Low grade oncocytic renal tumor (LOT): Clinicopathological characterization of 13 cases.

CONTEXT: Low grade oncocytic tumor (LOT) is a recently recognized renal oncocytic neoplasm with unique morphologic and immunohistochemical pattern (CK7 +, CD117 -) that differentiates them from oncocytoma and chromophobe renal cell carcinoma (ChrRCC). OBJECTIVE: To further evaluate the histomorphological characteristics as well as the clinical outcome of low grade oncocytic tumors, retrospectively. DESIGN: Thirteen cases of LOT were identified from 463 cases of renal oncocytic neoplasm in our pathology archive. All tumors were immunostained with CK7, CD117 and other relevant markers. The pathohistological features and follow up data of these cases were recorded. RESULTS: Median age of patients was 76 years old (range from 36 to 86), with male to female ratio of 2:11. None of the patients had a syndromic association/hereditary condition. Eleven tumors were unifocal in each affected kidney, and two were multifocal with 2 and 3 separated tumors, respectively. On microscopic examination, tumors show variety of growth patterns, namely solid, compact nested, focal tubular/tubuloreticular and trabecular patterns. The stroma can be hypocellular and edematous where the tumor cells are loosely arranged exhibiting cords and scattered single cell arrangement. Immunohistochemically, all thirteen cases displayed strong and diffuse CK7 positivity in tumor cells. Eleven cases were CD117 negative and the other two showed focal and weak CD117 positivity (< 5% of tumor cells). Uniform tumor cell positivity was found for AE1/3, EMA, PAX8, and e-cadherin. Negative staining results include CAIX, AMACR, CD10 and vimentin. All cases in our cohort demonstrate indolent behavior and show no evidence of disease recurrence, progression, or metastases during the follow-up period up to 96 months. CONCLUSION: LOT is an emerging new entity of renal oncocytic neoplasm and demonstrates indolent clinical behavior. Its unique morphologic features and immunohistochemical patterns (CK7 +, CD117 -) set them apart from oncocytoma and ChrRCC.

Metal-insulator transition and resistive switching in Y-doped CeO2 ceramics.

Y-doped ceria, Y0.16Ce0.84O1.92, is an oxide ion conductor that shows n-type conductivity under a small applied voltage. With increasing voltage, resistive switching by 2-3 orders of magnitude occurs that is reversible with some hysteresis and is enhanced in atmospheres of reduced pO2. The switching is a bulk effect, is not associated with Schottky barriers or with a crystallographic transition, occurs rapidly after a premonitory onset period depending on conditions and shows characteristics of a Mott transition. This is the third known example of low field-induced resistive switching in a bulk ceramic and represents an emergent phenomenon in materials that are taken outside their zone of thermodynamic stability.

Malignant germ cell tumors in men aged 50 years and over are associated with adverse pathologic features and higher stage at presentation.

BACKGROUND: Germ cell tumors (GCT) are the most common malignancy in men in the third and fourth decades of life. The occurrence of malignant GCT in men aged 50 years or over is rare, and their histopathologic characteristics and outcome is insufficiently characterized in the medical literature. Hence, we report the histopathologic features and clinical outcome of malignant GCTs in men aged ≥50 years at our institution. DESIGN: We performed a retrospective search of our database from 2005 to 2021 to identify men aged 50 years or older with malignant GCT. Cases of spermatocytic tumor were excluded. Clinical and histopathologic features of the tumors were reviewed. RESULTS: Forty-seven cases were identified, showing a sharp decline in incidence over the age of 65. Thirty-nine (83 %) tumors were testicular while eight (17 %) were non-testicular in presentation. Cases included 26 (55 %) seminomas, 15 (32 %) non-seminoma/mixed malignant GCT, and 5 (11 %) regressed testicular germ cell tumors. The most common component in mixed malignant GCTs was embryonal carcinoma (77 %), followed by seminoma and yolk sac tumor (62 % each). Germ cell neoplasia in situ (GCNIS) accompanied 57 % of the cases. Aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement and higher stage at presentation, were identified in a significant proportion of cases (36/47, 77 %). Clinical follow up showed six patients (14 %) died of disease-related causes. CONCLUSION: Our findings expand and corroborate the previously reported data on malignant GCT in older men. Unique characteristics include tendency for higher stage at presentation with adverse pathologic features and more aggressive clinical course.

