Small Cell Carcinoma Of Prostate Research Articles

CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

Prognostic nomogram, demographics and comparative analysis of prostate small cell and large cell neuroendocrine carcinoma.

e17010 Background: This retrospective study aims to examine the patient demographics, survival rates, and treatment methods for small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) of prostate origin while also identifying the main differences from common types of prostate cancer. Methods: Our analysis utilized the Surveillance, Epidemiology, and End Results database (SEER), and data was collected from 2000-2020. Results: A total of 718 cases of prostate small and large neuroendocrine carcinoma were identified. The median age was found to be 71.5 years and the median follow-up was 11.0 years (95% confidence interval (95% CI) = 9.2-12.8). Most patients were over the age of 80 years (33.8%) and Caucasians (74.4%). The overall 5-year survival was 8.0% (95% CI = 6.8-9.2). The 5-year cause-specific survival (CSS) was 16.2% (95% CI = 14.3-18.1). For treatment modality, the five-year survival for each were as follows: chemotherapy, 3.5% (95% CI = 2.1-4.9); surgery, 18.2% (95% CI = 13.6-22.8); multimodality therapy (surgery and chemotherapy), 4.8% (95% CI = 1.7-7.9); and combination (chemoradiation with surgery), 5.0% (95% CI = 1.0-9.0). The prognostic nomogram created to predict patient survivability matched the findings from the statistical analysis with a statistical difference found in race, income, housing, stage, and nodal status. This analysis showed a slight increase in mortality for patients of Asian race. In addition, there was a significant increase in death for patients of stage 3 tumors, as well as patients who underwent surgery and radiation. The nomogram also indicated a slight increase in mortality with tumors of greater size. Conclusions: Small-cell and large-cell neuroendocrine carcinomas of the prostate are rare; their aggressive nature calls for a deeper understanding and improved prognostic tools. By leveraging insights from registry-based studies, clinicians can better strategize treatment options, improving patient outcomes in this challenging arena of oncology.

Lurbinectedin in prostatic small cell and neuroendocrine carcinoma.

164 Background: Lurbinectedin (L) is a novel inhibitor of oncogenic transcription that was granted accelerated approval by the Food and Drug Administration in June 2020 for the treatment of metastatic small cell lung cancer (SCLC) following disease progression on or after platinum-based chemotherapy (PBC). Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) is a high-grade, invasive malignancy that accounts for < 1% of all prostate cancers. SC/NEPC is distinct from prostatic adenocarcinoma and behaves similar to SCLC. NCCN guidelines for SC/NEPC recommend following the SCLC treatment guidelines. Using these guidelines, L may be used as a second-line treatment in patients (pts) with SC/NEPC who progress on or after PBC. We aimed to characterize the baseline characteristics, clinical course and therapeutic outcomes of pts treated with L for SC/NEPC. Methods: After IRB approval, 18 cases were gathered from 4 academic oncology centers. Baseline patient data, prior treatments and L treatment outcomes, including best radiographic and serologic responses, overall survival (OS), progression-free survival (PFS) and treatment toxicity were assessed. The Kaplan-Meier method was used to calculate OS and PFS from the L start date. Clinical benefit rate (CBR) included pts with complete response (CR), partial response (PR) and stable disease (SD) on imaging. Results: At the time of first L dose, all had metastatic disease with 2-6 distinct sites of metastases, most commonly bone (14/18, 77.8%), lymph nodes (14/18, 77.8%) and liver (13/18, 72.2%); median age was 63.5 (Range: 53-84); 11 pts (61.1%) had an ECOG 0-1; 4 pts (22.2%) had an ECOG of 2-3. The median total number of systemic therapies administered prior to L was 4 (Range: 2-7). All pts received PBC prior to L. The most common dose of L prescribed was 3.2 mg/m2 every 21 days (15/18, 83.3%). Androgen deprivation therapy was administered in conjunction with L in 9 pts (50%). The median number of cycles of L was 5 (Range: 1-10). L was discontinued due to toxicity in 1 patient (5.6%), disease progression in 10 pts (55.6%), transition to hospice in 2 pts (11.1%), 3 pts (16.7%) died while receiving treatment (not due to L toxicity), and 2 pts (11.1%) remained on L at the time of data reporting. The median OS and PFS from date of first L dose was 6.01 months (0.23 – 16.69) and 3.35 months (0.16 – 7.79), respectively. CBR was 9/16 (56.3%) with partial response in 5 pts (31.3%), stable disease in 4 pts (25%), and progressive disease in 7 pts (43.8%). Two pts did not have post-treatment imaging available to assess response. There were no hospitalizations for L treatment related adverse events (tRAE). The most common tRAE were grade I and II fatigue and anemia; 9 pts (50%) experienced no tRAE. The only grade IV toxicity was neutropenia in 3 pts (16.7%). Conclusions: L is a well-tolerated and active treatment option for patients with SC/NEPC. Prospective studies are needed to determine the role of L in the treatment of SC/NEPC.

Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers.

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

Small-Cell Carcinoma of the Prostate - Challenges of Diagnosis and Treatment: A Next of Kin and Physician Perspective Piece.

This article was co-authored by a patient's relative describing their experiences of receiving a diagnosis and subsequent clinical management of a rare form of prostate cancer, neuroendocrine prostate cancer (NEPC). The difficulty of receiving this diagnosis, particularly as this was terminal with no options for systemic treatment, and experiences throughout this process are detailed. The relative's questions regarding the care of her partner, NEPC and clinical management are answered. The treating physician's perspective regarding clinical management is enclosed. Prostate cancer remains one of the most common cancer diagnoses, with small-cell carcinoma (SCC) of the prostate representing 0.5-2% of these. Prostatic SCC frequently develops in patients previously treated for prostate adenocarcinoma, more rarely arising de novo. Diagnosis and management present clinical challenges owing to its rarity, frequently aggressive disease course, lack of specific diagnostic and monitoring biomarkers, and treatment limitations. Current pathophysiological understanding of prostatic SCC, genomics and contemporary and evolving treatment options in addition to current guidelines are discussed. Written principally from the patient's relatives and physician experience with discussion of current evidence, diagnostic and treatment options, we hope this piece is informative for both patients and healthcare professionals alike.

Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study

SummaryTo determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).

Abstract PO-100: Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer

Abstract Background: B7-H3 (CD276, PD-L3) is an immunomodulatory molecule highly expressed in prostate cancer and belonging to the B7 superfamily that also includes PD-L1 (B7-H1). Immunotherapies (antibodies, antibody-drug conjugates, and CAR-T cells) targeting B7-H3 are currently in clinical trials; thus elucidating the clinical, molecular and tumor immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. Methods: We developed an automated, clinical-grade immunohistochemistry assay to digitally quantify B7-H3 protein expression across two racially diverse cohorts of primary prostate cancer (including one with previously reported transcriptomic data), a set of prostatic neuroendocrine small cell carcinoma, and pre- and post-treatment tumor tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression is significantly lower in self-identified Black patients and inversely correlates with percent African ancestry by ancestry-informative markers. This association with race is independent of the significant association of B7-H3 expression with ERG/ETS and PTEN status. CD276 mRNA level, but not B7-H3 protein expression, is significantly correlated with regulatory (FOXP3+) T-cell density. Finally, androgen receptor activity (AR-A) scores are significantly correlated with CD276 mRNA expression, and neoadjuvant intensive hormonal therapy is associated with a significant decrease in B7-H3 protein expression. Conclusion: These data underscore the importance of studying racially and molecularly diverse prostate cancer cohorts in the era of immunotherapy. Our study is among the first to use genetic ancestry markers to add to emerging evidence that prostate tumors from men of African ancestry may have a distinct immune milieu associated with B7-H3 expression. Citation Format: Adrianna A. Mendes, Jiayun Lu, Harsimar B Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, Karen S. Sfanos, Janielle Maynard, Ashley E. Ross, Steven P. Balk, Mary-Ellen Taplin, Emmanuel S. Antonarakis, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan. Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-100.

The opposing action of stromal cell proenkephalin and stem cell transcription factors in prostate cancer differentiation

