The importance of choosing the right strategy to treat small cell carcinoma of the cervix: a comparative analysis of treatments.

BACKGROUND: Standard treatments for small cell carcinoma of the cervix (SCCC) have not been established. In this study, we aimed to estimate the optimal treatment strategy for SCCC. METHODS: This was a multicenter retrospective study. Medical records of patients with pathologically proven SCCC treated between 2003 and 2016 were retrospectively analyzed. Overall survival (OS) was plotted using the Kaplan-Meier method. Log-rank tests and Cox regression analysis were used to assess the differences in survival according to stage, treatment strategy, and chemotherapy regimen. RESULTS: Data of 78 patients were collected, and after excluding patients without immunohistopathological staining, 65 patients were evaluated. The median age of the included patients was 47 (range: 24-83) years. The numbers of patients with International Federation of Gynecology and Obstetrics (FIGO) 2018 stages I-IIA, IIB-IVA, IVB were 23 (35%), 34 (52%), and 8 (12%), respectively. Of 53 patients who had undergone chemotherapy, 35 and 18 received SCCC and non-SCCC regimens as their first-line chemotherapy regimen, respectively. The 5-year OS for all patients was 49%, while for patients with FIGO stages I-IIA, IIB-IVA, IVB, it was 60, 50, and 0%, respectively. The 5-year OS rates for patients who underwent treatment with SCCC versus non-SCCC regimens were 59 and 13% (p < 0.01), respectively. This trend was pronounced in locally advanced stages. Multivariate analysis showed that FIGO IVB at initial diagnosis was a significant prognostic factor in all patients. Among the 53 patients who received chemotherapy, the SCCC regimen was associated with significantly better 5-year OS in both the uni- and multivariate analyses. CONCLUSION: Our results suggest that the application of an SCCC regimen such as EP or IP as first-line chemotherapy for patients with locally advanced SCCC may play a key role in OS. These findings need to be validated in future nationwide, prospective clinical studies.

Novel nomogram predicting cancer-specific survival and overall survival in patients with primary esophageal small-cell carcinoma: A surveillance, epidemiology, and end results-based study.

BACKGROUND: Small-cell carcinoma is a relatively infrequent pathological variety of esophageal cancer. In this study, a novel nomogram model was developed to evaluate the cancer-specific survival (CSS) and overall survival (OS) of patients with primary esophageal small-cell carcinoma (ESmCC). MATERIALS AND METHODS: In total, 502 patients with primary ESmCC were identified based on data from 1973 to 2015 retrieved from the surveillance, epidemiology, and end results database. Clinical characteristics such as age at diagnosis, gender, race, site, tumor stage, surgery, radiotherapy, and chemotherapy were included for multivariate logistic analyses to predict CSS and OS. Nomogram models for the prediction of CSS and OS in ESmCC patients were tested with the concordance index (C-index) method and calibration curves. RESULTS: From our multivariate analyses, race, stage, chemotherapy, and radiotherapy, but not surgery, were significantly associated with the CSS of ESmCC patients, while age at diagnosis, stage, chemotherapy, and radiotherapy were significantly associated with their OS. Nomograms were developed using age at diagnosis, race, gender, stage, surgery, radiotherapy, and chemotherapy to predict the two survival measures; these nomograms were verified as accurate in predicting OS and CSS in ESmCC patients, with C-index values of 0.736 and 0.731, respectively. CONCLUSIONS: By utilizing easily accessible clinicopathological information, we established a simple but useful tool for predicting the CSS and OS of ESmCC patients that could help to make personalized clinical decisions for patients with this rare malignancy. Cancer-specific survival, esophageal small-cell carcinoma, nomogram, overall survival, surveillance, epidemiology, and end results.

Chemotherapy with atezolizumab for small cell or neuroendocrine carcinoma of the prostate: A single institution experience.

