Search

Background Some melanomas closely resemble pigmented spindle cell nevi (PSCN) of Reed histologically. The distinction of these entities is important for clinical management. A recent study showed most PSCN (78%) are fusion-driven, commonly involving NTRK3 (57%). Conversely, BRAF V600E mutations are not characteristic of PSCN but are frequent in melanoma. Objective In this study, we assessed clinical, histologic and genomic differences between PSCN of Reed and Reed-like melanomas (RLMs). Methods We performed BRAF V600E immunohistochemistry (IHC) for 18 PSCN and 20 RLM cases. All 23 benign PSCN cases previously underwent whole transcriptome and targeted DNA sequencing with a 1711 gene panel. Results We previously demonstrated the majority of PSCN (18 of 23) has chimeric fusions. Among PSCN without a chimeric fusion, BRAF mutations were common. Noncanonical BRAF mutations were identified in 2 of 5 nonfusion cases, and 1 case had a canonical BRAF mutation. Alternatively, 70% of RLM demonstrated a BRAF V600E mutation. RLM also occurred more frequently in older patients. Limitations The overall sample size was small. Conclusions In diagnostically challenging cases, ancillary IHC studies can assist in distinguishing PSCN from RLM. Our study suggests positive staining by IHC for BRAF V600E and older age strongly favors a diagnosis of RLM.

According to the Chronic Kidney Disease Prognosis Consortium (CKD-PC), 1 in 4 patients age ≥ 65 in North America has some form of chronic kidney disease (CKD), while 3 in 100 will progress to kidney failure. The aim of this study was to evaluate whether bariatric surgery alters the progression of CKD to kidney failure in patients who are severely obese.We conducted a retrospective review of all patients who underwent bariatric surgery at our institution over the last 16 years. Kidney function and injury were assessed using the average estimated glomerular filtration rate and urinary albumin-to-creatinine ratio (uACR) over 3 months preoperatively and postoperative at 12-month follow-up. The risk of progression from CKD to kidney failure was assessed using the Chronic Kidney Disease Prognosis Consortium (CKD-PC) equation.Out of 2924 patients reviewed over this period of time, 69 (2.4%) had the recorded data necessary to assess kidney injury and the risk of disease progression to kidney failure. Patients within moderate and severe stages of CKD-related albuminuria improved the most at 12-month follow-up (by 48% and 79%; P = 0.0001 and P = 0.025, respectively). This translated to a relative risk reduction for progression to kidney failure in CKD ≥ stage 3 patients of 70% at 2 years and 60% at 5 years (both P = 0.001).Bariatric surgery seems to improve kidney injury, especially among patients with the most severe stages of CKD. Marked 2- and 5-year risk reduction in the progression from CKD to kidney failure was observed.

Background: Parathyroid glands are difficult to identify during total thyroidectomies and accidental resection can lead to problematic post-operative hypocalcemia. Our main goals were to evaluate the effectiveness of using near-infrared light (NIRL) auto-fluorescence intra-operatively for parathyroid-gland identification; and to measure its impact on postoperative hypocalcemia incidence.Study Design Total thyroidectomies were performed on 170 patients with different thyroid pathologies, block-randomized (1:1) into 2 equal groups. Among controls, traditional overhead white light (WL) was used throughout. In the experimental group, NIRL was used to enhance parathyroid gland recognition before thyroid dissection. The number of parathyroid glands identified was compared after thyroid dissection in controls using WL vs pre-dissection in the experimental using NIRL and with WL vs NIRL before thyroid dissection in the experimental group. Postoperative serum calcium levels and hypocalcemia rates were compared. Results: The mean number of parathyroid glands identified pre-dissection with NIRL was the same identified post-dissection with WL (3.5 vs 3.6). In the experimental group, converting from WL to NIRL increased the number of glands detected from 2.6 to 3.5 (p < 0.001), and revealed at least 1 previously missed gland in 67.1% of patients. Calcium levels ≤7.5 mg/dL were one-tenth as common in the NIRL group (p = 0.005). The adjusted odds of hypocalcemia developing increased by 15% for every 5-g increase in thyroid gland weight (odds ratio 1.15; 95% CI 1.06 to 1.25). All hypocalcemia resolved within 6 months. Conclusions: Using NIRL during thyroidectomy increases intraoperative identification of parathyroid glands, enhances their detection before thyroid dissection, and decreases the incidence of postoperative hypocalcemia. Fil: Dip, Fernando. instituto Argentino de Diagnóstico y Tratamiento; Argentina Fil: Falco, Jorge. Instituto Argentino de Diagnóstico y Tratamiento; Argentina Fil: Verna, Silvina. Instituto Argentino de Diagnóstico y Tratamiento; Argentina Fil: Prunello, Marcos Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Cs.bioquimicas y Farmaceuticas. Departamento de Matematica y Estadistica.; Argentina Fil: Loccisano, Matias. Instituto Argentino de Diagnóstico y Tratamiento; Argentina Fil: Quadri, Pablo. Instituto Argentino de Diagnóstico y Tratamiento; Argentina Fil: White, Kevin. Scienceright Research Consultations; Canadá Fil: Rosenthal, Raul. Cleveland Clinic Florida; Estados Unidos

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.