BackgroundLoss of prostate cancer differentiation or de-differentiation leads to an untreatable disease. Patient survival would benefit if this can be prevented or reversed. Cancer de-differentiation transforms luminal-like (differentiated) adenocarcinoma into less luminal-like and more stem-like (undifferentiated) small cell carcinoma through a sequential activation of stem cell transcription factors (scTF) POU5F1, LIN28A, SOX2 and NANOG. Like stem cells, prostate small cell carcinoma express this quartet of scTF as well as a 10-fold lower level of β2-microglobulin (B2M) than that of differentiated cell types. In organ development, prostate stromal mesenchyme cells mediate epithelial differentiation in part by secreted factors.MethodsThe identified prostate stromal-specific factor proenkephalin (PENK) was cloned, and transfected into scTF+B2Mlo stem-like small cell carcinoma LuCaP 145.1, reprogrammed luminal-like scTF−B2Mhi LNCaP, and luminal-like scTF−B2Mhi adenocarcinoma LuCaP 70CR. The expression of scTF, B2M and anterior gradient 2 (AGR2) was analyzed in the transfected cells.ResultsPENK caused down-regulation of scTF and up-regulation of B2M to indicate differentiation. When transfected into reprogrammed LNCaP, PENK reversed the reprogramming by down-regulation of scTF with attendant changes in cell appearance and colony morphology. When transfected into LuCaP 70CR, PENK up-regulated the expression of adenocarcinoma antigen AGR2, a marker associated with cancer cell differentiation.ConclusionsProstate cancer cells appear to retain their responsiveness to stromal PENK signaling. PENK can induce differentiation to counter de-differentiation caused by scTF activation. The many mutations and aneuploidy characteristic of cancer cells appear not to hinder these two processes. Loss of prostate cancer differentiation is like reprogramming from luminal-like to stem-like.

Apoptotic Cell Death Induction Through Pectin, Guar Gum and Zinc Oxide Nanocomposite in A549 Lung Adenocarcinomas

Previously, we reported the immunostimulatory potential of the nanocomposite prepared from biopolymers (Pectin and Guar gum) and zinc oxide (Pec-gg-ZnO) on human peripheral-blood lymphocytes leading to enhanced anti-cancer immunity. The current study aims to describe the direct anti-cancer potential of Pec-gg-ZnO nanocomposite and the relevant mechanism of cell death induction in human lung carcinomas (A549). The cytotoxicity assay revealed the anti-cancer potential of Pec-gg-ZnO nanocomposite towards A549 cells, cervical adenocarcinoma (HeLa), and prostatic small cell carcinoma (PC-3). The IC50 values were 83.67 ± 0.10 μg/ml, 87.25 ± 0.03 μg/ml and 85.95 ± 0.03 μg/ml for A549, HeLa and PC-3 cells, respectively. The nanocomposite's cancer cells' killing capabilities were significantly higher than pectin and guar gum alone. Hemolysis assay revealed that synthesized Pec-gg-ZnO nanocomposite is biocompatible at 2.5 mg/ml. S phase arrest with enhanced sub-G1 (apoptotic cells) population was examined in A549 cells treated with Pec-gg-ZnO nanocomposite. The nanocomposite caused apoptosis of target cells by inducing mitochondrial depolarisation, reactive oxygen species generation, caspase-3 and Poly (ADP-ribose) polymerase 1 (PARP1) activation resulting in DNA fragmentation. Collectively, the current data revealed that Pec-gg-ZnO nanocomposite is a novel polymer-based anti-cancer agent capable of inducing apoptotic pathways in cancer cells.

Pure Small Cell Carcinoma of Prostate in a Patient Presenting with Acute Urinary Retention: A Rare Case Report

Small cell carcinoma of the prostate is a rare and highly aggressive subtype of prostate cancers. In this case report, we evaluated a patient applied our outpatient clinic with acute urinary retention, whose pathology reported as pure small cell carcinoma of the prostate. A 73-year-old male patient was admitted to our outpatient clinic with acute urinary retention. Digital rectal examination was normal. The PSA value was 1.81 ng/dl. Prostate size was 101 cc. Open prostatectomy was performed. The pathology of the patient was reported as pure small cell prostate carcinoma. Four cycles of etoposide and cisplatin chemotherapy were administered to the patient. The patient died 13 months later after the first diagnosis. We evaluated the pathological and clinical findings of small cell carcinoma of the prostate.