INTRODUCTION: Chemotherapy in combination with immunotherapy has a proven survival benefit compared to chemotherapy alone in extensive stage small cell lung cancer (SCLC) and is the new standard of care. Since extrapulmonary small cell carcinomas (SCCs) are less common, treatment paradigms are reasonably extrapolated from SCLC regimens. We examined our institution's experience utilizing the combination of chemotherapy and immunotherapy (as used in SCLC) for SCC and neuroendocrine carcinoma of the prostate. METHODS: Utilizing an institutional database search tool, we queried the electronic medical record to identify patients with SCC or neuroendocrine carcinoma of the prostate who had been treated with atezolizumab and chemotherapy. We recorded patient characteristics, including age, pathology, and disease extent. Treatment characteristics included number of prior treatments, use of concominant androgen deprivation, number of cycles of immunotherapy, and prior systemic therapies (including those for adenocarcinoma of the prostate). Progression free survival (PFS) and overall survival (OS) were the primary outcomes. RESULTS: We identified seven men who received atezolizumab for metastatic prostate cancer with a small cell or neuroendocrine component. In six of the seven patients, the combination of carboplatin, etoposide, and atezolizumab was the first-line of treatment after diagnosis of small cell or neuroendocrine carcinoma. Two of the seven patients had de novo small cell/neuroendocrine pathology, while the other five had transformation from a preexisting adenocarcinoma. In the patients who received chemotherapy plus immunotherapy in the first-line setting, at a median follow-up of 6.5 months (range: 1.5-15.1) the median PFS was 3.4 months and median OS was 8.4 months. CONCLUSION: Small cell or neuroendocrine carcinoma of the prostate was associated with poor survival outcomes despite adding immunotherapy (atezolizumab) to chemotherapy (carboplatin and etoposide). To our knowledge, there has been no demonstrable benefit of adding immunotherapy to chemotherapy in this setting.

A Retrospective Study of 52 Patients With Primary Small Cell Carcinoma of the Esophagus Treated With Radical Surgery.

BACKGROUND: Primary small cell carcinoma of the esophagus (SCCE) is a rare and extremely fatal disease. We aim to evaluate the efficacy of radical surgery for resectable SCCE and to explore potential prognostic factors. METHODS: We retrospectively reviewed 52 consecutive SCCE patients who underwent radical surgery from February 1993 to November 2014 at a single institution. The Kaplan-Meier estimator with log-rank test was used to assess overall survival (OS), disease-free survival (DFS) and median survival time. Univariate and multivariable analyses were used to evaluate prognostic factors through Cox proportional hazard regression model. RESULTS: Twenty-five (48.1%) patients were treated with surgery alone, whereas 27 (51.9%) patients underwent adjuvant therapy after surgery. The median OS time was 17.4 months (95% CI: 13.5-21.3). The median DFS time was 13.4 months (95% CI: 7.7-19.0). Patients whose tumors were located in the lower part of thoracic esophagus and the esophagogastric junction showed significantly better OS (27.0 vs. 13.2 months, P = 0.016) and DFS (27.0 vs. 11.3 months, P = 0.017) than those located in the upper and middle parts. Patients with N0 status experienced significantly better OS (21.4 vs. 11.6 months, P = 0.012) and DFS (21.4 vs. 8.6 months, P = 0.012) than those with N+ status. Patients whose tumor lengths were shorter than 5 cm had a better OS (17.4 vs. 5.7 months, P = 0.035) than those longer than 5 cm. Patients who underwent chemotherapy experienced a significantly improved OS (21.0 vs. 14.1 months, P = 0.032) compared to surgery alone. Multivariable analysis showed that lower tumor location, shorter tumor length, pN0 status and chemotherapy independently predicted better OS; lower tumor location and pN0 status independently predicted better DFS. CONCLUSIONS: Radical surgery in combination with chemotherapy has better outcomes than surgery alone for resectable SCCE. Higher tumor location, longer tumor length, lymph node metastasis and not undergoing chemotherapy independently predict worse prognoses.

Nomogram for predicting the survival of patients with small cell carcinoma of the esophagus: A population study based on the surveillance, epidemiology, and end results database.

