Development and Validation of a Risk-Adapted Scoring Model for Metachronous Upper Tract Urothelial Carcinoma following Radical Cystectomy.

PURPOSE: The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance. MATERIALS AND METHODS: A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models. RESULTS: A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1-8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p <0.01), history of bacillus Calmette-Guérin treatment prior to RC (HR 2.20, p <0.01), carcinoma in situ at RC (HR 2.01, p <0.01) and pre-RC hydronephrosis (HR 1.48, p=0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1-3 points), and high risk (4+ points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort. CONCLUSIONS: We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC.

Skin-Related complications of Klippel-Trenaunay Syndrome: a retrospective review of 410 patients.

BACKGROUND: Little is known about skin-related complications in Klippel-Trenaunay syndrome (KTS), a complex vascular anomaly defined by capillary malformation (CM), venous malformation (VM) ± lymphatic malformation (LM) and limb overgrowth. Reported skin-related complications of KTS include ulceration, vascular ectasias (blebs), bleeding and infection. OBJECTIVE: To determine the spectrum, prevalence and predictors of skin-related complications in KTS. METHODS: A retrospective review of 410 patients fulfilling KTS criteria was performed to assess for the presence of skin-related complications. RESULTS: Skin-related complications were present in 45% of patients. Most prevalent were CM-related complications including blebs, bleeding, thickening (25%), cellulitis (22%) and ulceration (21%). Features positively associated with skin-related complications were presence of LM (OR 17.17; P < 0.001), VM on the buttocks/perineum/genitalia (OR 1.92; P = 0.009), CM on the feet (OR 1.77; P = 0.039) and male sex (OR 1.63; P = 0.034). Features negatively associated with skin-related complications were CM on the trunk (OR 0.59; P = 0.029) and tissue hypertrophy of the hands (OR 0.27; P = 0.025). CONCLUSION: Skin-related complications affect nearly half of patients with KTS. Those with lymphatic involvement or malformation presence in the undergarment area or feet are most at risk.

Tapinarof to treat psoriasis.

There is a need for new and effective topical treatment options for psoriasis. Recent phase I and II clinical trials have demonstrated efficacy of the novel nonsteroidal drug tapinarof to treat mild to moderate plaque psoriasis. Tapinarof is an aryl hydrocarbon receptor (AHR) agonist that induces antioxidant, immunomodulatory and epidermal differentiation regulation pathways. In this review, we examine the current preclinical and clinical studies with a focus on the mechanism of action, pharmacokinetics, safety and efficacy of tapinarof to treat psoriasis.

Orthopaedic diagnoses in patients with Klippel-Trenaunay syndrome.

PURPOSE: Klippel-Trenaunay syndrome (KTS) is a rare combined vascular malformation composed of capillary malformation, lymphatic and/or venous malformation and limb overgrowth, which commonly affects the extremities. Due to limb involvement, it is not uncommon for these patients to require referral to an orthopaedic surgeon. Herein we reviewed the prevalence of orthopaedic diagnoses in a large cohort of KTS patients and described the associated surgical interventions. METHODS: Between 1976 and 2012, 410 patients fulfilling strict criteria for KTS were evaluated at a single institution. Patient charts were reviewed for demographic information, details of the clinical evaluation, orthopaedic consultation and surgical interventions. RESULTS: A total of 264 of 410 patients (64%) with confirmed KTS required orthopaedic evaluation. Of these 264 patients, 84% had documented limb-length discrepancy. Other common diagnoses included: angular deformities (10%), scoliosis (9%), osteopenia/osteoporosis (7%), pathological fractures (6%), joint contracture (5%), degenerative joint disease (4%) and limb/joint pain (4%). Of the 264 patients evaluated by orthopaedic surgery, 133 patients (50.4%) underwent 169 surgeries. Surgery was most commonly performed for limb-length discrepancy (62%). Multivariable analysis confirmed an orthopaedic condition was more likely in patients with lymphatic malformation (odds ratio (OR) 3.78; p < 0.001), as well as in those with bone and/or soft-tissue hypertrophy of the lower extremity (OR 7.51; p < 0.001) or foot (OR 3.23; p < 0.001). CONCLUSION: Orthopaedic conditions are common in patients with KTS and approximately 50% require surgical intervention. Those with a lymphatic malformation and/or soft-tissue hypertrophy of the lower extremity are more likely to need surgery. LEVEL OF EVIDENCE: Level IV, Descriptive Case Series.

Leukocytoclastic vasculitis in children: clinical characteristics, subtypes, causes and direct immunofluorescence findings of 56 biopsy-confirmed cases.

BACKGROUND: Leukocytoclastic vasculitis (LCV) in children is a complex group of conditions. OBJECTIVES: This study presents the demographics, clinical features, direct immunofluorescence (DIF) results and suspected aetiologies of 56 biopsy-confirmed cases of leukocytoclastic vasculitis in children. METHODS: Retrospective review of 56 children seen at Mayo Clinic in Rochester, Minnesota, from 1993 to 2013 with clinical features and cutaneous biopsy consistent with LCV. RESULTS: Twenty-seven (48%) cases were found to be due to IgA vasculitis (Henoch-Schonlein purpura). The remaining cases were found to be due to cutaneous small-vessel vasculitis (n = 19, 34%), urticarial vasculitis (n = 5, 9%), ANCA-associated vasculitis (n = 4, 7%) and acute haemorrhagic oedema of infancy (n = 1, 2%). IgA vasculitis was found to be associated with abdominal pain (P = 0.008), whereas the non-IgA vasculitis group was associated with headache (P = 0.052). Children with IgA vasculitis had palpable purpura (P = <0.001), petechia (P = 0.057), vesicles (P = 0.009) and involvement of the buttock (P = 0.004) more frequently than the non-IgA vasculitis group. On DIF, perivascular IgA was positive in IgA vasculitis compared to non-IgA vasculitis cases (P = <0.001), the other conjugates were similar between the two groups. CONCLUSION: The most common subtype of biopsy-confirmed LCV in children is IgA vasculitis. Clinical features, exam characteristics and DIF results can be helpful in determining the subtype of cutaneous vasculitis in children.

