Surgical resection of a rare primary retroperitoneal mucinous borderline tumor of Müllerian Origin: A case report.

•Primary retroperitoneal mucinous tumors (PRMTs) are a rare group of cystic neoplasms consisting of three subtypes.•PRMTs are histologically similar to ovarian mucinous tumors but lack true ovarian tissue.•PRMTs should be considered in the differential diagnosis when encountering retroperitoneal cystic lesions.•During surgical resection tumor disruption should be avoided.•Surgical resection alone provides durable disease control for mucinous borderline tumors of low malignant potential.

Anatomy and embryology of congenital surgical anomalies: Congenital Anomalies of the Kidney and Urinary Tract.

Congenital anomalies of the kidney and urinary tract or "CAKUT" describes a spectrum of developmental disorders with a range of associated clinical presentations and functional consequences. CAKUT underlies the majority of chronic kidney disease and kidney replacement therapy requirement in children, but functional deterioration can also emerge in adulthood. Understanding the normal embryological processes involved in kidney development allows us to appreciate the timing and sequence of critical events implicated when things go wrong. In this review, we will describe the normal developmental mechanisms and relate this to what we currently know about the pathological processes involved in various forms of CAKUT. We will also review the proposed etiological factors, in particular genetics, involved in CAKUT.

Pallister-Hall syndrome, GLI3, and kidney malformation.

Pallister-Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI-Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of GLI3, a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of GLI3 in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (n = 78) revealed a prevalence of 26.9% (21/78) of CAKUT. Hypoplasia (± dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non-CAKUT PHS patients) in the middle third of the GLI3 gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant GLI3 result in the wide range and severity of clinical features observed in PHS.

Rare occurrence of pseudomyxoma peritonei (PMP) syndrome arising from a malignant transformed ovarian primary mature cystic teratoma treated by cytoreductive surgery and HIPEC: a case report.

BACKGROUND: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered. CASE PRESENTATION: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). CONCLUSIONS: Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity.

An assessment of oncofertility content on reproductive endocrinology and infertility clinic websites.

PURPOSE: To assess oncofertility content on fertility clinic websites as indicated by eight relevant keywords. Additionally, we sought to describe the relationship between oncofertility content and five predetermined clinic characteristics. METHODS: We examined 381 fertility clinic websites that are members of the Society for Associated Reproductive Technology (SART). Extracted data included clinic location, practice type (private vs academic), size (cycles/year), type of NCI designated center (cancer center vs comprehensive cancer center), and distance from the nearest NCI center. Additionally, we documented whether the clinic was located in a state mandating reproductive and infertility services and/or included fertility preservation for "iatrogenic infertility" as reported by the American Society for Reproductive Medicine (ASRM). Data were summarized using descriptive statistics and compared using chi-squared or t-test as appropriate. RESULTS: Of the 381 fertility clinic websites analyzed, 322 (85%) contained at least one oncofertility-related keyword. Most frequently used terms included cancer (79%) and fertility preservation (78%), while less frequently used terms included suppression (9.4%) and shielding (5.0%). Practices that initiated ≥ 501 cycles per year were more likely to mention one of the oncofertility keywords (OR 1.2; 95% CI 1.1-1.3). The associations of oncofertility website content with practice type, state-mandated fertility insurance coverage, and distance from an NCI-designated cancer center were not statistically significant. Large clinic size was the only predictive factor for inclusion of oncofertility website content. Further studies are required to evaluate whether inclusion of oncofertility content on clinic websites impacts the use of these services by patients with cancer. CONCLUSION: This is the first study correlating availability of oncofertility content on SART fertility clinic websites with consideration of geographic proximity to NCI designated cancer centers. Large clinic size was the only predictive factor for inclusion of oncofertility website content.

Isolated Ovarian Metastasis from Pancreatic Cancer Mimicking Primary Ovarian Neoplasia: Role of Molecular Analysis in Determining Diagnosis.