ABSTRACT: This study aims to establish an effective prognostic nomogram for small cell carcinoma of the esophagus (SCCE).A total of 552 patients with SCCE from 1975 to 2016 were extracted from the surveillance, epidemiology, and end results (SEER) database. A Cox proportional hazard regression model was used to analyze the prognostic factors of patients, and a nomogram was constructed. The nomogram was then validated internally by using a consistency index (C-index) and a correction curve to evaluate its predictive value.The Cox proportional hazard regression model showed that age, stage, surgery, primary site, radiotherapy, and chemotherapy were the prognostic factors of SCCE (P < .1), and they were used to construct the nomogram. The C-index of the nomogram for predicting survival was 0.749 (95% confidence interval [CI] = 0.722-0.776). The data were randomly divided into a modeling group and a validation group based on 7:3 for internal validation. The C-indices of the modeling and validation groups were 0.753 and 0.725, respectively, and they were close to 0.749. The calibration curves exhibited good consistency between the predicted and actual survival rates.The nomogram of the survival and prognosis of patients with SCCE in this study had a good predictive value and could provide clinicians with accurate and practical predictive tools. It could also be used to facilitate a rapid and accurate assessment of patients' survival and prognosis on an individual basis.

Chemotherapy Plus Radiotherapy Versus Radiotherapy in Patients With Small Cell Carcinoma of the Esophagus: A SEER Database Analysis.

BACKGROUND: Small cell carcinoma of the esophagus is a rare malignant tumor. We aimed to explore the chemotherapeutic efficacy on the prognosis of patients with small cell carcinoma of the esophagus who received radiotherapy. METHODS: To identify the population of interest, Surveillance, Epidemiology, and End Results data from 1996 to 2016 were chosen. Univariate and multivariate analyses were used to probe into prognosis factors. Multivariate Cox regression analysis was conducted to identify factors related to overall survival and cancer-specific survival. RESULTS: Overall, data from 162 patients were analyzed in this study. Tumor size (P = 0.014), T staging (P = 0.028), and chemotherapy (P < 0.001) were independent prognostic factors affecting overall survival. Patients with regional disease (hazard ratio = 5.435, P < 0.001) and distant metastasis (hazard ratio = 2.183, P < 0.001) who received radiotherapy alone had worse survival than those receiving chemoradiotherapy. Tumor size (P = 0.004) and chemotherapy (P < 0.001) were independent prognostic factors affecting cancer-specific survival. Tumor size was an independent factor affecting cancer-specific survival for patients receiving chemoradiation. CONCLUSIONS: Age, T staging, tumor size, primary site, and chemotherapy are independent prognosis factors affecting overall survival and cancer-specific survival in patients with small cell carcinoma of the esophagus who receive radiotherapy. Chemotherapy might further improve cancer-specific survival in patients with small cell carcinoma of the esophagus receiving radiotherapy at all stages.

Small Cell Carcinoma of the Head and Neck: Update on the University of Florida Experience.

We updated the University of Florida experience treating head and neck small cell carcinoma. Eight patients received a median of 67.7 Gy between 1989 and 2017. The 2-year rates of local, regional, distant, and disease control were 73, 60, 33, and 13%, respectively. The 2-year overall survival rate was 38%; median survival was 1.4 years. The longest disease-free period was 9.5 years after treatment with no evidence of disease. Radiotherapy is an acceptable treatment for these patients, who tend to have poor outcomes and distant metastatic disease. Superior systemic chemotherapy may improve outcomes and decrease the likelihood of distant recurrence.

Neuroendocrine carcinoma of the endometrium: A very rare gynecologic malignancy.