Malignant juxtaglomerular cell tumor.

Juxtaglomerular cell tumors (JGCTs) are rare, typically benign neoplasms; only rare cases are clinically or histologically malignant. We herein report the histologic, immunophenotypic, and molecular features of a clinically unsuspected, diagnostically challenging case of malignant JGCT in a 23-year-old man. The diagnosis is confirmed with electron microscopy. The case is notable for its marked mitotic activity, which has not been previously reported in JGCTs, and novel finding of GATA3 immunohistochemical positivity.

Incidence, predictors, and clinical outcomes of permanent pacemaker insertion following transcatheter aortic valve implantation in an Arab population.

PURPOSE: Conduction defects requiring permanent pacemaker insertion (PPI) are one of the most common complications after transcatheter aortic valve implantation (TAVI). The purpose of this study was to identify the incidence and predictors of this complication as well as to assess clinical outcomes of patients requiring PPI after TAVI in an Arab population. METHODS: In this single-center, retrospective cohort analysis, all patients who underwent TAVI from 2010 to 2018 were reviewed; seventy-four independent variables were collected per patient, and multivariate analysis was performed to identify predictors. In-hospital outcomes were examined as well as 30-day and 1-year endpoints as defined by the Valve Academic Research Consortium-2. RESULTS: There were 48 of 170 patients (28.2%) who required PPI within 30 days of TAVI. The median time from TAVI to PPI was 2 days (interquartile range: 0 to 5 days). Positive predictors of 30-day PPI were prior right bundle branch block (odds ratio [OR]: 4.10; 95% confidence interval [CI]: 0.37 to 0.79; p < 0.001), post-procedural development of new right bundle branch block (OR: 3.59; 95% CI: 1.07 to 12.03; p = 0.038), post-procedural development of new left bundle branch block (LBBB) (OR: 1.85; 95% CI: 1.21 to 2.84; p = 0.005), post-procedural prolongation of PR interval (OR: 1.02; 95% CI: 1.01 to 1.02; p < 0.001), and post-procedural QRS duration (OR: 1.01; 95% CI: 1.00 to 1.03; p = 0.02). However, post-procedural development of new LBBB no longer remained a significant predictor of PPI after excluding six patients with LBBB who underwent prophylactic PPI (p = 0.093). Negative predictors of 30-day PPI were the presence of diabetes (OR: 0.54; 95% CI: 037 to 0.79; p = 0.001), the use of prosthesis size 29 compared to 23 (OR: 0.55; 95% CI: 0.35 to 0.87; p = 0.010), and the use of prosthesis size 26 compared to 23 (OR: 0.31; 95% CI: 0.20 to 0.50; p < 0.001). PPI was associated with longer median hospital stay, but the result was borderline significant after multivariate adjustment (19 vs. 14 days; p = 0.052). There was no statistically significant difference in 30-day and 1-year clinical outcomes. CONCLUSION: One-third of patients required PPI after TAVI. Several risk factors can identify patients at risk for PPI particularly pre-existing right bundle branch block. Further studies are needed to assess the association between PPI and negative clinical outcomes.

Coronary Artery Ectasia with Acute Myocardial Infarction, A Case Report.

Coronary artery ectasia (CAE), also known as aneurysmal coronary artery disease, is defined as an abnormal diffuse (ectasia) or segmental (aneurysmal) dilatation of any branch of the coronary arteries. It is a well-recognized entity with 1.2-4.9% prevalence. Our case is a 46 year old male with no prior medical problem who presented to the ER with inferior ST elevation myocardial infarction (STEMI). The Coronary angiogram revealed multiple ectatic segments in the right coronary artery (RCA) with 100% stenosis in the middle segment. Upon wiring the RCA a big clot burden was noted on the ectatic segment. We planned to keep him on aggrastat infusion for 24 hours then re-cath him. The second cath showed complete resolution of the clot and the lesion was stented with drug eluting stent showing excellent final result. We found that our case is interesting and unique in exploring the association of CAE that presents with STEMI and how to treat it safely in the cath lab, knowing that CAE is an uncommon finding during coronary angiography. CAE is associated with many coronary artery disease (CAD) risk factors and etiologies as well as pathologic progression. Patients with CAE are usually asymptomatic but can still present with symptoms of coronary artery occlusion. There is still no standard treatment specific for CAE itself, but when presenting with occlusive symptoms, management is guided by the extent of occlusion similar to CAD.

Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.

PURPOSE: Very high-risk prostate cancer (PC) is associated with poor response to local and systemic treatments; however, few cases have been molecularly profiled. We studied clinical outcomes and molecular profiles of patients with clinically localized primary Gleason pattern 5 PC. PATIENTS AND METHODS: Clinicopathologic features, targeted somatic and germline sequencing, and PTEN, TP53, and ERG status by immunohistochemistry were assessed in patients undergoing surgery from 2005 to 2015; 60 consecutive patients were identified with Gleason score 5 + 4 = 9 or 5 + 5 = 10 PC after radical prostatectomy with available tissue and clinical follow-up. Clinicopathologic and genomic parameters were correlated with biochemical relapse, metastasis-free survival, time to castration resistance, and overall survival using Cox proportional hazards models. RESULTS: Of patients with somatic sequencing data and clinical follow-up, 34% had DNA repair gene mutations, including 22% (11 of 49) with homologous recombination and 12% (six of 49) with mismatch repair gene alterations. Homologous recombination mutations were germline in 82% (nine of 11) of patients. In addition, 33% (16 of 49) had TP53 mutation, and 51% (29 of 57) had PTEN loss. Overall, 43% developed metastasis, with a time to castration resistance of 12 months. On multivariable analysis of clinicopathologic variables, only ductal/intraductal histology (hazard ratio, 4.43; 95% CI, 1.76 to 11.15; P = .002) and seminal vesicle invasion (hazard ratio, 5.14; 95% CI, 1.83 to 14.47; P = .002) were associated with metastasis. Among genomic alterations, only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis, and neither remained significant in multivariable analyses. These data are retrospective and hypothesis generating. CONCLUSION: Potentially actionable homologous recombination and mismatch repair alterations are observed in a significant proportion of patients with very high-risk PC at the time of radical prostatectomy. These findings could inform the design of prospective trials in this patient population.

The first survey of the Saudi Acute Myocardial Infarction Registry Program: Main results and long-term outcomes (STARS-1 Program).

BACKGROUND: Prior acute coronary syndrome (ACS) registries in Saudi Arabia might not have accurately described the true demographics and cardiac care of patients with ACS. We aimed to evaluate the clinical characteristics, management, and outcomes of a representative sample of patients with acute myocardial infarction (AMI) in Saudi Arabia. METHODS: We conducted a 1-month snap-shot, prospective, multi-center registry study in 50 hospitals from various health care sectors in Saudi Arabia. We followed patients for 1 month and 1 year after hospital discharge. Patients with AMI included those with or without ST-segment elevation (STEMI or NSTEMI, respectively). This program survey will be repeated every 5 years. RESULTS: Between May 2015 and January 2017, we enrolled 2233 patients with ACS (mean age was 56 [standard deviation = 13] years; 55.6% were Saudi citizens, 85.7% were men, and 65.9% had STEMI). Coronary artery disease risk factors were high; 52.7% had diabetes mellitus and 51.2% had hypertension. Emergency Medical Services (EMS) was utilized in only 5.2% of cases. Revascularization for patients with STEMI included thrombolytic therapy (29%), primary percutaneous coronary intervention (PCI); (42.5%), neither (29%), or a pharmaco-invasive approach (3%). Non-Saudis with STEMI were less likely to undergo primary PCI compared to Saudis (35.8% vs. 48.7%; respectively, p <0.001), and women were less likely than men to achieve a door-to-balloon time of <90 min (42% vs. 65%; respectively, p = 0.003). Around half of the patients with NSTEMI did not undergo a coronary angiogram. All-cause mortality rates were 4%, 5.8%, and 8.1%, in-hospital, at 1 month, and at 1 year, respectively. These rates were significantly higher in women than in men. CONCLUSIONS: There is an urgent need for primary prevention programs, improving the EMS infrastructure and utilization, and establishing organized ACS network programs. AMI care needs further improvement, particularly for women and non-Saudis.

MSH2 Loss in Primary Prostate Cancer.

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2 Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts. Clin Cancer Res; 23(22); 6863-74. ©2017 AACR.

Analytic, Preanalytic, and Clinical Validation of p53 IHC for Detection of TP53 Missense Mutation in Prostate Cancer.