Abstract C012: Real-world use of circulating tumor DNA (ctDNA) in the clinical management of patients with solid tumors: A single institution’s experience

Abstract Background: The analysis of circulating tumor DNA (ctDNA) is becoming an instrumental tool in the practice of precision oncology. It not only provides a non-invasive method to study the mutational composition of solid tumors, particularly when there are limitations in tissue acquisition, but also helps capturing the biological heterogeneity and genomic evolution of advanced tumors. There is tremendous variability in utilization of ctDNA among oncologists in in various solid tumors and currently there are no guidelines. Methods: We evaluated the results of all Guardant360 ctDNA tests that were requested for clinical management in advanced cancers in our academic tertiary cancer center. We identified and annotated the most common genomic alterations and variants for each disease type. Moreover, we collected variant allele frequency variants (VAF) from each report and disease. The results for each type of neoplasm were compared to the others. Results: A total of 2199 tests for 1402 patients were performed between 2015 to January 2019. The test volume increased from 162/year in 2015 to 733/year in 2018. The tests were most commonly requested in patients with the diagnosis of advanced breast adenocarcinoma (ABC)(36%), followed by non-small cell lung cancer (NSCLC)(21%), colorectal cancer (CRC)(5%). 88% of reports included at least one alteration, with a median of 3 alterations per case and median of highest VAF of 1.1%. Prostate small cell carcinoma, contained the largest number of alterations/case (median: 9.5) and highest VAF (median: 7.1%). Among common neoplasms CRC had a significantly higher VAF (Median: 5.4%), compared to NSCLC and ABC (median <1%). Overall the most commonly mutated genes, in order of prevalence, included TP53 (90% of positive cases), PIK3CA (36%), EGFR (31%), NF1 (21%), and ERBB2 (20%). Conclusions: Utilization of ctDNA in the management of patients with solid tumors is drastically increasing. The data indicates that tests can identify genomic abnormalities in the majority of cases but, the number of mutations and VAF is variable in different types of tumors reflecting underlying biology and molecular heterogeneity. ctDNA should be used in the management of advanced solid tumors to improve understanding of disease genomic alterations and facilitate treatment selection. Citation Format: Amir Behdad, Firas Wehbe, Carmen Williams, Wenan Qiang, Athanasios Vasilopoulos, Massimo Cristofanilli MD FACP. Real-world use of circulating tumor DNA (ctDNA) in the clinical management of patients with solid tumors: A single institution’s experience [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C012. doi:10.1158/1535-7163.TARG-19-C012

Intracranial Metastases from Prostate Carcinoma: Classification, Management, and Prognostication

Prostate carcinomas rarely metastasize to the central nervous system but, when they do, dural localizations are as common as and far more aggressive than intraparenchymal ones. Those metastases can be further classified according to their extension toward the subdural or extradural space and can frequently simulate other pathologic conditions including chronic subdural hematomas, abscess, and primary bone tumors. Beside the challenges of the preoperative differential diagnostic and complexity of surgical planning and operative excision, subdural metastases seem to carry a much poorer prognosis. A series of consecutive patients admitted during a 12-year period through our oncall pathway for subdural/extradural collections or intraparenchymal lesions found, on histologic analysis, to represent intracranial prostate cancer metastases was retrospectively reviewed. A total of 19 patients were included, but only 3 were diagnosed with small cell prostate carcinoma, while the majority had a primary prostate adenocarcinoma. Metastases could be classified as pure subdural space lesions, dural-based lesions, extradural/bony lesions, and pure intraparenchymal lesions. All patients with subdural metastases and 3 out of 5 patients with dural-based lesions required an emergency intervention due to rapidly deteriorating neurologic status. The mean follow-up in our series was 37 months; only subdural localizations had a remarkably unfavorable outcome. Supported by our experience and the review of the literature, we suggest that a low threshold for contrast-enhanced computed tomography/magnetic resonance imaging is advisable in case of suspicious subdural collection, even in an emergency setting, for patients with previous medical history of prostate cancer.

Apoptosis induction in lung and prostate cancer cells through silver nanoparticles synthesized from Pinus roxburghii bioactive fraction.

The current study was carried out to synthesize silver nanoparticles (AgNPs) via bioactive fraction of Pinus roxburghii needles using a simple, cost-effective, and eco-friendly green chemistry method. As butanol fraction of P. roxburghii exhibited maximum anticancer activity on lung adenocarcinomas (A549) as compared to other fractions therefore, butanol fraction was used to synthesize silver nanoparticles (PNb-AgNPs). The characterization studies by UV-Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS) and selected area electron diffraction (SAED) confirmed the synthesis of the nanoparticles. The field emission scanning electron microscopy (FESEM) and high-resolution transmission electron microscopy (HRTEM) analysis showed the spherical structure of nanoparticles with an average diameter of approximately 80nm. Interestingly, PNb-AgNPs exhibited significant cytotoxicity towards both A549 and prostatic small cell carcinomas (PC-3) with IC50 values of 11.28 ± 1.28μg/ml and 56.27 ± 1.17μg/ml, respectively, while lacking toxicity against normal human breast epithelial cells (fR2) and human peripheral blood lymphocytes (PBL). Further, enhanced reactive oxygen species generation, mitochondrial depolarization, apoptotic cell population (sub-G1) and DNA fragmentation observed in cancer cells were treated with PNb-AgNPs. Apoptosis was demonstrated by caspase-3 and PARP-1 activation in PNb-AgNPs-pretreated cancer cells. These results strongly suggest that PNb-AgNPs are capable of inducing cancer cell death and could act as a therapeutic nanoformulation for cancer.