OBJECTIVE: To investigate the clinicopathologic characteristics, prognostic factors, outcome, and treatment of the neuroendocrine carcinoma (NEC) of the endometrium. MATERIALS AND METHODS: We retrospectively reviewed the clinicopathologic and survival data of 10 patients who underwent surgery for NEC. The patients were collected between 1999 and 2017 from four referral centers in Turkey. RESULTS: The median age of patients was 67 years (range: 34-75 years). The NEC of endometrium consist of 9 cases with small cell carcinoma (SC) NEC (two with mixed histotypes), and one with a large cell (LC) NEC. According to FIGO 2009 criteria, 70 % (7/10) of patients had advanced stage (III and IV) disease. All patients except one underwent surgical staging, eight patients received platinum-based chemotherapy (CTX) and of 6 those were additionally treated with radiotherapy (RT). Four patients died of disease ranging from 2 to 10 months and six were alive 12-72 months with no evidence of disease. In addition, 4 SC NEC cases raised in polypoid features had no evidence of disease from 24 to 72 months. DISCUSSION: NEC of the endometrium is a rare disease with poor prognosis, which frequently diagnosed in advanced stages. The main treatment modality was the administration of platinum-based CTX as an adjuvant to surgery or surgery and RT. Our result suggests that the polypoid feature of the tumor might be one of the best predictors for the prognosis of SC NEC.

Clinical characteristics and survival of extrapulmonary small cell carcinoma in 11 different primary tumor sites in the United States, 1975-2016.

OBJECTIVE: Few studies have investigated extrapulmonary small cell carcinoma (EPSCC) in a systematic way. This study is to analyze EPSCC in 11 tumor sites from different aspects in the United States (1975-2016). METHODS: In total 4397 patients diagnosed with EPSCC in 11 primary tumor locations were selected from the Surveillance, Epidemiology and End Results (SEER) database. The incidence of EPSCC in the last decade, and the 1, 3 and 5 year survival rates of each tumor site were also roughly calculated. Prognostic factors of EPSCC were investigated by Cox regression analysis. RESULTS: Statistically, the incidence of EPSCC was on the rise over the past 30 years. Of its 11 primary tumor sites, bladder was the most frequently affected while the stomach and kidney were rarely affected. Males were more susceptible to EPSCC than females. Married patients were more commonly afflicted by EPSCC, but had longer survival. Cases were most intensive in California and an increased trend had been observed. The 5 year overall survival (OS) rate ranged from 2.0% to 42.5% in patients with EPSCC in 11 tumor sites (p < .001). The OS was better for EPSCC in the breast and cervix. However, tumor sites in the colon, esophagus, pancreas, rectum and stomach were all associated with worse survival. Characteristics and prognosis of EPSCC in different tumor sites were statistically significant (p < .001). Age, gender, marital status, stage, surgery, radiotherapy and chemotherapy were equally significant factors of survival of EPSCC patients (p < .05). CONCLUSION: There was an increasing trend of EPSCC incidence. The survival of EPSCC in different tumor sites was significantly different. Tumor locations, age, gender, marital status, stage, surgery, radiotherapy and chemotherapy were all important factors of survival. This study has implications for EPSCC prevention and treatment.

Anti-PD-1 therapy plus chemotherapy showed superior and durable survival benefit in a patient with small cell esophageal cancer: A case report.

The prognosis of the small cell esophageal cancer (SCEC) patient in our study was poor due to lack of treatment options which were limited to surgery and chemotherapies, with a median overall survival (OS) of only 11.1 months according to previous studies. Herein, we adopted the regimen of immunotherapy plus chemotherapy, which exerted superior and durable benefit (OS > 19 months) in the patient in our study. Immunotherapy plus chemotherapy might therefore be a reasonable option for selected SCEC patients. In addition, well-designed trials for better evidence are required to verify the findings in this study.

Small Cell Carcinoma of the Ovary: Clinicopathologic and Immunohistochemical Analysis of 7 New Cases of a Rare Malignancy.

