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Introduction: Inflammatory juvenile conjunctival nevus (IJCN) is a rare condition affecting both children and adolescents. It has misleading clinical and histopathological features; therefore, careful assessment is necessary. We present a case of IJCN with a rare pathological type and misleading histopathological features. Case Presentation: A 13-year-old girl with IJCN in the right eye was treated with antiallergic and steroid eye drops but showed no response and was referred to our hospital for excisional biopsy. Slit-lamp examination revealed a nonpigmented juxtalimbal tumor in the right eye. Histopathologically, nevus cells with mild nuclear atypia proliferated within the conjunctival epithelium. Confluent growth of junctional nests, conjunctival cysts, and prominent inflammatory infiltration were also observed. Considering the young age of the patient and immunohistochemical characteristics (HMB-45, SOX10, p16 and Ki-67), the patient was finally diagnosed with IJCN. IJCN has three pathological subtypes – compound, subepithelial, and junctional – depending on the location of the nevus cells. This case was diagnosed as a rare junctional type, as most of the examined sections only showed lesions within the epithelium; no lesions were clearly identified extending beneath the epithelium. Conclusion: The pathological diagnosis of IJCN is difficult because some features of IJCN suggest malignancy. Detailed microscopic examination, immunohistochemical staining, and the patient’s young age helped render a final diagnosis.

Abstract Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post‐operative survival outcomes. To test this hypothesis, we utilised a multi‐institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease‐free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (ptrend

Abstract Background Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. Case presentation A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. Conclusions This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Intravascular lymphoma (IVL) is difficult to diagnose because its clinical presentation and laboratory and imaging findings are nonspecific. Herein, we report a case of IVL presenting as a lesion in the splenium of the corpus callosum. A 52-year-old man attended the emergency department with a 2-week history of progressively worsening abnormal behavior and gait disturbance. Magnetic resonance imaging on admission revealed an oval lesion in the splenium of the corpus callosum. The follow-up magnetic resonance imaging performed 2 months after disease onset revealed multiple high-signal areas in the bilateral cerebral white matter on T2-weighted images and diffusion-weighted images. The blood test results showed an elevated level of lactate dehydrogenase and serum-soluble interleukin-2 receptor. These findings were compatible with the diagnosis of IVL. IVL is often difficult to diagnose due to a wide variety of clinical presentations and imaging findings.

Abstract Background Mesh infection after inguinal hernia repair is a very rare complication. The incidence of late-onset mesh infection is approximately 0.1–0.2% of total hernia repair cases and can lead to serious complications if not treated promptly. Here, we report a rare case of discitis due to late-onset mesh infection, occurring 14 years after an inguinal hernia repair. Case presentation An 89-year-old man was brought to our hospital with right-sided abdominal pain and signs of hypoglycemia. He had a history of type 2 diabetes mellitus and had undergone inguinal hernia repair 14 years ago. Upon admission, laboratory tests revealed no elevated inflammatory markers. Computed tomography (CT) revealed a peri-appendicular abscess. Although the patient was administered empiric antibiotics, on day 3 of admission, his white blood cell count and C-reactive protein levels increased to 38,000/µl and 28 mg/dl, respectively. CT-guided drainage was attempted but was not successful. Escherichia coli was detected in both blood culture collections. On day 7 of admission, the patient complained of back pain; CT on day 10 revealed a peri-appendicular abscess with a soft tissue shadow anterior to the thoracic vertebrae at the 8th/9th level. Thoracic discitis, due to bacteremia originating from the mesh abscess, was suspected. We surgically resected the appendix, followed by removal of the plug and mesh abscess. The post-operative course of the patient was uneventful. For treating discitis, it is known that antibiotic therapy is required for a minimum of 6 weeks. Therefore, on the 30th day post-surgery, the patient was transferred to the orthopedic ward for continued treatment. Conclusions This report discusses a rare case of late-onset mesh infection leading to thoracic discitis. Since late-onset mesh infection cannot be treated solely with antibiotics, expeditious surgery should be selected when subcutaneous drainage fails. When an immunocompromised patient with bacteremia has a complaint of back pain, purulent spinal discitis should also be suspected.

