Feasibility and Outcomes of Renal Mass Biopsy for Anatomically Complex Renal Tumors.

OBJECTIVE: To compare the feasibility and outcomes of renal mass biopsies (RMB) of anatomically complex vs non-complex renal masses. METHODS: Our institutional renal tumor database was queried for patients who underwent RMB between 2005 and 2019 and with available nephrometry score. Complex masses were: (1) small (<2 cm), (2) entirely endophytic (nephrometry E=3), (3) hilar (h) or (4) partially endophytic (E=2) and anterior. Demographic and pathologic data were compared. Biopsies were deemed adequate if they resulted in a diagnosis. Concordance with surgical pathology was assessed. These were both presented using proportions. Factors associated with biopsy outcomes were identified using multivariable logistic regression. RMB sensitivity and specificity were calculated using contingency methods. RESULTS: A total of 306 RBMs were included, 179 complex and 127 non-complex. A total of 199 (65%) had an extirpative procedure. Complex lesions were less likely to have an adequate biopsy (89% vs 96%, P = .03), and to be concordant with final surgical pathology from an oncologic standpoint (89% vs 97%, P = .03). There was no significant difference in concordance of histology (76% vs 86%, P = .10) or grade (48 vs 51%, P = .66). On multivariable analyses, only male gender was associated with biopsy adequacy (OR 3.31, 95% CI 1.28-8.55, P = .01). Our overall sensitivity was 93%, specificity 93%, and accuracy 93%. There were no significant differences over time in biopsy outcomes during the study period. CONCLUSION: RMB of complex lesions is associated with excellent diagnostic yield, albeit lower than non-complex lesions. RMB should not be deferred in cases of anatomically complex lesions where additional data could improve clinical decision-making.

Prostate cancer active surveillance outcomes in a cohort composed primarily of African American and Hispanic American Men.

INTRODUCTION: Active surveillance outcomes in minority patients are poorly characterized, as most surveillance series are comprised primarily of Caucasian men. We aimed to characterize outcomes of African American and Hispanic men undergoing surveillance and to identify factors associated with transition to definitive treatment. MATERIAL AND METHODS: We performed a retrospective analysis of men undergoing active surveillance at our institution. Reasons for transition to definitive treatment were determined. Cessation of active surveillance was recommended for Gleason upgrading on surveillance biopsy. We characterized treatment-free survival for men on surveillance and compared this by race/ethnicity (as self reported by patients). Demographic and clinical variables associated with active surveillance cessation were identified using Cox proportional hazards regression. RESULTS: A total of 141 men were on active surveillance: 84 non-Hispanic Black/African American (59.6%), 32 Hispanic (22.7%), and 25 non-Hispanic White/Caucasian (17.7%). Two-year treatment-free survival for Caucasian, Black and Hispanic patients was 81.2%, 54.4%, and 75.0%, respectively. Pairwise Cox proportional hazards analysis showed significantly decreased treatment-free survival in Black compared to Caucasian men (HR 2.42, 95% CI 1.03-5.68). In African American men, cessation of active surveillance occurred most commonly due to grade reclassification at the time of confirmatory biopsy. CONCLUSIONS: Among our active surveillance cohort composed primarily of racial and ethnic minorities, we identified relatively high rates of progression to definitive treatment. African American race was associated with surveillance cessation on univariate analysis. These findings stress the importance of confirmatory biopsy and strict compliance with surveillance protocols in AA men to ensure timely detection of disease reclassification.

Transvesical robotic excision of a Müllerian duct remnant.

Müllerian duct remnants are rare and found in patients with disorders of sexual development. Presenting symptoms vary and many parents opt for surgical management. Literature on robotic repair is limited to small series, single case reports and all were approached extravesically. We present our case of a unique transvesical approach. Perioperative parameters were favorable with no complications, suggesting robotic repair is a safe and effective treatment strategy for these unique patients.

Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (ROBUUST Collaboration).

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

A Multi-Institutional Experience with Robotic Vesicovaginal and Ureterovaginal Fistula Repair After Iatrogenic Injury.