BACKGROUND: Small cell carcinoma of ovary (SCCO) is extremely rare. Two types of SCCO are recognized, the pulmonary type (SCCOPT) and the hypercalcemic type (SCCOHT). Establishing an accurate diagnosis is challenging, owing to its rarity and paucity of data describing the distinctive histopathologic and immunohistochemical (IHC) features. METHODS: This was a retrospective study conducted over a period of 4 years. All cases reported as SCCO on histopathology were retrieved. All the available clinical, histopathological, and IHC features were studied in detail. RESULTS: A total of 7 cases of SCCO were diagnosed during the study period. There were 4 cases of SCCOPT and 3 cases of SCCOHT and with mean age of 57.25 and 22 years, respectively. All the cases presented as stage IV disease. Among the SCCOPT cases, 3 showed bilateral involvement with 1 showing concurrent uterine endometrioid adenocarcinoma. Microscopy revealed small hyperchromatic cells with brisk mitosis and multifocal necrosis. On IHC, these were consistently positive for chromogranin, CD56, and synaptophysin. All the SCCOHT cases showed unilateral involvement. Microscopically, in addition to small hyperchromatic cells, larger "rhabdoid" tumor cells were also seen. On IHC, chromogranin was negative, with positivity for vimentin and epithelial membrane antigen. The expression of SMARCA4/BRG1 was lost while SMARCB1/INI1 was retained in all cases. All of these patients developed recurrence and died due to disease progression despite treatment. CONCLUSIONS: SCCO is an extremely infrequent ovarian malignancy with poor prognosis. Knowledge about its characteristic features is important for accurate tissue diagnosis and appropriate management.

Clinicopathological characteristics, treatment and prognosis of head & neck small cell carcinoma: a SEER population-based study.

BACKGROUND: To investigate the clinicopathological characteristics of head and neck small cell carcinoma (H&NSmCC) and identify prognostic factors on the basis of the Surveillance, Epidemiology and End Results (SEER) database. METHODS: Total of 789 primary cases from 1973 to 2016 were included. Univariate and multivariate analyses were performed to identify independent prognostic indicators. An H&NSmCC-specific nomogram was constructed and compared with the AJCC staging system by calculating the time-dependent area under the curve (AUC) of the receiver operating characteristic (ROC) curves. RESULTS: The incidence of H&NSmCC peaked during the period of 50 to 70 years old, and the most frequent location was the salivary gland. The 5-year disease specific survival (DSS) was 27%. In the multivariate survival analysis, AJCC III + IV stage [HR = 2.5, P = 0.03, I + II stage as Ref], positive N stage [HR = 1.67, P = 0.05, negative N stage as Ref], positive M stage [HR = 4.12, P = 0.000, negative M stage as Ref] and without chemotherapy [HR = 0.56, P = 0.023, received chemotherapy as Ref] were independently associated with DSS. The H&NSmCC-specific nomogram was built based on the independent prognostic indicators. The nomogram demonstrated better predictive capacity than the AJCC staging system for 5-year DSS [(AUC: 0.75 vs 0.634; Harrell's C-index (95% CI): 0.7(0.66-0.74) vs 0.59(0.55-0.62), P < 0.05]. CONCLUSION: N stage, M stage, AJCC stage and chemotherapy were independent prognostic indicators included in the prognostic nomogram model, which can better predict the survival of H&NSmCC than the AJCC staging system.

[Treatment and prognostic analysis of patients with primary esophageal small-cell carcinoma].

Objective: The study aimed to analyze the clinicopathological features, treatment, and prognosis factors of primary esophageal small-cell carcinoma (PESC). Methods: The clinical records and follow-up data of 100 patients with PESC were collected, and the clinicopathological features and treatments were examined. Log-rank test and Cox regression model were performed to identify the independent prognostic factors. Results: Progressive dysphagia, weight loss, and abdominal pain were the most common initial symptoms in the 100 patients with PESC. The primary tumor site mainly occurred in the middle of the chest (51%, 51/100), and the ulcer type was the most common under gastroscope (31%, 31/100). One or more positive markers of epithelial origin were present in all of the enrolled patients. At the time of diagnosis, 80 cases had limited disease (LD) and 20 cases had extensive disease (ED). The 1-, 3-, and 5-year survival rates of PESC patients were 57.0%, 18.0%, and 11.0%, respectively, with a median survival time (MST) of 13.8 months. In all PESC patients, multivariate Cox regression analysis indicated that the significant prognostic factors included the lesion length (OR=2.661, P<0.001), TNM staging (OR=1.464, P=0.016), and treatment methods (OR=0.333, P<0.001). Besides, in patients with LD, the lesion length (OR=2.638, P=0.001) and treatment methods (OR=0.285, P<0.001) were independent prognostic factors. The MST of patients in surgery + chemotherapy group (21.6 months) was longer than that of the surgery only group (8.3 months, P=0.021), while patients in surgery+ chemotherapy+ radiotherapy group were also associated with a longer MST than the chemotherapy + radiotherapy group (31.0 months, 9.8 months, respectively; P<0.001). Conclusions: PESC is a rare esophageal malignant tumor with poor prognosis. Our findings reveal that the lesion length, TNM staging, and treatment method are independent prognostic factors for PESC patients. Moreover, surgery-based comprehensive treatments may prolong the survival of patients with LD.

