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.

I dream of Gini: Quantifying inequality in otolaryngology residency interviews.

OBJECTIVES: Otolaryngology applicants routinely decry conflicting interview dates because this limits the number of interviews that one can attend, despite being offered an interview. Conversely, applicants also perceive that a large number of interviews are offered to a minority of applicants. We sought to verify and quantify the inequality in distribution of interviews attended. STUDY DESIGN: Retrospective analysis of the National Resident Matching Program (NRMP) 2016 Charting Outcomes in the Match and Electronic Residency Application Service (ERAS) historic specialty data. METHODS: The Gini coefficient, a commonly used indicator of economic inequality, was calculated using data from the 2016 Charting Outcomes in the Match to estimate the distribution of interviews attended. This data was compared to nine other specialties, comprising a wide range of competitiveness and specialty size. RESULTS: 26% (110 of 416) of otolaryngology applicants accounted for half (1,721 of 3,426) of all possible interview positions. The Gini coefficient ranged from 0.43 to 0.84 across 10 specialties, with a higher coefficient indicating higher inequality. The Gini coefficient among otolaryngology applicants was 0.43, indicating lower inequality than most other specialties. When including only applicants who interviewed, the Gini coefficient was 0.23. CONCLUSION: There is an unequal distribution of interview invitations, which likely reflects the reality of asymmetry in applicant competitiveness. Otolaryngology demonstrates the greatest equality in distribution, which may stem from a greater burden of hoarding. The specialty's perceived competitiveness mitigates factors such as cost and time, essentially encouraging more people to take as many interviews as they can. LEVEL OF EVIDENCE: NA Laryngoscope, 129:627-633, 2019.

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance.

Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.

Otolaryngology Residency Interviewing Dates and Practices: What Should an Applicant Expect?

OBJECTIVES/HYPOTHESIS: Scheduling otolaryngology interviews may be a challenge for residency applicants due to overlapping interview dates. Our objective was to identify otolaryngology interview date patterns and scheduling conflicts over the past six application cycles. STUDY DESIGN: Retrospective review of otolaryngology online forums (Otomatch.com and Student Doctor Network). METHODS: Online threads related to residency interview dates posted during the 2012 to 2013 through 2017 to 2018 interview seasons on Otomatch.com were reviewed. Program directors were contacted to complete any missing data. The χ- goodness-of-fit test and the χ2 test of independence was used to compare proportions. Analysis of variance was used to compare values across years. RESULTS: Data from an average of 98 programs (99%) per year were obtained. The majority of invitations arrived late October (49%), followed by early November (37.1%). Interviews occurred primarily in December (48.4%) and January (37.5%). Programs on average scheduled 2.47 (range, 0-4) interview dates. Most interviews fell on Fridays (28.7%) and Saturdays (22.7%) (P < .0001), with an increasing trend toward interviewing on consecutive days. There was substantial overlap in interview dates, with six dates alone accounting for an average of 31.3% of all interviews in a given interview cycle. CONCLUSIONS: The majority of otolaryngology interviews occur in December or January and fall on a Friday or Saturday. There is considerable overlap with the potential for scheduling conflicts. Our findings can help set expectations for applicants regarding interview invitations, as well as a strategy for scheduling interviews. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2280-2285, 2019.

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.