Objectives: To describe our multi-institutional experience with robotic repair of iatrogenic urogynecologic fistulae (UGF), including vesicovaginal fistulae (VVF) and ureterovaginal fistulae (UVF). Methods: We performed a retrospective review identifying patients who underwent robotic repair of VVF and UVF between January 2010 and May 2019. All patients failed conservative management with Foley catheter or upper tract drainage (ureteral stent and/or nephrostomy tube), respectively. Patient demographics and perioperative outcomes were analyzed. Success was defined as no vaginal leakage of urine postoperatively, in the absence of drains, catheters, or stents. Results: Of 34 patients, 22/34 (65%) had VVF and 12/34 (35%) had UVF repair. VVF etiology included radiation (1/22, 4.5%) and surgery (21/22, 95.5%). Four of 22 (18%) had undergone prior repair attempt. Median console time was 187 minutes (interquartile range [IQR]: 151-219), estimated blood loss (EBL) was 50 mL (IQR: 50-93), and median length of stay (LOS) was 1 day (IQR: 1-2). Two of 22 (9%) patients had a postoperative complication. At mean follow-up of 28.9 months, 20/22 (91%) VVF cases were clinically effective. UVF etiology was gynecologic surgery in all cases; 8/12 (67%) were left-sided, 4/12 (33%) were right-sided. None was repeat repairs. Two of 12 (17%) underwent ureteroureterostomy, and 10/12 (83%) had reimplant. Median console time was 160 minutes (IQR: 133-196), EBL was 50 mL (IQR: 50-112), and LOS was 1 day (IQR: 1-1). No complications were encountered. At mean follow-up of 29.3 months, 100% of UVF repairs were effective. Conclusions: Robotic repair of iatrogenic UGF may be effectively performed with low complication rates by experienced urologic surgeons.

Seeded Biopsy Tract Recurrence After Extirpative Surgery for Renal Cell Carcinoma.

Background: Renal mass biopsy (RMB) is an increasingly utilized modality in the work-up of patients with suspicious renal masses. Recurrence of renal cell carcinoma (RCC) from biopsy tract seeding is exceedingly rare in the literature. We report a case of such a phenomenon. Case Presentation: Our patient is a 75-year-old Caucasian man and former smoker with a functionally solitary left kidney, initially worked up for gross hematuria and left flank pain. Imaging revealed hydronephrosis and a left renal mass, which was biopsied. Pathology analysis demonstrated clear cell RCC, and a left robotic radical nephrectomy was performed with negative surgical margins. Sixteen months postoperatively, imaging revealed multiple small masses along the biopsy tract, suspicious for recurrence. These were biopsied and pathology analysis confirmed recurrent clear cell RCC. Conclusion: Despite its rarity, biopsy tract seeding is a serious complication of RMB. This warrants thorough counseling and shared decision making between providers and all patients with renal masses planning to undergo a RMB.

Surgical and Oncological Outcomes in Patients After Vascularised Flap Reconstruction for Locoregionally Advanced Penile Cancer.

BACKGROUND: Treatment of locoregionally advanced penile squamous cell carcinoma (LAPSCC) is challenging. The exact role (in terms of oncological benefit) of extensive surgery is not well established. Moreover, surgery invariably leads to large defects requiring reconstructive surgery. Rectus abdominis myocutaneous (RAM) and abdominal advancement flaps have an independent and constant blood supply, are easily harvested, and provide substantial skin coverage and soft tissue. OBJECTIVE: To determine the surgical and oncological outcomes in patients with LAPSCC undergoing surgical resection with RAM flaps. DESIGN, SETTING, AND PARTICIPANTS: From 2002 to 2016, a multi-institutional database identified 15 LAPSCC patients undergoing flap reconstructions. INTERVENTION: Local surgical resection with RAM or abdominal advancement flap reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative and pathologic data were collected. Postoperative complications were identified using the Clavien-Dindo classification for surgical complications. RESULTS AND LIMITATIONS: Fifteen patients (median age 61 yr) were treated, ten with curative intent. Thirteen patients received induction chemotherapy. Thirteen of the 15 patients (87%) experienced wound complications, including five Clavien-Dindo grade III complications. In 11/15 patients (73%), the disease recurred (median recurrence-free interval 106 d). The majority of recurrences (91%) were locoregional, and in four cases the patient also had lesions in distant organs. Ten of the 15 patients (67%) died of their disease. The overall median follow-up interval was 10.5 mo. The study was limited by its retrospective design, the absence of quality-of-life measurements, and the cohort size. CONCLUSIONS: The results of this study show that surgical resection with reconstruction is associated with a risk of perioperative complications, including high-grade Clavien-Dindo complications. With a cure rate of 27%, surgery must be carefully considered and there is a need for alternative treatments. Lack of robust quality-of-life-data is also a serious shortcoming in the decision process for this patient category. PATIENT SUMMARY: Surgery in locoregionally advanced penile cancer has a low cure rate. Reconstruction of defects is surgically feasible, albeit with a high risk of complications. Furthermore, decision-making lacks robust data on quality of life after surgery.