Background and Presentation: In this study, we present the case of a 64-year-old female with a chief complaint of abdominal pain and bloating, which had been persistent over a period of 4 months. Imaging revealed a 6.1-cm left-sided pancreatic mass as well as a 19.1-cm multiloculated cystic lesion in the pelvis, later revealed to be replacing the left ovary. The pancreatic mass was biopsied through endoscopic ultrasound-guided fine needle aspiration, and diagnosed as adenocarcinoma by cytology. The patient was treated with neoadjuvant chemotherapy and radiation before laparotomy for resection of the pancreas and left adnexal mass. Her response to treatment was followed radiologically and biochemically with cancer antigen (CA) 19-9 (114-35 U/mL), carcinoembryonic antigen (12-4.8 ng/mL), and CA-125 (119-15.3 U/mL) levels. She subsequently underwent an Appleby procedure, and resection of left pelvic mass and bilateral oophorectomy. Permanent sections revealed residual pancreatic ductal carcinoma with treatment effect, and a multicystic epithelial neoplasia of the left ovary for which the differential was primary ovarian carcinoma versus metastatic disease. Conclusions: Molecular mutational analysis was performed on sections of both the ovarian tumor and the pancreatic tumor to aid in diagnosis. The ovarian tumor in this case showed exactly the same mutations, KRAS G12R and TP53 G245S, as in the treated pancreatic cancer. This raised the high probability that these tumors originated from the same clonal event. The findings suggested that the ovarian tumor was an isolated metastasis of the pancreatic primary, despite the morphologic ambiguity between the two sites of neoplasia.

Clinical Characteristics and Histologic Features of Hysterectomy Specimens From Transmasculine Individuals.

OBJECTIVE: To describe the clinical characteristics of transmasculine individuals who underwent hysterectomy and characterize surgical pathology findings. METHODS: Under an institutional review board-approved protocol, transmasculine individuals who were undergoing hysterectomy and bilateral salpingectomy or bilateral salpingo-oophorectomy were retrospectively identified from a single institution. Past medical, surgical, obstetric, and gynecologic history were collected, including prior testosterone use, cervical cancer screening status, and preoperative pelvic imaging. Surgical pathologic findings of the endometrium, ovaries, and cervix were collected. RESULTS: A total of 72 individuals were included. The median age was 30 years (range 19-51). The majority of patients had private insurance (n=53, 74%) and were on testosterone at time of the preoperative visit (n=63, 88%). Forty-two patients (58%) reported anxiety, depression, or bipolar disorder, and 34 patients (47%) were taking an antidepressant or mood stabilizer. Of the 68 patients eligible for cervical cancer screening, 33 (49%) were up to date before their surgical consultation visits. Pelvic pain was the leading indication for surgery (n=65, 90%), and 29 patients (40%) had multiple listed indications for surgery. Surgical pathology results included cervical intraepithelial neoplasia 2-3 in three patients (4%), endometrial or cervical atrophy in 13 patients (18%), and ovarian or paratubal cysts in 16 patients (22%). CONCLUSION: This study describes the distinct clinical characteristics and surgical pathology findings that health care professionals should consider when caring for this unique patient population, including a relatively high rate of mental health conditions, pelvic pain as the leading indication for surgery, and the presence of endometrial or cervical atrophy and ovarian or paratubal cysts on surgical pathology.

Reducing Unnecessary Imaging in Children With Multicystic Dysplastic Kidney or Solitary Kidney.