Recent studies have described kinase fusions as the most common initiating genomic events in Spitzoid neoplasms. Each rearrangement generates a chimeric protein with constitutive activation of the tyrosine kinase domain, resulting in the development of a Spitzoid neoplasm. Identifying key initiating genomic events and drivers may assist in diagnosis, prognostication, and management. Retrospective, consecutive search of our database between 2009 and 2018 for Spitzoid neoplasms identified 86 cases. Whole transcriptome mRNA and DNA sequencing (1714 genes) detected 9% of cases (8/86) with structural rearrangements in MAPK genes other than BRAF and 47% (40/86) with kinase fusions previously described in Spitzoid neoplasms. We identified in-frame fusions of MAP3K8-DIPC2, MAP3K8-PCDH7, MAP3K8-UBL3, MAP3K8-SVIL (n=6), and ATP2A2-MAP3K3 (n=1) as well as a p.I103_K104 in-frame deletion of MAP2K1 (n=1), in the absence of well-recognized drivers of melanocytic neoplasia. Fluorescence in situ hybridization validated all cases (n=7) with available tissue. Cases occurred in younger patients (median age 18 y). Morphologically, cases were predominantly epithelioid (P=0.0032), often with some melanin pigment (P=0.0047), and high-grade nuclear atypia (P=0.012). A significant proportion were thought to be Spitzoid melanomas (3/8). Average follow-up time was 11 months. One MAP3K8-DIP2C Spitzoid melanoma involved 4/5 sentinel lymph nodes and led to a complete lymph node dissection with unremarkable follow-up at 9 months. One MAP3K8-DIPC2 atypical Spitz tumor raised concern for recurrence at 10 months and was reexcised. We present a distinct subtype of Spitzoid neoplasm characterized by structural alterations in MAPK genes, which are important to recognize given the potential for treatment with MAPK inhibitors in metastatic cases.

Rationale: The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p–enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143−/− and anti-miR-143-3p–treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.

Pulmonary endothelial cell apoptosis is a transient, yet defining pathogenic event integral to the onset of many pulmonary vascular diseases such as pulmonary hypertension (PH). However, there is a paucity of information concerning the molecular pathway(s) that control pulmonary arterial endothelial cell apoptosis. Here, we introduce a molecular axis that when functionally active seems to induce pulmonary arterial endothelial cell apoptosis in vitro and PH in vivo. In response to apoptotic stimuli, human pulmonary arterial endothelial cells exhibited robust induction of a programmed cell death 4 (PDCD4)/caspase-3/apoptotic pathway that was reversible by direct PDCD4 silencing. Indirectly, this pathway was also repressed by delivery of a microRNA-21 mimic. In vivo, genetic deletion of microRNA-21 in mice ( miR-21 −/− mice) resulted in functional activation of the PDCD4/caspase-3 axis in the pulmonary tissues, leading to the onset of progressive PH. Conversely, microRNA-21–overexpressing mice ( CAG-microRNA-21 mice) exhibited reduced PDCD4 expression in pulmonary tissues and were partially resistant to PH in response to chronic hypoxia plus SU 5416 injury. Furthermore, direct PDCD4 knockout in mice ( PDCD4 −/− mice) potently blocked pulmonary caspase-3 activation and the development of chronic hypoxia plus SU 5416 PH, confirming its importance in disease onset. Broadly, these findings support the existence of a microRNA-21–responsive PDCD4/caspase-3 pathway in the pulmonary tissues that when active serves to promote endothelial apoptosis in vitro and PH in vivo.