Purpose:TP53 missense mutations may help to identify prostate cancer with lethal potential. Here, we preanalytically, analytically, and clinically validated a robust IHC assay to detect subclonal and focal TP53 missense mutations in prostate cancer.Experimental Design: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. Fifty-four formalin-fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE prostate cancer tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of preanalytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy cohorts.Results: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), whereas the negative predictive value was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable HR for metastasis among cases with p53 nuclear accumulation compared with those without was 2.55 (95% confidence interval, 1.1-5.91).Conclusions: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical prostate cancer specimens. Clin Cancer Res; 23(16); 4693-703. ©2017 AACR.

Prevalence and Prognostic Significance of PTEN Loss in African-American and European-American Men Undergoing Radical Prostatectomy.

African-American (AA) men have a higher risk of lethal prostate cancer (PCa) compared to European-American (EA) men. However, the molecular basis of this difference, if any, remains unclear. In EA PCa, PTEN loss, but not ERG rearrangement, has been associated with poor outcomes in most studies. Although ERG rearrangement is less common in AA compared to EA PCa, the relative frequency of PTEN loss and the association of PTEN/ERG molecular subtypes with outcomes is unknown for AA PCa. We examined PTEN/ERG status by immunohistochemistry in self-identified AA patients undergoing radical prostatectomy at Johns Hopkins with tumor tissue available on tissue microarray (TMA; n=169) and matched these cases by pathologic parameters to 169 EA patients from the same TMAs. The rate of PTEN loss was significantly lower in AA compared to EA PCa (18% vs 34%; p=0.001), similar to the lower rate of ERG expression (25% vs 51%; p<0.001). To examine the association of PTEN/ERG status with oncologic outcomes, we created an additional TMA of 87 AA tumors with Gleason score > 4 + 3 = 7. Among the total population of AA men with outcome data from all TMAs (n=222), PTEN loss was associated with higher risk of biochemical recurrence (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.82) and metastasis (HR 3.90, 95% CI 1.46-10.4) in multivariable models. PATIENT SUMMARY: PTEN and ERG alterations in prostate cancer are less likely in African-American than in European-American men. However, PTEN loss remains associated with poor prostate cancer outcomes among African-American men.

Occlusal outcomes in combined orthodontic and orthognathic treatment.

OBJECTIVE: To investigate the treatment outcome in terms of the malocclusion features and the changes in the occlusion of patients undergoing orthodontic/orthognathic treatment using the Peer Assessment Rating (PAR) and the Index of Complexity, Outcome and Need (ICON) and to test the application of the Index of Orthognathic Functional Treatment Need (IOFTN) on this sample as a measure of orthognathic pre-treatment need. DESIGN: Retrospective longitudinal cohort study. SETTING: The orthodontic department at the Eastman Dental Hospital. MATERIAL AND METHODS: The study models of a sample of 100 orthodontic/orthognathic patients who were treated at the Eastman Dental Hospital were measured using the PAR index and ICON at three stages: pre-treatment, pre-surgery and at debond. Treatment need was assessed by measuring IOTN and IOFTN using start study models. RESULTS: 99% of the sample showed an improvement in PAR score, with 82% of the sample being greatly improved. ICON showed that 95% of the sample had an improvement of different degrees with 5% being not improved or worse. The IOFTN qualified 97% of the patients for orthognathic treatment when used retrospectively on the sample while the DHC of IOTN qualified the whole sample for orthodontic treatment. CONCLUSIONS: Orthodontic/orthognathic treatment showed improved and acceptable overall results. The PAR index and ICON were valid measures to investigate the outcome of orthognathic treatment. IOFTN proved to be a useful tool in determining and prioritizing orthognathic treatment based purely on functional need.

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer.

PURPOSE: RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate-resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin-fixed paraffin-embedded (FFPE) prostate tumors. EXPERIMENTAL DESIGN: We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by IHC and RT-PCR. RESULTS: The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts, and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared with admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (P < 0.0001 and P = 0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. CONCLUSIONS: RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. Clin Cancer Res; 22(18); 4651-63. ©2016 AACR.

Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia.

Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels > 100 mg/dL (2.5 mmol/L) after a mean (+/-standard deviation) of 55 +/- 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 +/- 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 +/- 35 mg/dL (3.8 +/- 0.9 mmol/L), and at 6 months, 120 +/- 31 mg/dL (3.1 +/- 0.8 mmol/L); P = 0.010]. After 6 months, an additional 32% achieved the target LDL level of <100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens.