Emerging Insights in Small-Cell Carcinoma of the Genitourinary Tract: From Diagnosis to Novel Therapeutic Horizons.

Small-cell carcinomas (SCCs) of the genitourinary (GU) tract are rare malignancies with high metastatic potential. The most common primary sites are the bladder and prostate, but case reports of primary SCC of the kidney, ureter, and urethra also exist. The majority of patients present with gross hematuria, irritative or obstructive urinary symptoms, and symptoms of locoregionally advanced or metastatic disease at initial presentation. SCC of the bladder presents with nodal or metastatic involvement in the majority of cases and requires the use of platinum-based chemotherapy in combination with surgery and/or radiation. SCC of the prostate is most commonly seen in the metastatic castrate-resistant setting, and aggressive variant disease presents with a greater propensity for visceral metastases, osteolytic lesions, and relatively low serum prostate-specific antigen for volume of disease burden. Multiple retrospective and prospective randomized studies support the use of a multimodal approach combining platinum-based systemic therapy regimens with radiation and/or surgery for localized disease. This evidence-based strategy is reflected in multiple consensus guidelines. Emerging data suggest that small-cell bladder and prostate cancers transdifferentiate from a common progenitor of conventional urothelial bladder carcinoma and prostatic acinar adenocarcinoma, respectively. Areas of active basic research include efforts to identify the key genetic and epigenetic drivers involved in the emergence of small cell cancers to exploit them for novel therapies. Here, we review these efforts, discuss diagnosis and currently supported management strategies, and summarize ongoing clinical trials evaluating novel therapies to treat this rare, aggressive GU cancer.

Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution.

Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of RB1, TP53, and PTEN expression and MYCN and AURKA amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3ßHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.

Contemporary Management of Bulbar Urethral Strictures.

Urethral stricture disease (USD) is a progressive scar-forming disease commonly encountered by urologists and is challenging to manage. USD most frequently occurs in the bulbar urethra. Patients typically present with chronic obstructive voiding symptoms but may develop recurrent urinary tract infections, detrusor failure, or renal disease. The authors review the pathophysiology, diagnostic workup, and evidence-based management of bulbar urethral strictures (BUS). There are multiple surgical options to treat BUS. Endoscopic techniques (eg, dilation and urethrotomy) are suitable for the initial management of short strictures but new evidence-based guidelines recommend against repeated endoscopic treatment. Urethroplasty is the gold standard treatment for BUS of all lengths, with anastomotic techniques appropriate for strictures <2 cm and tissue substitution performed for longer strictures. New techniques, such as non-transecting urethroplasty, lack long-term data but may represent a paradigm shift in the field. Future treatments may utilize tissue-engineered grafts and agents that inhibit inflammation and scar formation.

Interview date trends for dermatology residency from 2012-2017.

Data regarding dermatology residency interview patterns can better inform applicants regarding the application process as well as encourage further coordination among programs. Our objective was to describe dermatology residency interview date patterns over the past five applications cycles from 2012 to 2017. A retrospective review of dermatology online forums (the Dermatology Interest Group Association and Student Doctor Network) was performed from 2012 to 2017; these web-based public databases were reviewed for interview dates and interview offer dates. Data from 117 programs per year were obtained. The majority of interview offers arrived in early November (41.5%), followed by late November (40%). Interviews were conducted predominantly in December (25.7%) and January (66.3%). On average, programs scheduled 2.26 (range 1-13) interview dates. Most interviews were held on Thursday (23.9%) and Friday (28.7%). Our results suggest that there is an increasing trend of overlapping interview dates among programs. Being cognizant of dermatology residency interview date patterns can help prepare applicants for interview scheduling while avoiding scheduling conflicts.

Comparison of Pathological Stage in Patients Treated with and without Neoadjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma.

PURPOSE: High risk upper tract urothelial carcinoma has been associated with poor survival outcomes. Limited retrospective data support neoadjuvant chemotherapy prior to radical nephroureterectomy. To validate prior findings we evaluated differences in the pathological stage distribution in patients with high risk upper tract urothelial carcinoma based on the administration of neoadjuvant chemotherapy before radical nephroureterectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 240 patients with upper tract urothelial carcinoma at The Johns Hopkins Hospital from 2003 to 2017. Patients with biopsy proven high grade disease and a visible lesion on cross-sectional imaging were offered neoadjuvant chemotherapy prior to radical nephroureterectomy. A control group of a time matched cohort of patients with biopsy proven high grade disease underwent extirpative surgery alone. The chi-square and Fisher exact tests were used to evaluate clinical and pathological variables between the cohorts. RESULTS: There were 32 patients in the study group and 208 in the control group. Significantly lower pathological stage was noted in the study group than in the control group (p <0.001). Significantly fewer patients with pT2 disease or higher were treated with neoadjuvant chemotherapy (37.5% vs 59.6%, p = 0.02). There was a 46.5% reduction in the prevalence of pT3 disease or higher in study group patients without clinically node positive or low volume metastatic disease (25.9% vs 48.4%, p = 0.04). A 9.4% complete remission rate was observed in patients who underwent neoadjuvant chemotherapy. CONCLUSIONS: Patients with high risk upper tract urothelial carcinoma treated with neoadjuvant chemotherapy were noted to have a lower pathological stage distribution than patients treated with radical nephroureterectomy alone.

Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation.

Androgen receptor (AR)-mediated signaling is necessary for prostate cancer cell proliferation and an important target for therapeutic drug development. Canonically, AR signals through a genomic or transcriptional pathway, involving the translocation of androgen-bound AR to the nucleus, its binding to cognate androgen response elements on promoter, with ensuing modulation of target gene expression, leading to cell proliferation. However, prostate cancer cells can show dose-dependent proliferation responses to androgen within minutes, without the need for genomic AR signaling. This proliferation response known as the non-genomic AR signaling is mediated by cytoplasmic AR, which facilitates the activation of kinase-signaling cascades, including the Ras-Raf-1, phosphatidyl-inositol 3-kinase (PI3K)/Akt and protein kinase C (PKC), which in turn converge on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation, leading to cell proliferation. Further, since activated ERK may also phosphorylate AR and its coactivators, the non-genomic AR signaling may enhance AR genomic activity. Non-genomic AR signaling may occur in an ERK-independent manner, via activation of mammalian target of rapamycin (mTOR) pathway, or modulation of intracellular Ca(2+) concentration through plasma membrane G protein-coupled receptors (GPCRs). These data suggest that therapeutic strategies aimed at preventing AR nuclear translocation and genomic AR signaling alone may not completely abrogate AR signaling. Thus, elucidation of mechanisms that underlie non-genomic AR signaling may identify potential mechanisms of resistance to current anti-androgens and help developing novel therapies that abolish all AR signaling in prostate cancer.