Metastatic Small Cell Carcinoma of the Stomach.

Primary gastric small cell carcinoma (GSCC) is an extremely rare type of small cell carcinoma. Its aggressive nature with early widespread metastasis and late detection gives it a poor prognosis with overall survival of <12 months. GSCC is a type of neuroendocrine tumor, and because of its histopathological similarity to small cell lung carcinoma (SCLC), treatment regimen of GSCC includes the same chemotherapy agents as SCLC. We report a case of a 57-year-old man who presented with signs of partial gastrointestinal obstruction and was found to have a primary stage IV GSCC with metastasis to the liver.

Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis.

Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.

SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling.

Genetic mutations and epigenetic modifications affecting multiple cancer-related genes occur synergistically to drive tumorigenesis. Across a wide spectrum of cancers, pathogenic changes have been identified in members of the SWItch/Sucrose Non-Fermentable complex including its two catalytic subunits, SMARCA4 and SMARCA2. During cancer development, it is not uncommon to lose the function of either SMARCA4 or SMARCA2, however, loss of both together has been reported to be synthetic lethal and therefore unexpected. Co-deficiency of SMARCA4 and SMARCA2 occurs as a pathognomonic feature of the early-onset ovarian cancer Small-cell carcinoma of the ovary, hypercalcemic type. The loss of both catalytic subunits is also described in other rare undifferentiated neoplasms including Thoracic SMARCA4-deficient undifferentiated tumors, Malignant rhabdoid tumors and dedifferentiated or undifferentiated carcinomas, predominantly of lung, gastrointestinal, and endometrial origin. This review provides the first extensive characterization of cancers with concurrent SMARCA4 and SMARCA2 loss through the discussion of shared clinical and molecular features. Further, we discuss the mechanisms triggering the loss of catalytic activity, the cellular processes that are dysfunctional as a consequence, and finally, current therapeutic candidates which may selectively target these cancers.

Relationship between the expressions of DLL3, ASC1, TTF-1 and Ki-67: First steps of precision medicine at SCLC.

This study presents an observational, cross-sectional analysis of 64 patients diagnosed with small cell lung cancer (SCLC) at a reference laboratory for thoracic pathology between 2022 and 2024. The primary objective was to evaluate the expression of Delta-like ligand 3 (DLL3) and other neuroendocrine markers such as Chromogranin, and Synaptophysin, utilizing both traditional immunohistochemistry and digital pathology tools. Patients were primarily older adults, with a median age of over 71, and most biopsies were obtained from lung parenchyma. Immunohistochemistry (IHC) was performed using specific monoclonal antibodies, with DLL3 showing variable expression across the samples. Notably, DLL3 was expressed in 72.3% of the cases, with varied intensities and a semi-quantitative H-score applied for more nuanced analysis. ASCL1 was expressed in 97% of cases, with the majority considered low-expressors. Only 11% had high expression. TTF-1, traditionally not a conventional marker for the diagnosis of SCLC, was positive in half of the cases, suggesting its potential as a biomarker. The study underscores the significant variability in the expression of neuroendocrine markers in SCLC, with implications for both diagnosis and potential therapeutic targeting. DLL3, particularly, shows promise as a therapeutic target due to its high expression rate in the cohort. The use of digital pathology software QuPath enhanced the accuracy and depth of analysis, allowing for detailed morphometric analysis and potentially informing more personalized treatment approaches. The findings emphasize the need for further research into the role of these markers in the management and treatment of SCLC, considering the poor prognosis and high mortality rate observed in the cohort.

Impact of senescence cell signature in patients with non-small cell carcinoma and melanoma receiving PD-L1/PD-1 inhibitors.

