Analyzing National Incidences and Predictors of Open Conversion During Minimally Invasive Partial Nephrectomy for cT1 Renal Masses.

Objectives: To analyze predictors of open conversion during minimally invasive partial nephrectomy (MIPN) for cT1 renal masses. Methods: The National Cancer Database (NCDB) was investigated for kidney cancer patients who underwent partial nephrectomy (PN) between 2010 and 2015. Patients who underwent MIPN were stratified into converted and nonconverted groups. Sociodemographics, facility characteristics, and surgical outcomes were compared between the two groups, and multivariate logistic regression model was fitted to identify independent predictors of open conversion. Results: In total, 54,246 patients underwent PN for kidney cancer during the 6-year period. Of those, 18,994 (35%) were open partial nephrectomies (OPNs) and 35,252 (64%) were MIPN. Overall, 1010 (2.87%) of MIPNs were converted to OPN. There was an increasing utilization of MIPN from 50.35% in 2010 to 74.73% in 2015. Patients who had open conversion had more 30-day readmissions (5.95% vs 3.31%, p < 0.01). On multivariate analysis; high-volume facility (>30 MIPNs/year), year of surgery (2015 vs 2010), and robotic approach predicted a lower likelihood of conversion (odds ratio [OR] 0.52, confidence interval [CI] 0.44-0.62; OR 0.59, CI 0.47-0.73; and OR 0.31, CI 0.27-0.35; respectively, p < 0.001 for all). Conversely, Medicaid (vs private insurance; OR 1.75, CI 1.39-2.19, p < 0.001) and male sex (OR 1.26, CI 1.11-1.44, p < 0.001) were independent predictors of conversion. Conclusions: Open conversion in MIPN occurred in 2.87% of cases. There was an increasing utilization of MIPN associated with decreased conversion rates. Higher volume hospitals and progressing year of surgery were associated with less likelihood of conversion.

Robust response to nivolumab in patient with renal cell carcinoma inferior vena cava tumour thrombus.

A 47-year-old previously healthy man presented with acute moderate flank pain. Evaluation revealed left renal cell carcinoma, with inferior vena cava tumour thrombus invasion. Patient had no significant history or risk factors to pre-dispose him to genitourinary cancers. Surgery was deemed to not be appropriate due to distant metastases, but patient received targeted molecular therapy and immunotherapy with striking regression of the thrombus.

Primary renal angiosarcoma.

An older male patient with a history of tachycardia treated with atenolol presented to an outside hospital on 22 February 2017 with acute right flank pain. He had a CT scan which revealed a large right renal mass with acute haemorrhage. He was initially managed with interventional radiology guided embolism on 25 February 2017 due to the ongoing bleeding and haemodynamic instability. He was then transferred to our institution. He underwent right radical nephrectomy on 13 March 2017. His pathology revealed a 12.5×6×4.5 cm mass consistent with angiosarcoma of the right kidney with negative margins. Final pathology was pT2b with extension of the mass into the renal vein and perirenal adipose tissue. He was discharged soon after surgery. He was recommended to undergo adjuvant chemotherapy.

An Evaluation of Reported Follicle-stimulating Hormone, Luteinizing Hormone, Estradiol, and Prolactin Reference Ranges in the United States.

OBJECTIVE: To characterize US clinical laboratory reference range reporting and testing methods of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and prolactin. METHODS: One hundred and seventeen US laboratories were surveyed. Outcomes measured were variation in lower and upper limits of normal male reference ranges for serum FSH, LH, estradiol, and prolactin, method of analysis and source of reference range RESULTS: The upper limit of normal reference ranges for FSH, LH, estradiol, and prolactin varied substantially across laboratories compared to the lower limits. The range of upper limits of FSH, LH, estradiol, and prolactin respectively are 7.9-20.0, 4.9-86.5, 37.7-77.0, and 7.4-25.0. Ninety-four percent of laboratories performed measurements on in-house high throughput analyzer utilizing immunoassays. Seventy percent of reported reference ranges for each hormone were based on validation studies of the analyzer's package insert values. Ten percent of laboratories derived their own reference ranges. Both the validation studies and derivations were based on a limited number of patient samples, ranging from 20 to 200. CONCLUSION: Current reference ranges are based on small population studies of men with unknown medical histories, sexual or reproductive function. Influence of race and age has not been evaluated and could potentially be important in normal variation. The absence of standard information has yielded a spectrum of upper and lower normal values, which could delay an appropriate male infertility evaluation. Our findings highlight the need for a large population study of males with known normal sexual and reproductive function to formulate more accurate clinical reference ranges.

Large intra-abdominal seminoma in a left undescended testicle complicated by torsion.