Dose-intensive regimen treatment for small-cell carcinoma of the ovary of hypercalcemic type (SCCOHT).

PURPOSE: Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is a rare and rapidly lethal disease affecting young women. Cytoreductive surgery associated with chemotherapy followed by a high dose chemotherapy regimen (HDC) demonstrated improved outcomes in a unique prospective and several retrospective studies, and this report aimed to confirm these results in an independent and larger cohort. METHODS: Between 2006 and 2018, we conducted a multicentric prospective study on 44 women diagnosed with SCCOHT. Patients were treated homogeneously with optimal cytoreductive surgery and chemotherapy protocol for four to six cycles (PAVEP). In case of complete response, patients received HDC with stem-cell support, followed by pelvic radiotherapy. The primary endpoint was the event-free survival (EFS) in the per-protocol cohort. Secondary analysis explored the effect of HDC with outcomes. RESULTS: Mean age at diagnosis was 33 years old (range 13.8-75.8). 14 patients presented with stage FIGO I, 21 with stage III and 9 with stage IV. Median follow-up was 53.4 months. 38 patients underwent optimal surgery with up to 6 cycles of PAVEP. 30 received HDC, and 21 pelvic radiotherapy. 21 relapses were reported leading to death for 18 patients. Median EFS in the per-protocol cohort was 18.2 months, and 2-year EFS rate was 40%. HDC was significantly associated with better overall survival (p < .001). Grades 3/4 adverse events were frequent but, in most cases, manageable, although one grade-5 adverse-event occurred during HDC. CONCLUSION: Intensive regimen containing multidrug chemotherapy, HDC and pelvic radiotherapy, for the management of SCCOHT, demonstrated encouraging survival and should be proposed for all patients. However, the significant toxicity cost associated is of concern and it should be restricted to expert centers.

Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix based on population analyses.

OBJECTIVE: We aimed to assess the impact of the treatment modality on the outcome of small cell neuroendocrine cervical carcinoma (SCNEC) using the Surveillance Epidemiology and End Results (SEER) database. METHODS: Patients from the SEER program between 1981 and 2014 were identified. Significant factors for cancer-specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier survival and Cox regression methods. RESULTS: A total of 503 SCNEC patients were identified. The 5-year CSS and OS were 36.6% and 30.6%, respectively. The International Federation of Gynecology and Obstetrics (FIGO) stage I to IV distributions was 189 (37.6%), 108 (21.5%), 95 (18.9%), and 111 patients (22.0%), respectively. Within the patients with known treatment strategies, 177 (45.9%) were treated with radical surgery and 209 (54.1%) underwent primary radiotherapy. Local treatment strategies were independent prognostic factor for CSS and OS. The 5-year CSS for radical surgery and primary radiotherapy was 50.0% and 27.9%, respectively (P < .001). The 5-year OS for those who received radical surgery and primary radiotherapy was 57.8%, and 29.6%, respectively (P < .001). In FIGO stage I SCNEC, patients treated with radical surgery had superior CSS (P = .001) and OS (P = .003) than those with primary radiotherapy. However, in FIGO stage II and III SCNEC, there were no differences in CSS and OS with respect to different local treatment strategies. Our results also found that the addition of brachytherapy impacted OS in the FIGO stage III SENCE (P = .002). The 5-year CSS and OS of patients with FIGO IV were only 11.7% and 7.1%, respectively. CONCLUSIONS: SCNEC is a rare disease with aggressive clinical behavior. The findings indicate that radical surgery should be suggested for early-stage SCNEC and combining radiation therapy with brachytherapy should be suitable for patients with advanced stage.