Tumor cell senescence plays a crucial role in tumor immunity. We investigated whether the senescent cell signature (SCS) could predict prognosis in non-small cell carcinoma (NSCLC) and melanoma datasets treated with PD-L1/PD-1 inhibitors. Patients with high SCS expression exhibited elevated levels of interferon-gamma and T cell-inflamed signatures in three lung adenocarcinomas (LUAD), two squamous cell carcinoma (LUSC) and three melanoma datasets. The high SCS group was associated with PD-L1-related pathways such as IL6/JAK/STAT3 and TNF-alpha signaling via NF-kB in LUAD, LUSC, and melanoma datasets. A positive correlation was observed between several immune checkpoint markers and the SCS, indicating an immunosuppressive state in LUAD, LUSC and melanoma datasets. In patients treated with PD-1/PD-L1 inhibitors, a higher SCS was associated with a better prognosis, and a positive correlation between SCS and PD-L1 was observed in six independent NSCLC and three independent melanoma datasets. We used the LASSO Cox regression model to build a risk model focusing on the SCS genes that particularly predict prognosis. We confirmed that the model accurately predicts prognosis. However, the senescent immunohistochemical markers p16 and p21 could predict the response to PD-1/PD-L1 inhibitors in patients with LUSC and melanoma but not in patients with LUAD. SCS could serve as a valuable biomarker to complement PD-L1 expression in patients receiving PD-L1/PD-1 inhibitors.

Treatment and survival of non-metastatic small cell carcinoma of the bladder from multiple centers in China.

Small cell carcinoma of the bladder (SCCB) is a rare, highly malignant neuroendocrine tumor. This study attempted to analyze tumor characteristics, treatments and clinical outcomes in China. We conducted a retrospective analysis of patients diagnosed with non-metastatic SCCB at multi-institutions between January 2007 and January 2022. The Kaplan-Meier method was used to calculate survival. A total of 20 patients were included. 10 had localized disease (T1-2N0), and 10 had locally advanced disease (≥ T3 or N+). 13 received local treatment (partial cystectomy or transurethral resection of the bladder tumor) and 7 received radical treatment (radical cystectomy or radiotherapy). A total of 18 patients (90%) received chemotherapy (CT), either neoadjuvant CT (n = 5) or adjuvant CT (n = 13). The median OS for the receiving local treatment was 65.3 months (95% CI 0 to 138 months) and the corresponding 1-year, 2-year, and 3-year OS was 77%, 54%, and 54%, respectively. The median OS for the receiving radical treatment was not reached and the corresponding 1-year, 2-year, and 3-year OS was 100%, 100%, and 75%, respectively. The median PFS for receiving local treatment was 13.8 months (95% CI 9.3 to 18.3 months) and the corresponding 1-year, 2-year, and 3-year PFS was 46%, 31%, and 31%, respectively. The median PFS for the receiving radical treatment was not reached and the corresponding 1-year, 2-year, and 3-year PFS was 83%, 56%, and 56%, respectively. This study reported the largest cohort of non-metastatic SCCB among Chinese population. Given its metastatic potential, CT remained an essential part of the treatment. The survival outcomes of radical cystectomy and RT in non-metastatic SCCB were encouraging.

A Single Institution Experience in the Management of Localized Neuroendocrine Carcinoma of the Bladder.

BACKGROUND: Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches. MATERIALS AND METHODS: Patients with localized NEC-bladder treated with surgery or radiation between 2001-2021 were retrospectively identified. Rates of pathologic complete response (pCR) and downstaging were evaluated following NAC in surgically-treated patients. Progression-free survival (PFS) and overall survival (OS) were analyzed with univariable (log-rank) and multivariable (MVA; Cox regression) methods. RESULTS: Sixty-five patients were identified having a median age of 73. The tumor histology distribution was small cell (64.6%) or urothelial with NE differentiation (35.4%). Most patients (69.2%) received NAC. Patients received local therapy by surgery (78.5%) or chemoradiation (21.5%). The majority (62.7%) of surgical patients had ≥ pT2 with 37.3% having nodal involvement (pN+). The pCR and downstaging rates were 21.6% and 35.1%, respectively. At a median follow-up of 60 months (m), the median PFS and OS were 16.4m and 25.9m, respectively. NAC improved PFS (p=0.04) and downstaging improved PFS (p=0.012) and OS (p<0.001). Patients receiving NAC with ypN0 vs. ypN+ had median OS of 69.9m vs 15.3m, respectively (p<0.001). MVA identified receipt of NAC and pN as predictors of PFS; pN was predictive of OS. No differences in PFS or OS were seen between histology of primary tumor. The brain metastasis rate was 10.8% with all patients having small cell histology. CONCLUSIONS: Optimized therapy in NEC-bladder includes NAC followed by local consolidation. Ascertainment of ypN0 is associated with long term survival, while pN+ remains associated with poor outcomes.