1622 A Rare Case of Small Cell Carcinoma of the Rectum

INTRODUCTION: Small cell carcinoma (SCC) of the rectum is very rare, with an incidence rate of 0.2% of all colorectal malignancies. Amongst all primary SCCs of the gastrointestinal tract, the rectum is the least common site of occurrence. We present a rare case of SCC of the rectum of unknown primary. CASE DESCRIPTION/METHODS: A 58-year-old male with a past medical history of prostate adenocarcinoma (gleason 4 + 3 = 7, previously treated with chemoradiation and brachytherapy) presented with a one year history of rectal pain and hematochezia. Laboratory results were significant for hemoglobin of 14.2 grams/dL, platelets 185,000/microliter, prostate specific antigen of < 0.06 nanogram/mL. Computerized tomography scan of the chest and abdomen/pelvis revealed mild circumferential rectal thickening, prostatic brachytherapy seeds, increased size of pelvic lymph nodes, and a lytic lesion in the 7 th rib. A colonoscopy was performed with findings of a 4 centimeter ulcerated, non-circumferential, non-obstructing rectal mass just above the dentate line. Pathology from rectal biopsies was consistent with small cell carcinoma; immunohistochemistry was positive for AE1/AE3, CD56, Synaptophysin, and Thyroid Transcription Factor-1. Bone biopsy of the rib lesion was also consistent with small cell carcinoma. A magnetic resonance imaging of the prostate was obtained which demonstrated an enhancing focal lesion in the right apical peripheral zone, suggestive of recurrence of prostate malignancy. A prostate biopsy was not obtained as it would not affect the overall treatment plan. The patient was started on etoposide and cisplatin with plans to be closely monitored for disease response. DISCUSSION: Small cell carcinoma of the rectum remains a very rare diagnosis and there is only a paucity of information limited to brief case reports. Our patient’s case is unique in that he has a previous history of prostate adenocarcinoma and there have been hypotheses that certain prostate stem cells can differentiate into SCC; a prostate biopsy would have provided a more definitive answer as to the source of this patient’s primary malignancy. Regardless, the proposed treatment of SCC remains the same (whether this is of primary rectal origin or metastatic prostate SCC to the rectum) and involves chemotherapy along with consideration of surgery/radiotherapy based on the extent of disease.

Current trend of worsening prognosis of prostate small cell carcinoma: A population-based study.

ObjectiveTo determine the accurate age‐adjusted incidence of prostate small cell carcinoma (SCC), update the clinical and pathological characteristics, as well as survival data of prostate SCC from Surveillance, Epidemiology, and End Results (SEER) datasets.MethodsA total of 260 patients with prostate SCC were selected from the SEER database of the National Cancer Institute between 2004 and 2015. Age‐adjusted incidence (AAI) rates, the observed and relative survival rates were evaluated over time by the SEER*Stat Software version 8.3.5. Overall survival (OS) rates that stratified by summary stage and treatment effects were evaluated by Kaplan‐Meier method. The significant differences were assessed in a log‐rank test. Univariate and multivariate cox hazard regression analysis were performed to determine independent predictors of OS.ResultsThe incidence of prostate SCC has increased over time. The average age of prostate SCC patients was 70.25 years. More than 90% of tumors were poorly differentiated or undifferentiated. The majority of prostate SCC (77.7%) was at stage IV. 49% of patients had lymph node metastases and 68% of patients presented distant metastases (Compared with 60.5% of patients with distant metastases between 1973‐2003). Interestingly only 23.5% patients had high level PSA (>10 ng/mL). 58.8% of patients underwent chemotherapy, 25.4% of patients were treated by surgery, and 31.9% of patients were treated by radiotherapy. The observed survival rates of 1‐year, 2‐year, and 5‐year were 42.1%, 22.1%, and 12.5%, respectively (Compared with 47.9%, 27.5%, and 14.3%, respectively, between 1973 and 2003). Chemotherapy prolonged the OS of patients with regional (distant) metastases from 3 months (2 months) to 12 months (9 months). Multivariate cox regression analysis showed age, race, and stage were independent prognostic factors for prostate SCC patients.ConclusionProstate SCC is a highly malignant cancer and our analysis of recent data has shown its incidence is increasing. Incidence rate of metastatic prostate SCC has increased and the survival rates have worsened in recent years. However, chemotherapy shows some survival benefit for prostate SCC patients with regional and distant metastasis over other treatment methods. Further work is needed to understand the reason prognosis of this type prostate cancer is worsening.