Conditional ablation of the prorenin receptor in nephron progenitor cells results in developmental programming of hypertension.

Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells (NPCs) of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V-ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (Six2PRR-/- ) causes early neonatal death. Here, we identified genes that are regulated by PRR in Six2+ NPCs FACS-isolated from Six2PRR-/- and control kidneys on embryonic day E15.5 using whole-genome expression analysis. Seven genes with expression in CM cells previously shown to direct kidney development, including Notch1, ß-catenin, Lef1, Lhx1, Jag1, and p53, were downregulated. The functional groups within the downregulated gene set included genes involved in embryonic and cellular development, renal regeneration, cellular assembly and organization, cell morphology, death and survival. Double-transgenic Six2PRR-/- /BatGal+ mice, a reporter strain for ß-catenin transcriptional activity, showed decreased ß-catenin activity in the UB in vivo. Reduced PRR gene dosage in heterozygous Six2PRR+/- mice was associated with decreased glomerular number, segmental thickening of the glomerular basement membrane with focal podocyte foot process effacement, development of hypertension and increased soluble PRR (sPRR) levels in the urine at 2 months of age. Together, these data demonstrate that NPC PRR performs essential functions during nephrogenesis via control of hierarchy of genes that regulate critical cellular processes. Both reduced nephron endowment and augmented urine sPRR likely contribute to programming of hypertension in Six2PRR+/- mice.

MPGN and mixed cryoglobulinemia in a patient with hepatitis C - new treatment implications and renal outcomes.

. INTRODUCTION: The association of hepatitis C virus (HCV), cryoglobulinemia, and membranoproliferative glomerulonephritis (MPGN) is well known. Treatment of underlying HCV infection has greatly improved in recent years with the introduction of direct-acting antivirals (DAA), which have demonstrated curative sustained viral response (SVR) rates for select viral genotypes with the added benefit of less drug side effects. However, a mainstay of newer DAAs is sofosbuvir, which is contraindicated in patients with severe renal impairment. CASE HISTORY: We are reporting the case of a 65-year-old female with chronic systolic heart failure, hypertension, and chronic HCV genotype 1b with biopsy-proven type I MPGN with cryoglobulinemia type II, who presented with rapidly progressive renal failure requiring emergent hemodialysis. After initiation of DAA therapy including ombitasvir-paritaprevir-ritonavir plus dasabuvir, in conjunction with plasmapheresis, corticosteroids, and rituximab, there was significant improvement in renal function such that hemodialysis was no longer needed. DISCUSSION: This patient's HCV treatment is estimated to induce a greater than 90% SVR, which is notably promising for the reduction and/or reversal of HCV-related glomerulopathy. Most recent HCV guidelines from 2015 recommend this regimen; however, there is little data to evaluate the safety and efficacy of treatment. Therefore, it is valuable to report positive preliminary results at this time. Overall, we anticipate this treatment regimen to become a basis in the management of HCV-related renal disease; however, larger studies will still be needed to prove its efficacy in improving renal outcomes.

Relationship between human papillomavirus and penile cancer-implications for prevention and treatment.

Penile cancer is a rare disease in the United States, but rates are increasing, causing concern. Several risk factors have been associated with the disease, including human papillomavirus (HPV) infection. Knowledge of HPV pathogenesis has led to the development of a vaccine, which has proven instrumental in reducing the incidence of female HPV-related cancers, but results in men have yet to be elucidated. Fortunately, rates of vaccination are up-trending in both males and females in the past several years. In addition, targeted therapies are the focus of several ongoing research efforts. Some of these therapeutics are currently in use, while several are in trials. With continued patient education and research, both treatment and prevention of HPV-related pre-malignant lesions and penile cancer will likely diminish.