Using cancer phenotype sex-specificity to enable unbiased penetrance estimation of SMARCA4 pathogenic variants for small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

PURPOSE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in SMARCA4. Early bilateral oophorectomy is recommended for unaffected females with a SMARCA4 GPV. However, the penetrance of SMARCA4 GPVs for SCCOHT is highly uncertain and subject to ascertainment bias. METHODS: Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in SMARCA4 GPVs in females compared to males in UK Biobank, a population cohort for which recruitment was restricted to those age 40-69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry. RESULTS: We observed SMARCA4 GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (p = 0.028), representing a male:female odds ratio of 2.64 (95%CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given absence of other SMARCA4-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for BRCA1 and TP53. CONCLUSION: Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with SMARCA4 GPVs.

Aberrant CD45 Immunoreactivity in Neuroendocrine Neoplasms: A Diagnostic Pitfall-Report of 10 Specimens and Clinical Recommendations.

Leukocyte common antigen (LCA), or CD45, is classically thought of as a leukocyte-exclusive protein, and as such, CD45 immunohistochemistry (IHC) is often used as a key differentiator between non-Hodgkin lymphomas (NHLs) and morphologically similar neuroendocrine neoplasms (NENs). Herein, we report our experience regarding aberrant CD45 immunoreactivity in a series of NENs. A natural language search was used to retrieve desired archival patient files. All prior NENs which had a positive neuroendocrine diagnosis or IHC results (synaptophysin, chromogranin, CD56, and/or neuron-specific enolase), as well as CD45 staining performed, were reviewed for possible CD45 positivity (n = 686). Among these 686 NENs, 10 were aberrantly positive for CD45 staining. CD45 showed nuclear, cytoplasmic, and/or membranous staining in tumor cells. The significance of such staining is unclear. Albeit for a minority of patients, pathologists should be aware that NENs may aberrantly stain with CD45 and thereby pose a diagnostic pitfall. Therefore, broadening routine IHC panels is recommended to differentiate NENs more clearly from NHLs.

Impact of systemic therapy on clinical T1 small-cell neuroendocrine carcinoma of the bladder.

BACKGROUND: The purpose of this study was to analyze survival outcomes and pathologic response of patients with cT1N0 small-cell neuroendocrine carcinoma (SCNEC) of the bladder treated with neoadjuvant chemotherapy (neoCTX). MATERIALS AND METHODS: All cases of bladder SCNEC treated at our institution from January 1996 to July 2023 were identified. cT1N0 was defined as transurethral resection pathology showing lamina propria invasion with present and uninvolved muscularis propria. Pathologic downstaging and recurrences were evaluated. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox regression and Kaplan-Meier method. RESULTS: A total of 30 patients with cT1N0 bladder SCNEC were included. Median follow-up was 88 months [95% confidence interval (CI) 44-131 months]. NeoCTX was given to 21 (70%) patients with a median of 4 cycles (range 1-6 cycles). A total of 27 (90%) patients received definitive local therapy. In cT1 bladder SCNEC, neoCTX was associated with decreased odds of pathologic upstaging [odds ratio = 0.07 (95% CI 0.01-0.45), P = 0.004], decreased odds of relapse [odds ratio = 0.12 (95% CI 0.02-0.65), P = 0.01], improved DFS [hazard ratio (HR) 0.30, 95% CI 0.09-0.96, P = 0.04], and improved OS (HR 0.32, 95% CI 0.10-1.02, P = 0.05). Compared with cT2N0 treated with neoCTX, cT1N0 treated with neoCTX had improved median DFS (HR 0.44, 95% CI 0.19-1.03, P = 0.05) and improved median OS (HR 0.52, 95% CI 0.22-1.24, P = 0.14). CONCLUSIONS: NeoCTX had suggestive benefit in patients with cT1 bladder SCNEC with decreased odds of pathologic upstaging, metastatic relapse, and improved survival.

Unusual coexistence: A case of mixed small and large cell neuroendocrine tumor in a bladder previously affected by bilharzial cystitis.

Neuroendocrine tumors of the bladder are rare, accounting for less than 1% of all bladder tumors. Among these, large cell neuroendocrine carcinoma is an extremely uncommon subtype. We report on a histologically confirmed case of mixed both large and small cells neuroendocrine tumor of the bladder in a 64-year-old male with a history of bilharzial cystitis. The diagnosis was made after radical cystectomy with Immunohistochemical staining revealing positivity for synaptophysin, CD56, and AE1/3. While bilharzia is commonly linked to squamous cell carcinoma in the bladder, the potential relationship with neuroendocrine tumors is still relatively unexplored in this context. This case marks the first reported instance of the atypical coexistence of bilharzial cystitis and mixed large and small cell neuroendocrine carcinoma of the bladder. This unique case of coexisting highlights a rare phenomenon warranting further study. Similar associations have been documented in other organs, emphasizing the importance of exploring underlying mechanisms and clinical implications for improved patient care and outcomes.

