A patient with multiple primary malignant neoplasms with high variant allele frequencies of RB1, TP53, and TERT.

Multiple primary malignant neoplasms are a rare disease with tumors of different histology or morphology arising in various sites. Next-generation sequencing is essential in the etiology, diagnosis, treatment, and surveillance of this disease. No eight primary malignant neoplasm cases with high variant allele frequencies of RB1, TP53, and TERT have been reported. Herein, we report a 65-year-old male who exhibited eight primary malignancies of the vocal cord, pharynx, kidney, mouth floor, esophagus, and urinary bladder with different pathological types. The first seven tumors were early-stage tumors; the last tumor, small cell carcinoma of urinary bladder, showed liver metastasis at diagnosis. Next-generation sequencing results revealed extremely high somatic variant allele frequencies of RB1 c.1472 T > C, TP53 c.576A > G, and TERT c.-58-u66C > T (95.5%, 95.1%, and 51.0%, respectively). No germline mutations were detected. These findings denoted a heavy tumor burden and poor prognosis. This is the first report of eight primary malignant neoplasm cases with high variant allele frequencies of RB1, TP53, and TERT.

Successful treatment of recurrent small cell carcinoma of urinary bladder with pembrolizumab.

INTRODUCTION: Small cell carcinoma of urinary bladder is rare and has an aggressive malignant behavior and poor prognosis. Advanced bladder cancers are treated with immune checkpoint inhibitors, however, its efficacy for small cell carcinoma of urinary bladder is unclear. CASE PRESENTATION: A 54-year-old female, diagnosed with clinical stage T2N0M0 small cell carcinoma of urinary bladder, underwent radical cystectomy after three cycles of etoposide-cisplatin neoadjuvant chemotherapy. Despite the fact that pathological examination revealed no residual carcinoma in bladder in her cystectomy specimen, local recurrence of a 60-mm mass detected in the follow-up investigation 7.5 months later. This was completely treated by pembrolizumab without any adverse effects. Immunohistochemical staining revealed that the tumor had no programmed death ligand 1 expression but it showed CD8-positive T-lymphocyte infiltration into the tumor. CONCLUSION: Immune checkpoint inhibitors might have curative potentials for treatment of small cell carcinoma of urinary bladder.

High thermal amplitude auto-anti-"N" complicating pretransfusion compatibility tests on a patient with malaria and bladder cancer.

BACKGROUND: Antigen "N" is a high-frequency antigen of the MNS blood groups and carried on glycophorin B that is resistant to enzymatic cleavage by trypsin, and provides differential diagnosis of its antibody specificity to N being present of glycophorin A. Naturally occurring IgM antibodies to N are known to be clinically insignificant, as against the IgG counterpart with clinical relevance. AIM: Auto-anti-"N" association with the bladder cancer was explored for its clinical significance as well as its interference in grouping anomaly. MATERIALS AND METHODS: A warm environment was created while blood sampling for the laboratory work up as the patient had a high-titer auto-cold agglutinin causing spontaneous hemagglutination. The antibody was tested by standard serological methods with the red cell, antisera, and enzymes prepared in house or obtained commercially. RESULTS: The case was admitted to hospital with high fever and hematuria; he was diagnosed with malaria and bladder cancer. He required transfusions in the face of severe anemia. His blood sample posed problems in compatibility tests due to autoantibody present. Serological workup revealed its specificity as anti-"N." CONCLUSION: Auto-anti-"N" as a cause of severe anemia could not be attributed to, for concurrent malarial infection. However, its presence may have some association with the underlying malignant condition.

Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype.

Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and "p53-like" urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The "p53-like" subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management.

Inhibitory effects of high mobility group chromosomal protein N2 on growth ofbladder cancer T24 cells and ectopic tumor growth of nude mice / 实用医学杂志

Objective To investigate the inhibitory effects of high mobility group chromosomal protein N2 (HMGN2)on growth of human bladder cancer T24 cells and ectopic tumor growth of nude mice. Methods MTT and flow cytometry assay were conducted to detect cell growth of bladder epithelial cells(T24)cells in vitro. The transplantation tumor models in nude mice were constructed by injecting T24 cells in vivo. The para-tumorswere injected with PBS,HMGN2 protein and cisdichlorodiamineplatinum(DDP),respectively. Tumor volume and weight were calculated. The expression of cell proliferation-related proteins was detected by Western blot assay. Results MTT assay proved that HMGN2 could significantly inhibit the growth of T24 cells. Flow cytometry assay verified that HMGN2 could block T24 cells in S stage of the cell cycle. The average tumor volume and weight in the HMGN2 group and DDP positive control group were smaller than those in the PBS group(P<0.05,respectively), with the tumor inhibitory rate of 25% and 23%,respectively. The results of Westernblot showed that HMGN2 could decrease Bcl-2 expression and increase Bax expression in tumor. Conclusion HMGN2 has a significant antitumor effect on T24 cells and bladder carcinoma in nude mice,which may be associated with the induction of the apoptosis of carcinoma cells and the regulation of the cell cycle.

Temporal trends in receipt of adequate lymphadenectomy in bladder cancer 1988 to 2010.

INTRODUCTION AND OBJECTIVE: The importance of pelvic lymphadenectomy (LND) for diagnostic and therapeutic purposes at the time of radical cystectomy (RC) for bladder cancer is well documented. Although some debate remains on the optimal number of lymph nodes removed, 10 nodes has been proposed as constituting an adequate LND. We used data from the Surveillance, Epidemiology, and End Results database to examine predictors and temporal trends in the receipt of an adequate LND at the time of RC for bladder cancer. MATERIAL AND METHODS: Within the Surveillance, Epidemiology, and End Results database, we extracted data on all patients with nonmetastatic bladder cancer receiving RC in the years 1988 to 2010. First, we assess the proportion of individuals undergoing RC who received an adequate LND (≥10 nodes removed) over time. Second, we calculate odds ratios (ORs) of receiving an adequate LND using logistic regression modeling to compare study periods. Covariates included sex, race, age, region, tumor stage, urban vs. rural location, and insurance status. RESULTS: Among the 5,696 individuals receiving RC during the years 1988 to 2010, 2,576 (45.2%) received an adequate LND. Over the study period, the proportion of individuals receiving an adequate LND increased from 26.4% to 61.3%. The odds of receiving an adequate LND increased over the study period; a patient undergoing RC in 2008 to 2010 was over 4-fold more likely to receive an adequate LND relative to a patient treated in 1988 to 1991 (OR = 4.63, 95% CI: 3.32-6.45). In addition to time of surgery, tumor stage had a positive association with receipt of adequate LND (OR = 1.49 for stage IV [T4 N1 or N0] vs. stage I [T1 or Tis], 95% CI: 1.22-1.82). Age, sex, marital status, and race were not significant predictors of adequate LND. CONCLUSION: Adequacy of pelvic LND remains an important measure of surgical quality in bladder cancer. Our data show that over the years 1988 to 2010, the likelihood of receiving an adequate LND has increased substantially; however, a substantial minority of patients still does not receive LND. Further study into factors leading to adequate LND is needed to increase the use of this important technique.

Risk factors, therapy and survival outcomes of small cell and large cell neuroendocrine carcinoma of urinary bladder.

The risk factors, the optimal therapy and prognostic factors contributing to poor outcomes of neuroendocrine urinary bladder carcinoma are not fully elucidated because of its rarity. We reviewed the medical records of neuroendocrine bladder carcinoma patients treated at the University of Nebraska Medical Center between 1996 and 2011. Eighteen patients, 55% female with a median age of 77 years, had stage IV disease at diagnosis in 50% of cases. There was a high prevalence of smoking (78%), medical co-morbidities (94%), prior cancer history (22%) and family history of cancer (61%). Treatment modalities included surgery (72%), platinum-based chemotherapy (50%) and/or radiation (22%). Median overall survival was 18.5 months (95% confidence interval, 7-36 months). Patients with Stage II and III cancer who underwent radical surgery with or without neoadjuvant chemotherapy had a median survival of 37 months. In addition to smoking, for the first time, our study indicates that the personal or family history of cancer may increase risk to neuroendocrine bladder cancer. Advanced age and stage at diagnosis, and the presence of multiple co-morbidities contribute to poor overall survival. Patients with early-stage disease are likely to benefit from a combination of radical surgery and platinum-based neoadjuvant chemotherapy.