National Trends and Predictors of Locally Advanced Penile Cancer in the United States (1998-2012).

BACKGROUND: We analyzed the trends in presentation of squamous cell carcinoma (SCC) of the penis and determined the socioeconomic predictors for locally advanced (cT3-cT4) disease in the United States. PATIENT AND METHODS: The National Cancer Database was queried for patients with clinically nonmetastatic penile SCC and staging available from 1998 to 2012. Temporal trends per tumor stage were evaluated, and a multivariable logistic regression model was used to identify predictors for advanced presentation during the study period. RESULTS: A total of 5767 patients with stage ≤ T1-T2 (n = 5423) and T3-T4 (n = 344) disease were identified. Increasing trends were noted in all stages of penile SCC with a greater proportion of advanced cases over time (P = .001). Significant predictors of advanced presentation were age > 55 years, the presence of comorbidities, and Medicaid or no insurance (P < .05 for all). CONCLUSION: More penile SCC is being detected in the United States. Our results have demonstrated older age, presence of comorbidities, and Medicaid or no insurance as potential barriers to early access of care in the male population. Understanding the current socioeconomic gaps could help guide targeted interventions in vulnerable populations.

Advances in Understanding of Penile Carcinogenesis: The Search for Actionable Targets.

Penile cancer (PeCa) is a rare malignancy with potentially devastating effects. Squamous cell carcinoma is the most common variant with distinct precancerous lesions before development into invasive disease. Involvement of the inguinal lymph nodes is the most important prognostic factor in PeCa, and once disease is present outside the groin, prognosis is poor. Metastatic PeCa is challenging to treat and often requires multidisciplinary approaches in management. Due to its rarity, molecular understanding of the disease continues to be limited with most studies based on small, single center series. Thus far, it appears PeCa has diverse mechanisms of carcinogenesis affecting similar molecular pathways. In this review, we evaluate the current landscape of the molecular carcinogenesis of PeCa and explore ongoing research on potential actionable targets of therapy. The emergence of anti-epidermal growth factor receptor (EGFR) and other immunotherapeutic strategies may improve outcomes for PeCa patients.

Robotic Buccal Ureteroplasty: a Review of the Current Literature.

PURPOSE OF REVIEW: This study aimed to provide an overview of the literature on buccal mucosal ureteroplasty for ureteral stricture disease, with a specific focus on the application of the robotic platform to buccal ureteroplasty. RECENT FINDINGS: In our review, we highlight the results of Zhao et al. from the New York University School of Medicine Department of Urology, as well as our own results from Temple University Hospital. Zhao et al. published the first series of four patients who underwent robotic buccal ureteroplasty. Mean stricture length was 3.0 cm, and at a mean follow-up of 15 months, all repairs remained patent. We also describe our results in 10 patients who underwent robotic buccal ureteroplasty at Temple University Hospital. Median stricture length was 3.0 cm, and at a median follow-up of 5 months, all repairs remain patent. Robotic buccal ureteroplasty offers a promising option for repair of complex ureteral strictures.

Membranoproliferative Glomerulonephritis in Pregnancy.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy. MATERIALS AND METHODS: The management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review. RESULTS: Some successful outcomes used antiplatelet therapy and plasmapheresis, but high-dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes. CONCLUSIONS: The data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant.

Bilateral benign renal oncocytomas and the role of renal biopsy: single institution review.

BACKGROUND: The goal was to assess the natural history and management of patients with pathologically proven bilateral (synchronous) RO after undergoing initial partial nephrectomy (PN). METHODS: All patients underwent either robotic/laparoscopic or open PN by two experienced genitourinary oncologists from 2005-2013. Final pathology was determined by surgical excision, CT-guided percutaneous core biopsy (CT-biopsy) or fine needle aspiration (FNA). Patient demographics, tumor characteristics (pathologic data, location, size) type of surgery, pre/post estimated glomerular filtration rate (eGFR) and surgical complications were recorded. RESULTS: Twelve patients were identified with bilateral RO. Median age at the time of surgery was 68 years (46-77) (Table 1). The median size of the largest tumor(s) resected was 2.75 cm (1.5-5.5 cm) and second largest tumor(s) was 1.75 cm (1.0-4.0 cm). Four patients underwent bilateral staged PN and one patient underwent simultaneous bilateral PN (horseshoe kidney). Two patients underwent RFA at the time of biopsy of the contralateral mass after PN. Five patients underwent CT-bx/FNA (5/5) of the contralateral mass followed by active surveillance. Mean follow up was 34 months. There was no significant change in median creatinine pre- and post-operatively. One patient was lost to follow up and one patient died of unknown causes 5 years post-operatively. eGFR decreased an average of 16.96% post-operatively, including a single patient whose eGFR increased by 7.8% after surgery and a single patient whose eGFR did not change (Table 2). CONCLUSIONS: Patients with bilateral renal masses and pathologically proven RO can be safely managed with active surveillance after biopsy confirmation of the contralateral mass.