Neuroendocrine neoplasms of the thymus.

Neuroendocrine neoplasms of the thymus (tNENs), including typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma, are rare tumors with scarce clinical and pathological data available in the literature. They share many common features with neuroendocrine neoplasms in other organs, such as those in the lungs, while demonstrating some distinct clinical and pathological features. This review aims to give an updated overview of each category of tNENs, focusing primarily on the pathologic diagnosis and differential diagnosis of these tumors.

First reported case of primary small cell cancer of the pancreas with positive TTF-1 tumor marker.

Small cell carcinomas are very aggressive malignancies that are most often linked with lung cancer, although they may also develop in the pancreas, colon, rectum, skin, and cervix. SCC of the pancreas accounts for about 1% of these neoplasms. An 88-year-old male with several comorbidities who presented with significant weight loss was diagnosed with metastatic pancreatic neuroendocrine carcinoma after complaining of persistent epistaxis and back pain. This case underscores the significance of using atypical tumor markers, such as thyroid transcription factor 1, to diagnose small-cell pancreatic cancer. It also emphasizes the importance of a multidisciplinary, patient-centered approach to managing these aggressive tumors.

Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies-Therapeutic Vulnerabilities in Treatment-Resistant Subtypes.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

Cytomorphologic analysis of pulmonary neuroendocrine tumors - The physical effect of abrasion and aspiration on cytomorphology.

Neuroendocrine tumors of the lung display characteristic cytomorphologic features allowing direct diagnosis. The specificity of these features in distinguishing subtypes of neuroendocrine tumors, and their differences among types of cytologic specimen poses as interpretative potential pitfalls. This study reviewed and compared bronchial, effusion fluid and fine-needle aspiration cytology specimens of neuroendocrine tumors of the lung to address these issues. Histology-proven cytology specimens of neuroendocrine tumors were reviewed for cytomorphological parameters focusing on reported specific neuroendocrine nuclear and background features. Totally, 46 cases (26 bronchial, 11 effusion and 9 aspirate specimens), corresponding to 37 small cell carcinomas, 7 neuroendocrine carcinomas and 2 carcinoids were reviewed. Nuclear moulding (n = 35/37, 95 %), naked nuclei (n = 33/37, 89 %) and marked nuclear irregularity (n = 32/37, 86 %) were the three most common features of small cell carcinoma. The only specific feature for small cell carcinoma was the lack of prominent nucleoli (p = 0.004). For pulmonary carcinoids, in addition to the above features, other features associated with neuroendocrine carcinoma reviewed including crush artifact and necrotic material were absent. Compared to bronchial and aspiration cytology, crush artifact (p < 0.001) and necrotic material (p = 0.014) were absent on effusion fluid specimens and naked nuclei were less frequently seen (p = 0.022), while prominent nucleoli were more often observed (p = 0.005). Nuclear moulding, irregularity and naked nuclei are common but not unique features to small cell carcinomas. Effusion fluid specimens have "cleaner" backgrounds while displaying greater nuclear atypia. The type of cytologic preparation/specimen is an important factor which must be considered during diagnostic interpretation.

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'.

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

BACKGROUND: Breast 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 PRESENTATION: A 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. CONCLUSION: Although very rare, the possibility of breast metastasis should be considered when malignancy is suspected in other organs.

Prognostic factors and treatment strategies of limited-stage primary esophageal small-cell carcinoma-a SEER database analysis.

Background: Primary esophageal small-cell carcinoma (PESC) is a rare tumor with poor efficacy, and there is currently no standardized treatment method. Our aim is to explore the prognostic factors and possible optimal treatment modalities for limited-stage PESC. Methods: We retrospectively searched the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2019 for data of patients with limited-stage PESC. Kaplan-Meier method was used to plot survival curves, calculate survival rates, and Log-rank was used to test the differences among survival curves. Prognostic factors were explored through univariate and multivariate Cox regression survival analyses; Cox regression survival analysis was also conducted to analyze the risk of death among treatment groups and compare the survival differences among each treatment group. The non-single treatment (ST) group was defined as the comprehensive treatment (CT) group and it was compared against the ST group. Results: A total of 186 cases of limited-stage PESC were included in the study, there were differences in survival time among different groups due to differences in age, year, median household income, and N stage (P<0.001, P=0.041, P=0.002, P=0.001). The median overall survival (mOS) of the surgical group (19 months) was longer than that of the nonsurgical group (11 months) (P=0.01). The mOS of the chemotherapy group (16 months) was longer than that of the non-chemotherapy group (4 months) (P<0.001). The mOS of the radiotherapy group (16 months) was longer than that of the non-radiotherapy group (8 months) (P<0.001). Univariate analysis showed that age ≥80 years (P=0.006), year (1997-2007) (P=0.01), year (2008-2019) (P=0.01), N2 (P=0.003), surgery (P=0.02), radiotherapy (P<0.001), and chemotherapy (P<0.001) were prognostic factors affecting overall survival (OS) in limited-stage PESC patients. Multivariate analysis showed that SEER stage (P=0.02), age (P=0.007), radiotherapy (P<0.001), surgery (P=0.006), and chemotherapy (P<0.001) were independent prognostic factors affecting OS in patients of limited-stage PESC. Prognosis was better in the non-monotherapy group than in each monotherapy group. The CT group is superior to the ST group (P<0.001). The surgery combined with chemotherapy (SC) group had the longest mOS and the highest reduced risk of death, but there was no statistical difference. Conclusions: SEER stage, age, radiotherapy, chemotherapy, and surgery were independent prognostic factors in limited-stage patients; CT outperformed ST; the SC group had the longest median survival, but showed no statistical difference.

Assessing treatment effects with adjusted restricted mean time lost in observational competing risks data.

BACKGROUND: According to long-term follow-up data of malignant tumor patients, assessing treatment effects requires careful consideration of competing risks. The commonly used cause-specific hazard ratio (CHR) and sub-distribution hazard ratio (SHR) are relative indicators and may present challenges in terms of proportional hazards assumption and clinical interpretation. Recently, the restricted mean time lost (RMTL) has been recommended as a supplementary measure for better clinical interpretation. Moreover, for observational study data in epidemiological and clinical settings, due to the influence of confounding factors, covariate adjustment is crucial for determining the causal effect of treatment. METHODS: We construct an RMTL estimator after adjusting for covariates based on the inverse probability weighting method, and derive the variance to construct interval estimates based on the large sample properties. We use simulation studies to study the statistical performance of this estimator in various scenarios. In addition, we further consider the changes in treatment effects over time, constructing a dynamic RMTL difference curve and corresponding confidence bands for the curve. RESULTS: The simulation results demonstrate that the adjusted RMTL estimator exhibits smaller biases compared with unadjusted RMTL and provides robust interval estimates in all scenarios. This method was applied to a real-world cervical cancer patient data, revealing improvements in the prognosis of patients with small cell carcinoma of the cervix. The results showed that the protective effect of surgery was significant only in the first 20 months, but the long-term effect was not obvious. Radiotherapy significantly improved patient outcomes during the follow-up period from 17 to 57 months, while radiotherapy combined with chemotherapy significantly improved patient outcomes throughout the entire period. CONCLUSIONS: We propose the approach that is easy to interpret and implement for assessing treatment effects in observational competing risk data.

Neoadjuvant chemoimmunotherapy for small cell carcinoma of the esophagus: Clinical efficacy and biomarker exploration.

Small cell carcinoma of the esophagus (SCCE) is a rare and highly malignant type of esophageal cancer with no standard treatment, facing challenges of resistance to conventional therapies. This study presents the cases of one extensive-stage and two limited-stage SCCE patients treated with chemoimmunotherapy. The two limited-stage patients underwent surgery post-treatment and experienced notable and enduring positive responses. This represents the first documented application of neoadjuvant chemoimmunotherapy in limited-stage SCCE patients. Additionally, comprehensive immunohistochemical analysis and whole exome sequencing were performed on the case patients. The findings revealed that infiltration of CD8+ T cells and PD-L1 expression in the SCCE tumor were key factors for favorable responses in SCCE patients receiving chemoimmunotherapy.