Introduction Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme. Methods Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues. Results Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of seven patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in four patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA. Discussion/Conclusion Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.

Rapid tumor growth after cessation of molecularly targeted drugs, called “disease flare,” may occur and affect the prognosis of lung cancer. However, this phenomenon has never been reported in ROS proto-oncogene 1 (ROS1) fusion-positive lung adenocarcinoma. Herein, we report a disease flare in a patient with ROS1 fusion-positive lung adenocarcinoma. A 60-year-old female was diagnosed with stage IVA ROS1 fusion-positive lung adenocarcinoma via bronchoscopy. Although crizotinib, an ROS1 tyrosine kinase inhibitor, achieved a partial response, a mass lesion appeared in the patient’s right kidney 12 months after starting crizotinib, which was diagnosed pathologically as crizotinib-associated renal cysts (CARCs). Given that readministration of crizotinib repeatedly induced CARC-like aseptic inflammation that appeared to be disseminated around surgical site, crizotinib treatment had to be abandoned. Around 25 days after crizotinib cessation, she was referred to the emergency department with a convulsive seizure and hemiparesis due to new, rapidly growing brain metastases. Whole-brain irradiation and administration of another ROS1 tyrosine kinase inhibitor, entrectinib, markedly ameliorated the metastases and improved hemiparesis. This has been the first report of a disease flare after crizotinib cessation due to CARCs in a patient with ROS1 fusion-positive lung adenocarcinoma. Attention should be paid to disease flare, especially in the brain, when molecularly targeted medication is stopped due to adverse events in ROS1 fusion-positive lung adenocarcinoma. Switching to drugs that penetrate the blood-brain barrier could overcome disease flare in the brain.

Abstract Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.

This paper explores financial spillovers between emerging Asia and advanced economies using principal component analysis to extract common shocks in Asia. We first investigate stock market spillovers across the regions and find that spillovers from emerging Asia became significant after the global financial crisis. However, our industry-level analysis shows that the increased spillovers can be attributed to the first principal component (PC) in the manufacturing sector rather than to the first PC in the financial sector. This implies that the rise of the Asian manufacturing sector in the global market played a key role in enhancing the stock market spillovers. We next examine bilateral spillovers in short-term and long-term rates. In the tapering period, we find significant spillovers in long-term rates from the first PC in emerging Asia to Europe and the United States. However, these spillovers were much smaller than the stock market spillovers in magnitude.

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.

Summary: The patient-derived xenograft (PDX) model is a versatile tool used to study the tumor microenvironment (TME). However, limited studies have described multi-tumor PDX screening strategies to detect hub regulators during cancer-stroma interaction. Transcriptomes of cancer (human) and stroma (mouse) components of 70 PDX samples comprising 9 distinctive tumor types were analyzed in this study. PDX models recapitulated the original tumors' features, including tumor composition and putative signaling. Particularly, kidney renal clear cell carcinoma (KIRC) stood out, with altered hypoxia-related pathways and a high proportion of endothelial cells in the TME. Furthermore, an integrated analysis conducted to predict paracrine effectors in the KIRC cancer-to-stroma communication detected well-established soluble factors responsible for the hypoxia-related reaction and the so-far unestablished soluble factor, apelin (APLN). Subsequent experiments also supported the potential role of APLN in KIRC tumor progression. Therefore, this paper hereby provides an analytical workflow to find hub regulators in cancer-stroma interactions.