Differences in placental telomere length suggest a link between racial disparities in birth outcomes and cellular aging.

BACKGROUND: Health disparities begin early in life and persist across the life course. Despite current efforts, black women exhibit greater risk for pregnancy complications and negative perinatal outcomes compared with white women. The placenta, which is a complex multi-tissue organ, serves as the primary transducer of bidirectional information between the mother and fetus. Altered placental function is linked to multiple racially disparate pregnancy complications; however, little is known about racial differences in molecular factors within the placenta. Several pregnancy complications, which include preeclampsia and fetal growth restriction, exhibit racial disparities and are associated with shorter placental telomere length, which is an indicator of cellular stress and aging. Cellular senescence and telomere dynamics are linked to the molecular mechanisms that are associated with the onset of labor and parturition. Further, racial differences in telomere length are found in a range of different peripheral tissues. Together these factors suggest that exploration of racial differences in telomere length of the placenta may provide novel mechanistic insight into racial disparities in birth outcomes. OBJECTIVE: This study examined whether telomere length measured in 4 distinct fetally derived tissues were significantly different between black and white women. The study had 2 hypotheses: (1) that telomere length that is measured in different placental tissue types would be correlated and (2) that across all sampled tissues telomere length would differ by race. STUDY DESIGN: In a prospective study, placental tissue samples were collected from the amnion, chorion, villus, and umbilical cord from black and white singleton pregnancies (N=46). Telomere length was determined with the use of monochrome multiplex quantitative real-time polymerase chain reaction in each placental tissue. Demographic and pregnancy-related data were also collected. Descriptive statistics characterized the sample overall and among black and white women separately. The overall impact of race was assessed by multilevel mixed-effects linear regression models that included empirically relevant covariates. RESULTS: Telomere length was correlated significantly across all placental tissues. Pairwise analyses of placental tissue telomere length revealed significantly longer telomere length in the amnion compared with the chorion (t=-2.06; P=.043). Overall telomere length measured in placenta samples from black mothers were significantly shorter than those from white mothers (ß=-0.09; P=.04). Controlling for relevant maternal and infant characteristics strengthened the significance of the observed racial differences (ß=-0.12; P=.02). Within tissue analyses revealed that the greatest difference by race was found in chorionic telomere length (t=-2.81; P=.007). CONCLUSION: These findings provide the first evidence of racial differences in placental telomere length. Telomere length was significantly shorter in placental samples from black mothers compared with white mothers. Given previous studies that have reported that telomere length, cellular senescence, and telomere dynamics are molecular factors that contribute to the rupture of the amniotic sac, onset of labor, and parturition, our findings of shorter telomere length in placentas from black mothers suggest that accelerated cellular aging across placental tissues may be relevant to the increased risk of preterm delivery in black pregnancies. Our results suggest that racial differences in cellular aging in the placenta contribute to the earliest roots of health disparities.

Antineutrophil cytoplasmic antibodies crescentic allograft glomerulonephritis after sofosbuvir therapy.

Antineutrophil cytoplasmic antibodies (ANCA) are well known to be associated with several types of vasculitis, including pauci-immune crescentic glomerulonephritis, a form of rapid progressive glomerular nephritis (RPGN). ANCA vasculitis has also been reported after administration of propylthiouracil, hydralazine, cocaine (adulterated with levimasole), allopurinol, penicillamine and few other drugs. All previously reported cases of drug-associated ANCA glomerulonephritis were in native kidneys. Sofosbuvir is a new and effective drug for hepatitis C virus infection. Here, we report a case of ANCA vasculitis and RPGN following sofosbuvir administration in a kidney transplant recipient. It also represents the first case of drug-associated ANCA vasculitis in a transplanted kidney. Further drug monitoring is necessary to elucidate the degree of association and possible causal effect of sofosbuvir and perinuclear ANCA vasculitis.