BACKGROUND AND OBJECTIVES: Children with isolated unilateral multicystic dysplastic kidney (MCDK) or congenital solitary kidney (CSK) undergo serial renal ultrasonography with variable frequency until they are transitioned to adult care. A growing body of literature suggests the value of frequent ultrasonography in this population is limited, providing no benefit to overall outcomes. Despite emerging evidence, ultrasound remains overused, resulting in avoidable health care expenditures and unnecessary use of resources. With our initiative, we aimed to improve quality of care by reducing avoidable ultrasounds in these children. METHODS: This was a single-center, prospective, interrupted time series of children <18 years with ultrasound-confirmed isolated unilateral MCDK or CSK in the outpatient nephrology clinic to evaluate the effect of a decision-making algorithm on the proportion of children receiving an avoidable ultrasound. An algorithm depicting a consensus, evidence-based protocol for managing pediatric MCDK or CSK was refined through content expert feedback and usability testing to standardize frequency of ultrasonography. Ultrasounds were deemed necessary after birth, at 6 months, and at 2, 5, 10, and 15 years. Differences pre- and postintervention were determined by using a U chart and t and F tests for significance. RESULTS: The algorithm resulted in a 47% reduction (P < .001) in the proportion of avoidable ultrasounds ordered in children with MCDK and CSK. This reduction was sustainable over a 6-month period and would result in at least $46 000 annual savings. CONCLUSIONS: Introduction of a clinical decision-making algorithm was associated with a reduction in avoidable ultrasound testing. Improving adherence across providers may allow for an even more pronounced reduction.

Surgical and Radiological Management of Complicated Uterine Leiomyoma Aided by 3D Models in a Patient with Fibrodysplasia Ossificans Progressiva.

BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of the connective tissue. Over time, patients with FOP experience decreased range of motion in the joints and the formation of a second skeleton, limiting mobility. Patients with FOP are advised to avoid any unwarranted surgery owing to the risk of a heterotopic ossification flare-up. For patients who do require a surgical procedure, a multidisciplinary team is recommended for comprehensive management of the patient's needs. CASE REPORT A 27-year-old woman with FOP underwent a hysterectomy for removal of a suspected necrotic uterine fibroid. To aid in presurgical planning and management, patient-specific 3-dimensional (3D) models of the patient's tracheobronchial tree, thorax, and lumbosacral spine were printed from the patient's preoperative computed tomography (CT) imaging. The patient required awake nasal fiberoptic intubation for general anesthesia and transversus abdominus plane block for regional anesthesia. Other anesthesia modalities, including spinal epidural, were ruled out after visualizing the patient's anatomy using the 3D model. Postoperatively, the patient was started on a multi-modal analgesic regimen and a course of steroids, and early ambulation was encouraged. CONCLUSIONS Patients with FOP are high-risk surgical patients requiring the care of multiple specialties. Advanced visualization methods, including 3D printing, can be used to better understand their anatomy and locations of heterotopic bone ossification that can affect patient positioning. Our patient successfully underwent supracervical hysterectomy and bilateral salpingectomy with no signs of fever or sepsis at follow-up.

Diaphragm hernia after debulking surgery in patients with ovarian cancer.

Over 80% of patients with epithelial ovarian cancer present with advanced disease, FIGO stage III or IV at the time of diagnosis. The majority require extensive upper abdominal surgery to obtain complete gross resection. This may include splenectomy, distal pancreatectomy, partial hepatectomy, cholecystectomy, and usually diaphragmatic peritonectomy or resection. Following surgery, diaphragmatic hernia-a very rare but serious complication-may occur. We describe four cases of left-sided diaphragmatic hernia resulting after debulking surgery, which included left diaphragm peritonectomy and splenectomy, in patients with advanced ovarian cancer. In association with the current shift towards more extensive debulking surgery for ovarian cancer, more patients may present with postoperative left-sided diaphragm hernia, making the prevention, diagnosis, and management of this complication important to practicing gynecologic oncologists. Intraoperatively the diaphragm should be checked thoroughly to rule out any defects, which should be closed. A diaphragmatic hernia may be easily misdiagnosed because the patient can present with various symptoms. While rare, these hernias require prompt identification, intervention and surgical correction to avoid serious complications.

Digital Quantification of Ki-67 and PHH3 in the Classification of Uterine Smooth Muscle Tumors.

