L1CAM Monoclonal Antibody Targets Small Cell Lung Carcinoma Cells.

Few effective treatments are available for small cell lung cancer (SCLC), indicating the need to explore new therapeutic options. Here, we focus on an antibody-drug conjugate (ADC) targeting the L1 cell adhesion molecule (L1CAM). Several publicly available databases reveal that (1) L1CAM is expressed at higher levels in SCLC cell lines and tissues than in those of lung adenocarcinoma and (2) the expression levels of L1CAM are slightly higher in SCLC tissues than in adjacent normal tissues. We conducted a series of in vitro experiments using an anti-L1CAM monoclonal antibody (termed HSL175, developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. Our HSL175-DT3C conjugates theoretically kill cells only when the conjugates are internalized by the target (L1CAM-positive) cells through antigen-antibody interaction. The conjugates (an ADC analog) were effective against two SCLC-N (NEUROD1 dominant) cell lines, Lu-135 and STC-1, resulting in decreased viability. In addition, L1CAM silencing rendered the two cell lines resistant to HSL175-DT3C conjugates. These findings suggest that an ADC consisting of a humanized monoclonal antibody based on HSL175 and a potent anticancer drug would be effective against SCLC-N cells.