Background— Pulmonary arterial hypertension (PAH) is a hyperproliferative vascular disorder observed predominantly in women. Estrogen is a potent mitogen in human pulmonary artery smooth muscle cells and contributes to PAH in vivo; however, the mechanisms attributed to this causation remain obscure. Curiously, heightened expression of the estrogen-metabolizing enzyme cytochrome P450 1B1 (CYP1B1) is reported in idiopathic PAH and murine models of PAH. Methods and Results— Here, we investigated the putative pathogenic role of CYP1B1 in PAH. Quantitative reverse transcription–polymerase chain reaction, immunoblotting, and in situ analysis revealed that pulmonary CYP1B1 is increased in hypoxic PAH, hypoxic+SU5416 PAH, and human PAH and is highly expressed within the pulmonary vascular wall. PAH was assessed in mice via measurement of right ventricular hypertrophy, pulmonary vascular remodeling, and right ventricular systolic pressure. Hypoxic PAH was attenuated in CYP1B1 −/− mice, and the potent CYP1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene (TMS; 3 mg · kg −1 · d −1 IP) significantly attenuated hypoxic PAH and hypoxic+SU5416 PAH in vivo. TMS also abolished estrogen-induced proliferation in human pulmonary artery smooth muscle cells and PAH–pulmonary artery smooth muscle cells. The estrogen metabolite 16α-hydroxyestrone provoked human pulmonary artery smooth muscle cell proliferation, and this mitogenic effect was greatly pronounced in PAH–pulmonary artery smooth muscle cells. ELISA analysis revealed that 16α-hydroxyestrone concentration was elevated in PAH, consistent with CYP1B1 overexpression and activity. Finally, administration of the CYP1B1 metabolite 16α-hydroxyestrone (1.5 mg · kg −1 · d −1 IP) caused the development of PAH in mice. Conclusions— Increased CYP1B1-mediated estrogen metabolism promotes the development of PAH, likely via the formation of mitogens, including 16α-hydroxyestrone. Collectively, this study reveals a possible novel therapeutic target in clinical PAH.

Background— Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO · ) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ET B ), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species generation and decreasing NO · levels. We hypothesized that aldosterone modulates PAH by disrupting ET B -eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress. Methods and Results— In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO · metabolites in the absence of left-sided heart failure. In human pulmonary artery endothelial cells, endothelin-1 increased aldosterone levels via peroxisome proliferator-activated receptor gamma coactivator-1α/steroidogenesis factor-1–dependent upregulation of aldosterone synthase. Aldosterone also increased reactive oxygen species production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ET B to decrease endothelin-1–stimulated eNOS activity. Substitution of ET B -Cys405 with alanine improved ET B -dependent NO · synthesis under conditions of oxidant stress, confirming that Cys405 is a redox-sensitive thiol that is necessary for ET B -eNOS signaling. In human pulmonary artery endothelial cells, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated reactive oxygen species generation and restored ET B -dependent NO · production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in 2 animal models of PAH in vivo. Conclusions— Our findings demonstrate that aldosterone modulates an ET B cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO · and promote PAH.

This review introduces the fundamental concepts of network medicine and explores the feasibility and potential impact of network-based methods on predicting and ameliorating individual manifestations of human cardiovascular disease.Complex cardiovascular diseases rarely result from an abnormality in a single molecular effector, but, rather, nearly always are the net result of multiple pathobiological pathways that interact through an interconnected network. In the postgenomic era, a framework has emerged of the potential complexity of the interacting pathways that govern molecular actions in the human cell. As a result, network approaches have been developed to understand more comprehensively those interconnections that influence human disease. 'Network medicine' has already led to tangible discoveries of novel disease genes and pathways as well as improved mechanisms for rational drug development.As methodologies evolve, network medicine may better capture the complexity of human pathogenesis and, thus, re-define personalized disease classification and therapies.

Background— Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli. Methods and Results— Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21 –null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH. Conclusions— A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH.

A 68-year-old woman was referred to the Oculofacial Plastic and Reconstructive Surgery service for evaluation of a left upper eyelid lesion that was worrisome for carcinoma. The mass measured 8 × 8 mm; it was well-circumscribed, pink, and firm with distortion of the eyelid margin, central ulceration, and loss of the lashes. The patient denied previous surgery or trauma in this area, but she had a history of blepharopigmentation (tattoo eyeliner) of all 4 eyelids approximately 7 years prior. Incisional biopsy revealed inflammatory changes consistent with a localized reaction to the tattoo pigment granules. Local kenalog injection was attempted with improvement of the overall appearance but with persistent deformity including irregularity of the margin and loss of lashes. The persistent abnormal appearance was worrisome for an underlying carcinoma missed on the initial incisional biopsy and prompted a full-thickness wedge resection and reconstruction of the abnormal area. The results of biopsy of the excised tissue confirmed absence of malignant neoplasm and showed changes consistent with tattoo granuloma. Tattoo granuloma of the eyelid should be considered in the differential diagnosis of eyelid lesions worrisome for carcinoma in patients with a history of blepharopigmentation.

An unusual cause of portal hypertension in a 65 year old woman: congenital hepatic fibrosis

The development of pneumoperitoneum as a result of botox injection for treatment of achalasia

Intravenous pantropazole: physician understanding of indications and their prescribing patterns leading to hospital restrictions