Man With Painless Vision Loss

A 53-year-old man with metastatic small cell prostate cancer presented with 10 days of painless vision decrease in his right eye, accompanied by optical debris and a dull diffuse headache but no acute systemic symptoms. Physical examination demonstrated nasal hemianopia in the right eye and intact visual fields in the left eye. The visual acuity, pupillary examination, and extraocular movements were normal bilaterally. The emergency physician performed bedside ocular ultrasonography (Figure 1) to rule out retinal detachment and confirmed the diagnosis with magnetic resonance imaging (MRI) of the brain and orbits (Figure 2).Figure 2Orbital MRI with T-1 weighting, demonstrating a 6-mm choroidal lesion (arrow).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Choroidal metastasis of small cell prostate carcinoma. Fundoscopic examination demonstrated a bullous mass in the temporal macula, with serous retinal detachment. MRI revealed a 6-mm intraocular lesion with six 1- to 2-mm intracranial lesions. At the patient’s request, he was discharged with outpatient oncology follow-up. The differential diagnosis for partial vision loss includes retinal detachment, vitreous detachment, vitreous hemorrhage, and lens dislocation,1Walker R.A. Adhikari S. Eye emergencies.in: Tintinalli J.E. Stapczynski J.S. Ma O.J. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th ed. McGraw-Hill Education, New York, NY2016: 1572-1575Google Scholar and ultrasonography can be critical for rapid evaluation.2Tham E. Ocular ultrasound.in: Carmody K.A. Moore C.L. Feller-Kopman D. Handbook of Critical Care and Emergency Ultrasound. McGraw-Hill, New York, NY2011: 185Google Scholar Fixed lesions are pathognomonic of choroidal detachment.3Lyon M. Jehle D.V. Ocular.in: Ma O.J. Mateer J.R. Reardon R.F. Ma and Mateer's Emergency Ultrasound. 3rd ed. McGraw-Hill Education, New York, NY2014: 250Google Scholar Although prostate cancer metastasizes to the choroid,4Folberg R. The eye.in: Kumar V. Abbas A.K. Fausto N. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Saunders Elsevier, Philadelphia, PA2010: 1356Google Scholar orbital metastases, regardless of cause, imply a median survival of 15 months.5Shields J.A. Shields C.L. Brotman H.K. et al.Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture.Ophthalmic Plast Reconstr Surg. 2001; 17: 346-354Crossref PubMed Scopus (249) Google Scholar

Lineage relationship between prostate adenocarcinoma and small cell carcinoma

BackgroundProstate cancer displays different morphologies which, in turn, affect patient outcome. This fact prompted questions about the lineage relationship between differentiated, more treatable prostate adenocarcinoma and poorly differentiated, less treatable non-adenocarcinoma including small cell carcinoma, and the molecular mechanism underlying prostate cancer differentiation.MethodsNewly available non-adenocarcinoma/small cell carcinoma PDX LuCaP lines were analyzed for expression of stem cell transcription factors (scTF) LIN28A, NANOG, POU5F1, SOX2, which are responsible for reprogramming or de-differentiation. cDNA of these genes were cloned from small cell carcinoma LuCaP 145.1 into expression vectors to determine if they could function in reprogramming.ResultsExpression of scTF was detected in small cell carcinoma LuCaP 93, 145.1, 145.2, and non-adenocarcinoma LuCaP 173.1, 173.2A. Transfection of scTF from LuCaP 145.1 altered the gene expression of prostate non-small cell carcinoma cells, as well as fibroblasts. The resultant cells grew in stem-like colonies. Of note was a 10-fold lower expression of B2M in the transfected cells. Low B2M was also characteristic of LuCaP 145.1. Conversely, B2M was increased when stem cells were induced to differentiate.ConclusionsThis work suggested a pathway in the emergence of non-adenocarcinoma/small cell carcinoma from adenocarcinoma through activation of scTF genes that produced cancer de-differentiation.

