Pleomorphic high grade endometrial stromal sarcoma with YWHAE gene amplification may be a novel variant with poor prognosis.

Endometrial stromal neoplasms are classified by the World Health Organization (WHO) into endometrial stromal nodule (ESN), low grade (LGESS), high grade (HGESS), and undifferentiated uterine sarcoma (UUS). HGESS is subclassified based on molecular findings, YWHAE or BCOR. The HGESS with YWHAE::NUTM2A/B (alias YWHAE::FAM22A/B) fusion usually have relatively monomorphic (as with most fusion-associated malignancies) rounded to epithelioid cells with eosinophilic cytoplasm, vesicular nuclei, nucleoli, and mitotic figures >10/10 HPF. We present a 66-year-old woman with post-menopausal bleeding found to have a heterogeneous solid-cystic uterine mass on CT who underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic lymph node dissection. A 15.0×9.0 cm variegated uterine mass with hemorrhage and necrosis was identified. Histologically, the tumor was hypercellular with haphazard fascicles, microcysts, and tongue-like destructive myometrial invasion. Tumor cells exhibited marked pleomorphism and high mitotic activity with atypical mitotic figures. There was extensive cyclin-D1 and subset CD10 immunopositivity. FISH showed YWHAE amplification but without rearrangement. Interestingly, we found only two other reported cases of pleomorphic HGESS with YWHAE gene amplification upon review of 259 cases from cBioPortal database, one of which was reported as carcinosarcoma with heterologous elements. Of note, all three YWHAE amplified cases were diagnosed at high-stage and succumbed to disease within six months. Our case appears to be the third case of YWHAE-amplified pleomorphic HGESS, possibly a new variant of uterine sarcoma with aggressive biologic behavior that needs further evaluation.

Narrative Review of Hypercoagulability in Small-Vessel Vasculitis.

Pauci-immune necrotizing and crescentic glomerulonephritis (GN) is the most common etiology of rapidly progressive GN. Clinical presentation in those afflicted is usually related to rapid loss of kidney function. We report the case of a 70-year-old woman who came to medical attention for signs and symptoms related to lower-extremity deep vein thrombosis (DVT). At presentation, the patient had biochemical abnormalities consistent with active GN, which quickly progressed to rapid loss in kidney function requiring renal replacement therapy. Kidney biopsy revealed small-vessel vasculitis with glomerular crescents. Serologic studies were negative for antineutrophil cytoplasmic antibody antibodies and other causes of acute GN. Plasmapheresis, immunosuppressive, and anticoagulant therapies were prescribed. Absence of other apparent end-organ involvement with vasculitis pointed toward renal-limited small-vessel vasculitis, yet presence of unprovoked DVT argues for systemic vascular inflammation. This case illustrates that venous thrombosis can be the presenting manifestation in patients with vasculitis and silent, severe end-organ involvement. The epidemiology and pathophysiology of venous thromboembolism in small-vessel vasculitis are discussed in this report.

Interpathologist Diagnostic Agreement for Non-Small Cell Lung Carcinomas Using Current and Recent Classifications.

CONTEXT.­: Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES.­: To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure. DESIGN.­: We used a Web-based survey to present core images of 54 NSCLC cases to 22 practicing pathologists for diagnosis, initially as H&E only, then as H&E plus mucin and 4 IHC stains. Each case was diagnosed according to published 2004, 2011, and 2015 NSCLC classifications. Cohen's kappa was calculated for the 231 pathologist pairs as a measure of IPDA. RESULTS.­: Twenty-two pathologists diagnosed 54 NSCLC cases by using 4 published classifications. IPDA is significantly higher for H&E/mucin/IHC diagnoses than for H&E-only diagnoses. IPDA for H&E/mucin/IHC diagnoses is highest with the 2015 classification. IPDA is estimated higher after collapse of stated diagnoses into subhead or dichotomized classes. IPDA for H&E/mucin/IHC diagnoses with the 2015 World Health Organization classification is similar for community and academic pathologists, and is higher when pathologists have pulmonary pathology expertise, have more than 6 years of practice experience, or diagnose more than 100 new lung carcinoma cases per year. CONCLUSIONS.­: Higher IPDA is associated with use of mucin and IHC stains, with the 2015 NSCLC classification, and with pathologists' pulmonary pathology expertise, practice duration, and frequency of lung carcinoma cases.

Altered Morphology and Immunohistochemical Characteristics in Metastatic Malignant Melanoma After Therapy With Vemurafenib.

Metastatic melanoma is traditionally diagnosed using classic morphologic features in addition to immunohistochemical studies. The authors report a case of metastatic malignant melanoma where both morphology and immunohistochemistry were altered after treatment. This 51-year-old patient presented with metastatic melanoma to the brain and axilla. Initially, both metastases showed classic morphology and diffuse staining with the pan-melanoma antibody cocktail. This cocktail is a combination of 3 antibodies commonly used to diagnose melanocytic neoplasms: Melan-A (MART-1), tyrosinase, and HMB-45. In combination, the cocktail is highly sensitive for detecting melanocytic neoplasms and is commonly used to diagnose metastatic melanoma. Her tumor was positive for the BRAF 1799T>A (V600E) mutation, and she was treated with BRAF inhibitor therapy (vemurafenib). However, the axillary tumor recurred after treatment with vemurafenib. The recurrent tumor showed a markedly different morphology and complete loss of staining with the pan-melanoma antibody cocktail. This loss of staining accompanied by the change in morphology was an observation not previously documented after therapy with vemurafenib. This case demonstrates a potential pitfall in the diagnosis of metastatic or recurrent malignant melanoma.

Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome.

Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl salt-sensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1(+) cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.

A human monoclonal antibody against the collagen type IV α3NC1 domain is a non-invasive optical biomarker for glomerular diseases.

Progressive kidney disease is a significant clinical problem. However, despite research aimed toward developing improved predictors of disease, the major tool to assess kidney ultrastructure damage is the kidney biopsy. Here we tested the capability of a labeled human monoclonal antibody (F1.1), directed against the NC1 domain of α3(IV) collagen, to detect pathologic kidney alterations in vivo using mouse models of nephrotoxic serum-induced nephritis and puromycin aminoglycoside nephrosis. The F1.1 antibody-fluorophore conjugate signal rapidly localized specifically to injured glomeruli in both the severe and mild kidney disease models while minimally labeling healthy kidney. This differential labeling is likely due to cryptic NC1-domain exposure as enzymatic or chemical treatment of healthy human or mouse kidney sections significantly increased F1.1 binding to the glomeruli. Finally, kidney tissue from patients with renal disease show significant glomerular staining by F1.1 indicating that exposure of the NC1 domain occurs in clinically relevant circumstances. Thus, NC1 domain exposure may represent an in situ biomarker for assessment of kidney injury. Our study suggests that F1.1 and similar antibodies may represent a new class of non-invasive renal imaging reagents.

Lack of evidence for a remote effect of renal ischemia/reperfusion acute kidney injury on outcome from temporary focal cerebral ischemia in the rat.

OBJECTIVE: Acute kidney injury (AKI) and ischemic stroke may occur in the same cardiac surgical patient. It is not known if an interaction exists between these organ injuries. Isolated renal ischemia/reperfusion is associated with dysfunction in remote, otherwise normal organs, including the brain. In a rat model of simultaneous bilateral renal artery occlusion (BRAO) and middle cerebral artery occlusion (MCAO), the authors tested the hypothesis that AKI would worsen experimental stroke outcome. DESIGN: Sixty thermoregulated anesthetized rats were randomized to (1) 40-minute BRAO, (2) 80-minute MCAO, or (3) simultaneous BRAO + MCAO. Serum creatinine was measured at baseline and 2 and 7 days after organ reperfusion. Neurologic function and brain and kidney histologies were measured on day 7. In a parallel study, serum cytokines were measured over 16 hours. SETTING: Laboratory. PARTICIPANTS: Male Wistar rats. INTERVENTIONS: Combined or isolated BRAO and MCAO. MEASUREMENTS AND MAIN RESULTS: AKI was similar between the BRAO and BRAO + MCAO groups, with greater 48-hour creatinine increases (p < 0.02) and renal histopathologic scores (p < 0.001) in these groups than with MCAO alone. Neurologic scores correlated with cerebral infarct size (p = 0.0001). There were no differences in neurologic score (p = 0.53) and cerebral infarct volume (p = 0.21) between the MCAO and BRAO + MCAO groups. There was no association between cerebral infarct size or neurologic score and 48-hour creatinine increase. Interleukin-6 was increased during reperfusion (p < 0.0001), but a difference among groups was absent (p = 0.41). CONCLUSIONS: In contrast to the effects reported for AKI on normal remote organs, AKI had no influence on infarct size or neurologic function after experimental ischemic cerebral stroke.

TrkB signaling is required for behavioral sensitization and conditioned place preference induced by a single injection of cocaine.

Exogenous brain-derived neurotrophic factor (BDNF) can regulate behavioral sensitization and conditioned place preference (CPP) when animals are exposed to repeated cocaine administration. However, it is unclear whether BDNF signaling through the TrkB receptor can mediate these behavioral responses when animals are given a single cocaine exposure. Because TrkB knockout mice die as neonates, we engineered a transgenic mouse that expressed a dominant negative form of TrkB (dnTrkB) in a conditional and reversible manner. We assessed also activation of endogenous TrkB by quantifying levels of phosphorylated TrkB (p-TrkB) in the nucleus accumbens (NAc). We found that a single exposure to cocaine was sufficient to increase p-TrkB within the NAc 9-12h after administration. Expression of the dnTrkB transgene not only prevented the acute cocaine-induced increase in p-TrkB, but it also prevented behavioral sensitization and CPP following a single cocaine injection. These findings demonstrate that TrkB activation is required both for behavioral sensitization and CPP to a single cocaine exposure. The fact that enhanced TrkB activation is induced within 9h of a single injection of cocaine suggests that inhibition of TrkB signaling commencing hours after cocaine exposure may prevent at least the initial antecedents to the sensitizing and reinforcing effects of this psychostimulant.

Cystic fibrosis: newborn screening in America.

Cystic fibrosis is the most common lethal genetic disease in Caucasians, manifesting as progressive lung dysfunction, pancreatic insufficiency, and intestinal disease. CF was traditionally diagnosed clinically, either because of a family history or occurrence of meconium ileus, or as a result of intestinal malabsorption and chronic pulmonary disease. In 1979, it was discovered that immunoreactive trypsinogen was increased in neonatal dried-blood specimens on Guthrie cards, making it possible to screen neonates. During the past decades, survival rates of patients with CF have improved significantly (see Figure 5). To continue this progress, universal newborn screening has been implemented in many states as an addition to the arsenal of therapies and strategies to improve survival. National newborn-screening programs to identify CF patients after birth have been adopted for a number of years in Europe, Australia, and Canada. As expected, many benefits have been seen due to the early identification of CF patients, including improved survival, better lung function and growth with less intensive therapy, and reduced cost of therapy. To date, 37 states in the United States have adopted similar programs, in the hopes of improving CF outcomes. This welcome trend should help improve the lives of CF patients living in America.