A 39-year-old man presented with a 2-day history of worsening constant, dull diffuse lower abdominal pain with associated constipation and known history of left undescended testicle. He was evaluated at an outside hospital where a non-contrasted CT scan revealed a 20 cm well-circumscribed soft tissue mass within the pelvis.He was referred and further imaging revealed a 12 cm heterogeneous mass with foci of air that appeared to be contiguous with the left spermatic cord. This constellation of findings could represent torsion of undescended left testicle with infarction or underlying malignancy. Tumour markers were only significant for elevated lactate dehydrogenase of 1445. A subsequent ultrasound-guided biopsy of the mass demonstrated seminoma.Surgical resection revealed a large intra-abdominal mass emanating from the left spermatic cord with 270° of torsion. There appeared to be a left atrophic remnant testicle at the base of the mass with final pathology confirming the diagnosis of classic seminoma.

Current Practices of Measuring and Reference Range Reporting of Free and Total Testosterone in the United States.

PURPOSE: The evaluation and management of male hypogonadism should be based on symptoms and on serum testosterone levels. Diagnostically this relies on accurate testing and reference values. Our objective was to define the distribution of reference values and assays for free and total testosterone by clinical laboratories in the United States. MATERIALS AND METHODS: Upper and lower reference values, assay methodology and source of published reference ranges were obtained from laboratories across the country. A standardized survey was reviewed with laboratory staff via telephone. Descriptive statistics were used to tabulate results. RESULTS: We surveyed a total of 120 laboratories in 47 states. Total testosterone was measured in house at 73% of laboratories. At the remaining laboratories studies were sent to larger centralized reference facilities. The mean ± SD lower reference value of total testosterone was 231 ± 46 ng/dl (range 160 to 300) and the mean upper limit was 850 ± 141 ng/dl (range 726 to 1,130). Only 9% of laboratories where in-house total testosterone testing was performed created a reference range unique to their region. Others validated the instrument recommended reference values in a small number of internal test samples. For free testosterone 82% of laboratories sent testing to larger centralized reference laboratories where equilibrium dialysis and/or liquid chromatography with mass spectrometry was done. The remaining laboratories used published algorithms to calculate serum free testosterone. CONCLUSIONS: Reference ranges for testosterone assays vary significantly among laboratories. The ranges are predominantly defined by limited population studies of men with unknown medical and reproductive histories. These poorly defined and variable reference values, especially the lower limit, affect how clinicians determine treatment.

An evaluation of diabetes-related measures of control after 6 months of clinical pharmacy specialist intervention.

PURPOSE: To evaluate the effectiveness of a pharmacist management regarding the percentages of patients meeting American Diabetes Association (ADA) treatment goals for diabetes and specific Veterans Health Administration (VA) performance measures individually and in combination after 6 months of intervention. METHODS: We retrospectively evaluated the electronic medical record of all new patients seen between October 1, 2007 and March 31, 2009, with an A1c >7%. Primary objectives included the percentages of patients meeting ADA treatment goals individually and in combination after 6 months in addition to the percentage meeting the 3 VA performance goals individually and in combination. RESULTS: One-hundred and ninety-seven patients met inclusion criteria. There were 6% of patients who met all ADA goals and 79% who met all VA performance measure goals at study end. Individual goal analyses revealed 43% of patients at a goal A1c of <7%, 55% of patients were at low-density lipoprotein (LDL) goal, 45% of patients at systolic blood pressure (SBP) goal, and 51% of patients at diastolic blood pressure (DBP) goal. Evaluation for VA performance measures showed that 91% patients at goal for A1c, 55% at LDL goal, 70% at systolic BP goal, and 87% met diastolic BP goal. CONCLUSIONS: Six months of pharmacist intervention resulted in improvement in patients achieving ADA and VA performance measure goals individually and in combination.

In vitro and in vivo characterization of SGI-1252, a small molecule inhibitor of JAK2.