Aggressive variant prostate cancer (AVPC) molecular signature in castration-sensitive, de novo metastatic prostate cancer (M1PCa).

5052 Background: AVPC are a subset of prostate cancers (PC) that share clinical features with the small-cell prostate carcinomas, a rare morphological variant with atypical and virulent behavior. They are estimated to represent 30% of lethal PC and are characterized by a molecular signature of combined defects (≥2) in Tp53, RB1 and PTEN (AVPC_MS). The AVPC_MS is associated with androgen indifference in preclinical models and predicts for benefit from the addition of carboplatin to cabazitaxel in men with castration resistant prostate cancer (CRPC). The prevalence and significance of the AVPC_MS in castration sensitive M1PC is unknown. Methods: In a Phase II trial 119 men with M1PC treated with 6 months of standard systemic therapy (SST) were randomized to the addition of local therapy. PCa samples obtained at diagnosis and after 6 months of SST were stained for markers including Tp53, RB1 and PTEN, and subject to whole genome sequencing. Tp53 was considered defective if expressed in ≥ 10% of tumor cells, and RB1 and PTEN if in ≤ 10%. Progression free survival (PFS) was estimated from SST start. Results: To date specimens from 38 men have been evaluated. Immunohistochemistry (IHC) results are shown below. The median PFS of men with AVPC_MSPOSITIVE vs AVPC_MSNEGATIVEbaseline prostate tumors was 9.3 vs 15 months (HR 1.09, 95%CI 0.42-2.87, P=0.852). Conclusions: The rate at which the AVPC molecular signature is detected in castration sensitive M1PCa appears similar to that in CRPC. This may have therapeutic implications. Updated molecular and outcome data will be presented upon acceptance. [Table: see text]

Extensive Metastases in Prostatic Carcinoma with Normal Prostate-Specific Antigen and Raised Carcinoembryonic Antigen – Small Cell Carcinoma of Prostate: A Rare Entity

AbstractSmall cell carcinoma of prostate is a neuroendocrine tumor of prostate seen in 0.5%–2% of men with carcinoma prostate. Prostate-specific antigen (PSA) is a common tumor marker which is often raised in prostatic carcinoma. However, prostatic carcinoma can progress with normal or low serum PSA levels at the time of diagnosis. Carcinoembryonic antigen (CEA) is a tumor marker of different carcinomas. Small cell carcinoma prostate is a highly aggressive tumor which can progress with normal or low serum PSA levels and raised CEA levels. We report a case of 65-year-old male with enlarged prostate with extra-prostatic spread, hepatic metastases, metastatic retroperitoneal and pelvic lymph nodes, osteoblastic metastasis in lumbar spine with normal serum PSA, and raised CEA levels. Prostatic biopsy was suggestive of small cell carcinoma.

Pure Small Cell Carcinoma of Prostate: A Report of 8 Cases

Purpose: To describe characteristics of pure small cell carcinoma of prostate (SCCP) and assess the prognostic factors. Patients and Methods: We summarized data of pure SCCP from published studies and ours and made Kaplan-Meier analysis and Cox regression to evaluate prognosis factors. Results: A total of 2,213 patients with prostate cancer was identified, of which eight (0.36%) patients were pure SCCP. The mean age at diagnosis was 61 years old. And there were 2 patients diagnosed at 34 and 50 years old respectively. Symptoms of these patients were similar to patients with prostate adenocarcinoma. Serum prostate specific antigen of 7 patients was at normal level. Five patients received chemotherapy, average overall survival (OS) was 9.75 months; 3 only received conservative treatment, average OS was 4 months. By univariate and multivariate Cox analysis, chemotherapy is an independent predictor of survival. Kaplan-Meier analysis demonstrated that chemotherapy was associated with longer OS. Conclusion: Clinical characteristics, examination and treatment strategy of pure SCCP are very different from prostate adenocarcinoma. According to the data from published studies and from our studies, the average survival of patients receiving chemotherapy is longer than those who received other treatment modalities.