Uterine smooth muscle tumors are the most common tumors of the female genital tract and include leiomyoma (LM) and its variants, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Accurate diagnosis of LMS is determined by nuclear atypia, mitotic count, and the presence or absence of tumor cell necrosis, a process which is often difficult and subjective. In this study, we correlated digital quantification of proliferation marker Ki-67 and mitotic marker phosphohistone H3 (PHH3) to mitotic count, classification of uterine smooth muscle tumors, and clinical outcomes. A total of 39 cases (17 LMS, 5 STUMP, 10 LM with bizarre nuclei, and 7 LM) were included. Mitotic count, Ki-67, and PHH3 were significantly correlated. When comparing the LMS group to the STUMP, LM with bizarre nuclei, and LM groups combined, LMS showed a significantly greater digital quantification of Ki-67 (median 10.6% vs. 0.4%, P<0.001) and PHH3 (median 0.5% vs. 0.14%, P=0.022). Ki-67 was a better predictor of LMS compared with PHH3 (area under the curve 0.92 vs. 0.73, P=0.017). Above a threshold Ki-67 value of 3.8%, the sensitivity was 82% and specificity was 91%. Clinical outcomes were available for 10 patients (8 LMS and 2 STUMP), and inferior progression-free survival was noted for patients with higher Ki-67 values. Overall, this study suggests that digital quantification of Ki-67 can potentially aid in diagnosis of LMS.

Stereotactic body radiation therapy for oligometastatic gynecologic malignancies: A systematic review.

OBJECTIVE: To assess the efficacy and safety of stereotactic body radiation therapy (SBRT) for oligometastatic gynecologic malignancies. METHOD: A comprehensive search of the PubMed, Medline, and EMBASE databases was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. "Oligometastatic" was defined as a limited number of uncontrolled/untreated metastatic lesions (typically ≤ 5), including regional nodal metastases. Primary outcomes were response rate (complete response or partial response), local control of oligometastatic lesions, and toxicity. RESULTS: Of 716 screened records, 17 studies (13 full length articles, 4 conference abstracts) were selected and analyzed as 16 unique studies. A total of 667 patients were treated with ~1071 metastatic lesions identified. Primary sites included ovarian (57.6%), cervical (27.1%), uterine (11.1%), vaginal (0.4%), vulvar (0.3%), and other/unspecified (3.4%). Most patients (65.4%) presented with a single metastatic lesion. Metastatic lesion sites included the abdomen (44.2%), pelvis (18.8%), thorax (15.5%), neck (4.6%), central nervous system (4.3%), bone (1.6%), and other/unspecified (11%). Of the lesions, 64% were nodal. Response rate (among 8 studies) ranged from 49% to 97%, with 7/8 studies reporting > 75% response rate. Local control ranged from 71% to 100%, with 14/16 studies reporting ≥ 80% local control. No grade ≥ 3 toxicities were observed in 9/16 (56%) studies. Median progression-free survival (PFS) (among 10 studies) ranged from 3.3 months to 21.7 months. Disease progression most commonly occurred outside of the SBRT radiation field (79% to 100% of failures). CONCLUSIONS: SBRT for oligometastatic gynecologic malignancies is associated with favorable response and local control rates but a high rate of out-of-field progression and heterogeneous PFS. Additional study into rational combinations of SBRT and systemic therapy appears warranted to further improve patient outcomes.

Suppressor of fused controls cerebellum granule cell proliferation by suppressing Fgf8 and spatially regulating Gli proteins.

Cerebellar granule cell (GC) development relies on precise regulation of sonic hedgehog (Shh)-Gli signalling activity, failure of which is associated with motor disorders and medulloblastoma. Mutations in the pathway regulator suppressor of fused (Sufu), which modulates Gli activators and repressors, are linked to cerebellar dysfunction and tumourigenesis. The mechanism by which Sufu calibrates Shh signalling in GCs is unknown. Math1-Cre-mediated deletion of Sufu in mouse GC progenitors (GCPs) demonstrated that Sufu restricts GCP proliferation and promotes cell cycle exit, by promoting expression of Gli3R and suppressing Gli2 levels. Sufu is also required to promote a high threshold of pathway activity in GCPs. Remarkably, central cerebellar lobules are more deleteriously impacted by Sufu deletion, but are less sensitive to downstream genetic manipulations to reduce Gli2 expression or overexpress a Gli3R mimic, compared with anterior lobules. Transcriptome sequencing uncovered new Sufu targets, especially Fgf8, which is upregulated in Sufu-mutant GCPs. We demonstrate that Fgf8 is necessary and sufficient to drive Sufu-mutant GCP proliferation. This study reveals new insights into the spatial and temporal regulation of cerebellar Shh-Gli signalling, while uncovering new targets, such as Fgf8.