Down-regulation of ADRB2 expression is associated with small cell neuroendocrine prostate cancer and adverse clinical outcomes in castration-resistant prostate cancer.

OBJECTIVES: The net oncogenic effect of ß2-adrenergic receptor ADRB2, whose downstream elements induce neuroendocrine differentiation and whose expression is regulated by EZH2, is unclear. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. METHODS AND MATERIALS: This was a retrospective analysis of a multi-center, prospectively enrolled cohort of mCRPC patients. Metastatic biopsies were obtained at progression, and specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and clustering based on unsupervised hierarchical transcriptome analysis and correlated with EZH2 expression; an external dataset was used for validation. The association between ADRB2 expression and overall survival (OS) was assessed by log-rank test and a multivariable Cox proportional hazard model. RESULTS: One hundred and twenty-seven patients with progressive mCRPC had sufficient metastatic tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P < 0.01) and correlated inversely with EZH2 expression (r = -0.28, P < 0.01). These findings were validated in an external cohort enriched for neuroendocrine differentiation. Patients with tumors harboring low ADRB2 expression (lowest quartile) had a shorter median OS than those with higher (9.5 vs. 20.5 months, P = 0.02). In multivariable analysis, low ADRB2 expression was associated with a trend toward shorter OS (HR for death = 1.54, 95%CI 0.98-2.44). Conversely, higher expression of upstream transcriptional regulator EZH2 was associated with shortened OS (HR for death = 3.01, 95%CI 1.12-8.09). CONCLUSIONS: Low ADRB2 expression is associated with neuroendocrine differentiation and is associated with shortened survival. EZH2 is a potential therapeutic target for preventing neuroendocrine transdifferentiation and improving outcomes in mCRPC. Further studies of agents targeting ß-adrenergic signaling are warranted.

Hospitalization and definitive radiotherapy in lung cancer: incidence, risk factors and survival impact.

BACKGROUND: Unplanned hospitalization during cancer treatment is costly, can disrupt treatment, and affect patient quality of life. However, incidence and risks factors for hospitalization during lung cancer radiotherapy are not well characterized. METHODS: Patients treated with definitive intent radiation (≥45 Gy) for lung cancer between 2008 and 2018 at a tertiary academic institution were identified. In addition to patient, tumor, and treatment related characteristics, specific baseline frailty markers (Charlson comorbidity index, ECOG, patient reported weight loss, BMI, hemoglobin, creatinine, albumin) were recorded. All cancer-related hospitalizations during or within 30 days of completing radiation were identified. Associations between baseline variables and any hospitalization, number of hospitalizations, and overall survival were identified using multivariable linear regression and multivariable Cox proportional-hazards models, respectively. RESULTS: Of 270 patients included: median age was 66.6 years (31-88), 50.4% of patients were male (n = 136), 62% were Caucasian (n = 168). Cancer-related hospitalization incidence was 17% (n = 47), of which 21% of patients hospitalized (n = 10/47) had > 1 hospitalization. On multivariable analysis, each 1 g/dL baseline drop in albumin was associated with a 2.4 times higher risk of any hospitalization (95% confidence interval (CI) 1.2-5.0, P = 0.01), and baseline hemoglobin ≤10 was associated with, on average, 2.7 more hospitalizations than having pre-treatment hemoglobin > 10 (95% CI 1.3-5.4, P = 0.01). After controlling for baseline variables, cancer-related hospitalization was associated with 1.8 times increased risk of all-cause death (95% CI: 1.02-3.1, P = 0.04). CONCLUSIONS: Our data show baseline factors can predict those who may be at increased risk for hospitalization, which was independently associated with increased mortality. Taken together, these data support the need for developing further studies aimed at early and aggressive interventions to decrease hospitalizations during treatment.

Survival of Contemporary Patients With Non-metastatic Small-cell Carcinoma of Urinary Bladder, According to Alternative Treatment Modalities.

BACKGROUND: The objective of this study was to test the effect of chemotherapy and/or radical cystectomy (RC) and/or radiotherapy (RT) on survival of patients with non-metastatic small-cell carcinoma of the urinary bladder (SCCUB). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results registry (2001-2016), we identified patients with non-metastatic (T1-4, N0, M0) SCCUB. Treatment was defined as: chemotherapy alone, chemotherapy + RC, and chemotherapy + RT. Temporal trends, cumulative incidence plots, and multivariable competing risks regression models were used. RESULTS: Of 595 patients with SCCUB, 230 (38.5%), 159 (27%), and 206 (34.5%) were treated with chemotherapy alone, chemotherapy + RC, and chemotherapy + RT, respectively. The rates of chemotherapy + RC increased (estimated annual percentage changes [EAPC], +5.9%; P = .002). Conversely, chemotherapy alone (EAPC, -1.7%; P = .1) and chemotherapy + RT rates decreased (EAPC: -2.2%; P = .08). Overall, 5-year cancer-specific mortality (CSM) rates were 44%, 29%, and 40% for patients treated with chemotherapy alone, chemotherapy + RC, and chemotherapy + RT, respectively (P = .004). Relative to chemotherapy alone, patients treated with chemotherapy + RC experienced lower CSM (hazard ratio, 0.5; P < .001). Conversely, patients treated with chemotherapy + RT did not exhibit any CSM benefit (hazard ratio, 0.8; P = .2), when compared with chemotherapy alone. CONCLUSION: In contemporary patients with SCCUB with non-metastatic disease, the rates of chemotherapy + RC are increasing. Conversely, the rates of combined chemotherapy with RT and chemotherapy alone are decreasing. These patterns of treatment are in agreement with better cancer control in patients with SCCUB. In consequence, until more robust data become available, the combination of chemotherapy and RC should represent the recommended treatment strategy.

Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines.

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.

Tumor-Infiltrating Immune Cells and PD-L1 as Prognostic Biomarkers in Primary Esophageal Small Cell Carcinoma.

Primary esophageal small cell carcinoma (PESCC) is a weakly prevalent but lethal malignancy with early metastasis and a poor prognosis. Currently, neither effective prognostic indicators nor curative therapies are available for PESCC. Immunotherapy has now evolved into one of the most promising therapies for cancer patients. Tumor-infiltrating immune cells which are integral to the tumor immune microenvironment (TIME) are recognized as highly important for prognosis prediction, while the responsiveness to immune checkpoint blockade may be subject to the features of TIME. In this study, we aim to identify the TIME and provide indication for the applicability of immune checkpoint therapy in PESCC. We found that PD-L1 expression was detected in 33.33% (27/81) of all the patients, mostly exhibiting a stroma-only pattern and that it was positively associated with tumor-infiltrating immune cells (CD4+, CD8+, and CD163+). In 74.07% of PD-L1-positive specimens, PD-L1+CD163+ cells were colocalized more with CD4+ than CD8+ T cells. 83.95% (68/81) of all the specimens were infiltrated with more CD4+ than CD8+ T cells. Further analysis showed FoxP3+ Tregs constituted 13-27% of the total CD4+ T cell population. The Kaplan--Meier analysis indicated several factors that contribute to poor survival, including negative PD-L1 expression, rich CD4 expression, rich FoxP3 expression, a low CD8/CD4 ratio, and a high FoxP3/CD8 ratio. A nomogram model was constructed and showed good performance for survival prediction. These results highlight that a suppressive TIME contributes to poor survival of patients with PESCC. TIME analyses might be a promising approach to evaluate the possibility and effect of immune checkpoint-based immunotherapeutics in PESCC patients.