Henoch-Schönlein purpura and systemic disease in children: retrospective study of clinical findings, histopathology and direct immunofluorescence in 34 paediatric patients.

BACKGROUND: Henoch-Schönlein purpura (HSP), an IgA-mediated small vessel vasculitis, is the most common form of vasculitis in children. HSP is commonly associated with systemic involvement of the gastrointestinal tract, joints and kidneys. Renal involvement is the main cause of morbidity and mortality in HSP. OBJECTIVES: To characterize the clinical, histopathological and direct immunofluorescence (DIF) findings, and to correlate the findings with systemic disease in 34 children with HSP seen at our institution. METHODS: This was a retrospective review of paediatric patients with HSP and with available biopsy specimens seen at our institution between 1993 and 2013. RESULTS: Thirty-four paediatric patients were identified (mean age 10·7 years). Renal involvement was found in 17 (50%) patients, gastrointestinal tract involvement in 22 (65%) and joint involvement in 23 (68%). Renal involvement was significantly associated with papillary dermal oedema on histopathology (P < 0·01) and the presence of perivascular C3 on DIF (P = 0·01). The presence of lesions above the waist was significantly associated with gastrointestinal involvement (P = 0·03), as was the presence of clinically apparent oedema (P = 0·01). CONCLUSIONS: This study suggests that in children with HSP, microscopic dermal oedema and C3 on DIF may be predictive of renal involvement. Patients with clinically apparent oedema and lesions above the waist are more likely to have gastrointestinal involvement.

Gleason grading after neoadjuvant hormonal therapy retains prognostic value for systemic progression following radical prostatectomy.

BACKGROUND: The Gleason grading system in prostatectomy specimens following receipt of neoadjuvant therapy has been considered inaccurate. However, with continuing expansion of novel therapeutics, it is important to understand whether the Gleason system can be effectively utilized in this setting. The aim of this study was to assess the ability of the Gleason grading system to predict systemic progression among prostatectomy specimens treated with neoadjuvant hormone therapy (NHT). METHODS: This was a single-institution retrospective analysis from 1987 to 2009 of 13,427 patients who underwent radical prostatectomy (RP) without NHT and 1148 patients with NHT. NHT consisted of leuprolide alone (n = 415), antiandrogen therapy alone (n = 400) and combined treatment (n = 333). Kaplan-Meier analysis estimated 15-year systemic progression-free survival among NHT and non-NHT patients. Cox proportional hazard regression models estimated risk of systemic progression following RP according to NHT use and nonuse. RESULTS: Median duration of NHT was 3 months (interquartile range (IQR) 2-4) whereas median follow-up after RP was 8.3 years (IQR 5-10.8). NHT patients were more likely to be D'Amico high risk, have locally advanced pathologic T stage (≥ pT3), pathologic Gleason scores (GS) of 8-10 and lymph node involvement (P<0.0001 for all). NHT use was associated with lower rates of positive surgical margins, more downgrading to pT0 and less GS upgrading from biopsy (P ≤ 0.001 for all). GS could not be assigned to only 3% of NHT patients. On multivariate analysis, pathologic GS remained a predictor of systemic progression (SP) following NHT (hazard ratio (HR) 1.6, P = 0.005), but the association was less strong compared with non-NHT patients (HR 2.9, P < 0.0001). CONCLUSIONS: Utilization of the Gleason system appears feasible among hormonally pretreated prostatectomy specimens and shows continued prognostication for systemic progression. Confirmatory investigations are needed before the Gleason system can be reliably applied in the setting of neoadjuvant therapy.

Clinicopathological predictors of systemic progression and prostate cancer mortality in patients with a positive surgical margin at radical prostatectomy.

BACKGROUND: Although a positive surgical margin (PSM) at radical prostatectomy (RRP) has been consistently linked to an increased risk of biochemical recurrence, the impact of margin status on patient survival continues to be debated. We evaluated long-term outcomes of patients with a PSM at RRP and determined predictors of systemic progression (SP) and mortality in these men. METHODS: We reviewed our institutional registry of 16,749 patients who underwent RRP between 1990 and 2008 to identify 2895 patients with a PSM. Median follow-up was 10.6 years. Postoperative survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to analyze clinicopathological variables associated with SP and death from prostate cancer. RESULTS: A 15-year SP-free and cancer-specific survival was 90 and 93%, respectively. On multivariate analysis, higher tumor volume, increased pathological Gleason score and advanced pathological tumor stage were associated with significantly increased risks of SP and death from prostate cancer, whereas number and location of PSM did not predict mortality. CONCLUSIONS: The risks of SP and prostate cancer death in patients with a PSM remain low on long-term follow-up. Tumor variables are the primary determinants of cancer death. These results should be considered when evaluating patients with a PSM for adjuvant therapy.

A novel class of apical sodium co-dependent bile acid transporter inhibitors: the 2,3-disubstituted-4-phenylquinolines.

A series of 2,3-disubstituted-4-phenylquinolines were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT). Alkyl and ester substitution at the 3-position showed comparable activities while substitution at the 2-position was much more sensitive to the nature of the substituent. The synthesis and in vitro potency data are presented for this novel class of compounds.