OBJECTIVE: Constitutive activation of the Janus kinase 2 (JAK2) due to a somatic mutation (JAK2(V617F)) arising in hematopoietic stem cells plays a central role in the pathophysiology of myeloproliferative neoplasms (MPNs). To investigate the hypothesis that drugs that inhibit JAK2 have therapeutic potential, we developed a small molecule inhibitor, SGI-1252, that targets the adenosine triphosphate-binding and solvent pocket of the protein. MATERIALS AND METHODS: Established cells lines each expressing different JAK2(V617F) copy numbers, a cell line transfected with wild-type and mutant JAK2, ex vivo expanded erythroid progenitor cells from patients with MPNs, and a murine xenograft model were used to characterize the activity of SGI-1252. RESULTS: In vitro studies showed that SGI-1252 potently inhibits the kinase activity of wild-type JAK2, JAK2(V617F) and JAK1, but not JAK3. SGI-1252 blocked phosphorylation of signal transducers and activators of transcription 5, a downstream target of JAK2 and inhibited expression of the JAK2-dependent antiapoptotic gene BCL-X(L). Additional studies confirmed induction of apoptosis in JAK2(V617F)-positive cell lines by SGI-1252. Moreover, cell lines transfected with either wild-type JAK2 or JAK2(V617F) were equally susceptible to the antiproliferative effects of SGI-1252 and the antiproliferative activity of SGI-1252 toward ex vivo--expanded erythroid progenitors from patients with polycythemia vera and primary myelofibrosis appeared independent of the JAK2(V617F) allele burden. Pharmacodynamic studies in a murine xenograft model demonstrated both anti-tumor activity and inhibition of signal transducers and activators of transcription 5 phosphorylation by SGI-1252, and the drug was active and well-tolerated whether delivered intraperitoneally or orally. CONCLUSIONS: Together, these studies support further development of SGI-1252 for clinical use.

Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C.

Fibrocystin, a type I membrane protein of unknown function, is the protein affected in the autosomal recessive form of polycystic kidney disease. Here we show that fibrocystin undergoes regulated proteolysis. Several proteolytic cleavages occur within the predicted ectodomain, whereas at least one cleavage occurs within the cytoplasmic portion. The latter generates a C-terminal intracellular fragment that harbors the nuclear localization signal KRKVSRLAVTGERTATPAPKIPRIT and translocates to the nucleus. Proteolytic cleavage of fibrocystin occurs constitutively in long term cultures of polarized inner medullary collecting duct cells (mIMCD-3). Activation of protein kinase C and release of intracellular Ca2+ are required for proteolysis under these conditions. In short term cultures of human embryonic kidney 293 cells (HEK-293), proteolytic cleavage of fibrocystin can be elicited by stimulation of intracellular Ca2+ release or activation of protein kinase C. These results identify a novel Ca2+-dependent pathway that signals from fibrocystin located in the cell membrane to the nucleus.

The meandering mesenteric artery: a historic review and surgical implications.

PURPOSE: The aim of this study was to review the literature regarding collateral mesenteric circulation with emphasis on the mesenteric meandering artery (of Moskowitz). Standard vascular embryology and anatomy are described as are the collateral mesenteric vessels that can develop with arterial stenosis or occlusion. A discussion on the correct usage of terms for describing mesenteric collateral vessels follows. METHODS: We undertook review of the historical literature to discuss the surgical implications of the meandering mesenteric artery. RESULTS: Despite a long history of study by anatomists and surgeons, confusion still persists regarding both the number and correct descriptive terminology of the collateral mesenteric vessels. CONCLUSIONS: The use of the vague historic term "arc of Riolan" should be discarded for the more precise term "meandering mesenteric artery." The meandering mesenteric artery should routinely be preserved in all surgical procedures, to include resection for cancer, given its critical function in providing collateral mesenteric circulation. Further evaluation in the asymptomatic patient, however, is unnecessary.

Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis.

Hepatocyte nuclear factor-1beta (HNF-1beta) is a homeodomain-containing transcription factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1beta produce congenital cystic abnormalities of the kidney, and previous studies showed that HNF-1beta regulates the expression of the autosomal recessive polycystic kidney disease (ARPKD) gene, Pkhd1. Here we show that the C-terminal region of HNF-1beta contains an activation domain that is functional when fused to a heterologous DNA-binding domain. An HNF-1beta deletion mutant lacking the C-terminal domain interacts with wild-type HNF-1beta, binds DNA, and functions as a dominant-negative inhibitor of a chromosomally integrated Pkhd1 promoter. The activation of the Pkhd1 promoter by wild-type HNF-1beta is stimulated by sodium butyrate or coactivators CREB (cAMP-response element)-binding protein (CBP) and P/CAF. The interaction with CBP and P/CAF requires the C-terminal domain. Expression of an HNF-1beta C-terminal deletion mutant in transgenic mice produces renal cysts, increased cell proliferation, and dilatation of the ureter similar to mice with kidney-specific inactivation of HNF-1beta. Pkhd1 expression is inhibited in cystic collecting ducts but not in non-cystic proximal tubules, despite transgene expression in this nephron segment. We conclude that the C-terminal domain of HNF-1beta is required for the activation of the Pkhd1 promoter. Deletion mutants lacking the C-terminal domain function as dominant-negative mutants, possibly by preventing the recruitment of histone acetylases to the promoter. Cyst formation correlates with inhibition of Pkhd1 expression, which argues that mutations of HNF-1beta produce kidney cysts by down-regulating the ARPKD gene, Pkhd1. Expression of HNF-1alpha in proximal tubules may protect against cystogenesis.