Lineage-specific roles of hedgehog-GLI signaling during mammalian kidney development.

Aberrant hedgehog (Hh) signaling during embryogenesis results in various severe congenital abnormalities, including renal malformations. The molecular mechanisms that underlie congenital renal malformations remain poorly understood. Here, we review the current understanding of the lineage-specific roles of Hh signaling during renal morphogenesis and how aberrant Hh signaling during embryonic kidney development contributes to renal malformation.

Characterization of Adnexal Masses Using Contrast-Enhanced Subharmonic Imaging: A Pilot Study.

OBJECTIVES: This pilot study evaluated whether contrast-enhanced subharmonic imaging (SHI) could be used to characterize adnexal masses before surgical intervention. METHODS: Ten women (with 12 lesions) scheduled for surgery of an ovarian mass underwent an SHI examination of their adnexal region using a modified LOGIQ E9 scanner (GE Healthcare, Waukesha, WI) with an endocavitary transducer, in which digital clips were acquired by pulse destruction-replenishment SHI across the lesions. Time-intensity curves were created offline to quantitatively evaluate SHI parameters (fractional tumor perfusion, peak contrast intensity, time to peak contrast enhancement, and area under the time-intensity curve), which were compared to pathologic characterizations of the lesions. RESULTS: Of the 12 masses, 8 were benign, and 4 were malignant. A qualitative analysis of the SHI images by an experienced radiologist resulted in diagnostic accuracy of 70%, compared to 56% without contrast, whereas an inexperienced radiologist improved from 50% to 58% accuracy, demonstrating the benefit of SHI. A quantitative analysis of SHI parameters produced diagnostic accuracy as high as 81%. Peak contrast intensity was significantly greater in malignant than benign masses (mean ± SD, 0.109 ± 0.088 versus 0.046 ± 0.030 arbitrary units; P = .046). Malignant masses also showed significantly greater perfusion than benign masses (24.79% ± 25.34% versus 7.62% ± 6.50%; P = .045). When the radiologist reads were combined with the most predictive quantitative SHI parameter (percent perfusion), diagnostic accuracy improved to 84% for the experienced radiologist and 96% for the novice radiologist. CONCLUSIONS: Results indicate that SHI for presurgical characterization of adnexal masses may improve the determination of malignancy and diagnostic accuracy, albeit based on a small sample size.

Metformin as a Therapeutic Target in Endometrial Cancers.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

Utilizing V-Y fasciocutaneous advancement flaps for vulvar reconstruction.

OBJECTIVES: We aimed to analyze the outcomes of patients who underwent vulvectomy with subsequent V-Y fasciocutaneous flap reconstruction. METHODS: All medical records of all patients who underwent vulvectomies with V-Y fasciocutaneous flap reconstruction from January 2007 to June 2016 were retrospectively reviewed. Patient clinical and surgical data, demographics, and outcomes were abstracted. RESULTS: Of the 27 patients, 42 flaps were transferred. A simple vulvectomy was performed in 8 (30%) patients, partial radical vulvectomy in 15 (56%), and radical vulvectomy in 4 (15%). The median area of defect was 30 cm2. Minor wound separations occurred in 9 patients (33%). Infectious complications occurred in 4 patients (15%); this included urinary tract infections in 2 (50%), postoperative fevers in 2 (50%), and sepsis in 1 (25%) patient with a UTI. There were no instances of flap necrosis, wound dehiscence, or wound infections. Black race was more likely to be associated with an infectious complication with 3 (75%) patients, compared to white race with 1 (4%) patient (p < .01). The presence of diabetes was more likely to be associated with an infectious complication in 2 (67%) patients, compared to 1 (4%) in non-diabetic patients (p < .01). No other significant association was found during analysis of demographics, medical comorbidities, vulvar pathology, or surgical factors affecting V-Y fasciocutaneous flap infectious complications or minor wound separations. CONCLUSIONS: The use of a V-Y fasciocutaneous advancement flap for vulvar reconstruction is safe and associated with mostly minor complications. Infectious complications were more frequently associated with diabetes, black race, and HIV.

Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes murine nephrogenesis via TGFß signaling.

Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (Smo-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFß2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFß2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFß2 signaling axis acts to control nephrogenesis.

Protein Kinase 2ß Is Expressed in Neural Crest-Derived Urinary Pacemaker Cells and Required for Pyeloureteric Contraction.

Nonobstructive hydronephrosis, defined as dilatation of the renal pelvis with or without dilatation of the ureter, is the most common antenatal abnormality detected by fetal ultrasound. Yet, the etiology of nonobstructive hydronephrosis is poorly defined. We previously demonstrated that defective development of urinary tract pacemaker cells (utPMCs) expressing hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) and the stem cell marker cKIT causes abnormal ureteric peristalsis and nonobstructive hydronephrosis. However, further investigation of utPMC development and function is limited by lack of knowledge regarding the embryonic derivation, development, and molecular apparatus of these cells. Here, we used lineage tracing in mice to identify cells that give rise to utPMCs. Neural crest cells (NCCs) indelibly labeled with tdTomato expressed HCN3 and cKIT. Furthermore, purified HCN3+ and cKIT+ utPMCs were enriched in Sox10 and Tfap-2α, markers of NCCs. Sequencing of purified RNA from HCN3+ cells revealed enrichment of a small subset of RNAs, including RNA encoding protein kinase 2ß (PTK2ß), a Ca2+-dependent tyrosine kinase that regulates ion channel activity in neurons. Immunofluorescence analysis in situ revealed PTK2ß expression in NCCs as early as embryonic day 12.5 and in HCN3+ and cKIT+ utPMCs as early as embryonic day 15.5, with sustained expression in HCN3+ utPMCs until postnatal week 8. Pharmacologic inhibition of PTK2ß in murine pyeloureteral tissue explants inhibited contraction frequency. Together, these results demonstrate that utPMCs are derived from NCCs, identify new markers of utPMCs, and demonstrate a functional contribution of PTK2ß to utPMC function.

Microcystic, Elongated, and Fragmented Pattern Invasion in Ovarian Endometrioid Carcinoma: Immunohistochemical Profile and Prognostic Implications.

Microcystic, elongated, and fragmented (MELF) pattern invasion is a poor prognostic indicator in uterine endometrioid carcinoma, but its existence, biology, and prognostic value have not been described in ovarian endometrioid carcinoma. We evaluated cases of ovarian endometrioid carcinoma without synchronous uterine endometrioid carcinoma for MELF and other histologic features. To evaluate tumor biology, we assessed an immunohistochemical profile, including MLH1, PMS2, MSH2, MSH6, ß-catenin, e-cadherin, CK19, and cyclin D1. A retrospective chart review evaluated clinical and demographic features and survival. The Fisher exact test analyzed data. The Kaplan-Meier method assessed overall survival. Forty-two patients met inclusion criteria. MELF was found in 45%. Two MELF cases showed MSH2/MSH6 deficiency and 2 conventional cases showed PMS2 deficiency. Clear cell features were seen exclusively in MELF cases (P-value=0.044). No difference was identified in overall survival, cancer recurrence, serous features, concurrent endometriosis, lymphovascular space invasion, lymph node metastasis, bilaterality of disease, extranodal metastasis, or remainder of immunohistochemical profile. MELF occurs at similar rates in ovarian endometrioid carcinoma and uterine endometrioid carcinoma and can be helpful in defining ovarian endometrioid carcinoma as it proves definitive invasion. Recurrence and overall survival in ovarian endometrioid carcinoma are not affected by MELF. Clear cell features are identified exclusively in MELF cases. Different mismatch repair proteins are lost in MELF compared with conventional ovarian endometrioid carcinomas. Given its association with clear cell features and mismatch repair protein loss, presence of MELF may be useful in clinical decisions regarding surgical staging and Lynch syndrome screening.