Algorithmic Approach With Clinical Pathology Consultation Improves Access to Specialty Care for Patients With Systemic Lupus Erythematosus.

OBJECTIVES: Harris Health System (HHS) is a safety net system providing health care to the underserved of Harris County, Texas. There was a 6-month waiting period for a rheumatologist consult for patients with suspected systemic lupus erythematosus (SLE). The objective of the intervention was to improve access to specialty care. METHODS: An algorithmic approach to testing for SLE was implemented initially through the HHS referral center. The algorithm was further offered as a "one-click" order for physicians, with automated reflex testing, interpretation, and case triaging by clinical pathology. RESULTS: Data review revealed that prior to the intervention, 80% of patients did not have complete laboratory workups available at the first rheumatology visit. Implementation of algorithmic testing and triaging of referrals by pathologists resulted in decreasing the waiting time for a rheumatologist by 50%. CONCLUSIONS: Clinical pathology intervention and case triaging can improve access to care in a county health care system.

Metadherin Expression is Associated with Extrathyroidal Extension in Papillary Thyroid Cancer Patients.

BACKGROUND: Metadherin (MTDH) is widely recognized as a promising molecular marker for tumor recurrence and poor survival in many cancers. By multiple pathways, MTDH promotes oncogenesis, metastasis, and chemoresistance. This study investigated the role of MTDH in papillary thyroid carcinoma (PTC) to determine its potential association with aggressive clinical and pathologic features, including its relation in tumors harboring a BRAF (V600E) mutation. METHODS: Expression of MTDH was assessed by immunohistochemistry in 96 cases of PTC, including primary thyroid malignancies and lymph node metastases. The status of BRAF (V600E) mutation was determined by real-time polymerase chain reaction. RESULTS: Overexpression of MTDH was observed in 26 % (23/88) of primary PTC cases. High-intensity staining was observed in 75 % (6/8) of lymph nodes with metastatic PTC and moderate staining in 25 % (2/8) of cases. Normal adjacent thyroid tissue and benign thyroid controls were found to have significantly lower MTDH expression than cancer tissue (p < 0.05). Apical staining of MTDH was observed in 19 % of thyroid tumors and not observed in normal thyroid tissue. Interestingly, MTDH expression was associated with extrathyroidal extension (p < 0.05) and not associated with age, gender, overall tumor stage, or BRAF (V600E) mutation status. CONCLUSION: In a subset of PTC patients, MTDH was overexpressed and associated with extrathyroidal extension. Further studies are warranted to explore the utility of MTDH to improve risk stratification of current molecular panels for PTC.

Prorenin receptor is critical for nephron progenitors.

Deficient nephrogenesis is the major factor contributing to renal hypoplasia defined as abnormally small kidneys. Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H(+)-ATPase. Global loss of PRR is lethal in mice and PRR mutations are associated with a high blood pressure, left ventricular hypertrophy and X-linked mental retardation in humans. To circumvent lethality of the ubiquitous PRR mutation in mice and to determine the potential role of the PRR in nephrogenesis, we generated a mouse model with a conditional deletion of the PRR in Six2(+) nephron progenitors and their epithelial derivatives (Six2(PRR-/-)). Targeted ablation of PRR in Six2(+) nephron progenitors caused a marked decrease in the number of developing nephrons, small cystic kidneys and podocyte foot process effacement at birth, and early postnatal death. Reduced congenital nephron endowment resulted from premature depletion of nephron progenitor cell population due to impaired progenitor cell proliferation and loss of normal molecular inductive response to canonical Wnt/ß-catenin signaling within the metanephric mesenchyme. At 2 months of age, heterozygous Six2(PRR+/-) mice exhibited focal glomerulosclerosis, decreased kidney function and massive proteinuria. Collectively, these findings demonstrate a cell-autonomous requirement for the PRR within nephron progenitors for progenitor maintenance, progression of nephrogenesis, normal kidney development and function.