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

The number of cancer patients undergoing dialysis has been increasing, and the number of these patients on chemotherapy is also increasing. Imatinib is an effective and safe therapy for KIT-positive gastrointestinal stromal tumors (GIST), but the efficacy and safety of imatinib in dialysis patients remain unclear. Because clinical trials have not been conducted in this population, more investigations are required. We report on a 75-year-old Japanese man undergoing dialysis who presented with massive tarry stool from a duodenal GIST. The duodenal GIST was 14 cm in diameter with multiple liver and bone metastases. The patient underwent an urgent pancreaticoduodenectomy to achieve hemostasis. After surgery, he was administered imatinib 400 mg/day. No severe adverse event including myelosuppression, congestive heart failure, liver functional impairment, intestinal pneumonia, or Steven-Johnson syndrome occurred, and the liver metastasis remained stable for 4 months. During chemotherapy, hemodialysis continued three times per week without adverse events. We suggest that regular-dose imatinib is an effective and safe treatment in patients with GIST undergoing dialysis. In addition, we present a literature review of the effectiveness and safety of imatinib treatment in dialysis patients.

Abstract It is widely accepted that impaired bioavailability of endothelial nitric oxide (NO) plays a critical role in the pathophysiology of pulmonary arterial hypertension (PAH). However, there are published data that show that relatively many PAH patients respond favorably to acetylcholine‐induced pulmonary vasodilation during their follow‐up period, when diverse stages of the disorder are included. We hypothesized that NO bioavailability varies depending on the progression of PAH. Adult rats were exposed to the VEGF receptor blocker Sugen5416 and 3 weeks of hypoxia followed by return to normoxia for various additional weeks. All rats developed increased right ventricular systolic pressure (RVSP) and occlusive lesion formation at 1, 3, 5, and 8 weeks after the Sugen5416 injection. Acute NO synthase blockade did not change the elevated RVSP at the 1‐week time point, while it further increased RVSP markedly at the 3‐, 5‐, and 8‐week time points, leading to death in all rats tested at 8 weeks. Acetylcholine caused significant reduction in RVSP at the 8‐week but not the 1‐week time point, whereas sodium nitroprusside decreased the pressure similarly at both time points. Increased NO‐mediated cGMP production was found in lungs from the 8‐week but not the 1‐week time point. In conclusion, despite its initial impairment, NO bioavailability is restored and endogenous NO plays a critical protective role by counteracting severe pulmonary vasoconstriction in established stages of PAH in the Sugen5416/hypoxia/normoxia‐exposed rats. Our results provide solid pharmacological evidence for a major contribution of a NO‐suppressed vasoconstrictor component in the pathophysiology of established PAH.

The shunt portosystemic or portosystemic deviation (PSD) are unique or multiples vascular communications between the systemic circulaton and the portal circulation, that permit blood flow reaches the circulatory system without first passing trhought the hepatic metabolization. May be acquired or congenital and can also be classified as intrahepatic located within the liver or extrahepatic located outside the liver parenquima. The acquired form is usually associated with intra-hepatic disorders. They usually suggest tortuous vessels that communicate with the caudal vena cava in the region of the left kidney. The congenital form is associated with genetic lineage and one of the most affected is Maltese breed. This case report describes the diagnostis and treatment of a eight year-old female Maltese dog presenting extrahepatic Portosystemic Shunt. The patient showed signs of hepatic encephalopathy, such as restlessnees, weakness, deambulation, head tremor and impaired visual. Complementary exam demonstrated: postprandial glicemia near the lower limit of reference, alkaline phosphatase (ALP) and alanine aminotransferase (ALT) increased and hipoalbuminemia. Ultrasonography revealed the presence of vesical calculus and bilateral kidney, liver decreases and increased echogenicity, gallbladder with anechoic content and high cellularity may suggest liver/ colangiohepatopatia and extrahepatic DPS was detected. The use of Doppler assisted in identifying the location of the bypass communication and the turbulence detecting the extrahepatic DPS. Protein-restricted diet and antibiotic therapy with amoxicillin achieved good results. The clinical treatment was decided make only the clinical and maintain the quality of life of the patient.O shunt portossistêmico ou desvio portossistêmico (DPS) são comunicações vasculares únicas ou múltiplas entre a circulação sistêmica e a circulação portal, que permite que o sangue portal chegue ao sistema circulatório sem antes passar pela metabolização hepática. Podem ser adquiridos ou congênitos e também podem ser classificados como intra-hepático, localizado dentro do fígado, ou extra-hepático, localizado fora do parênquima hepático. A forma adquirida normalmente está associada com distúrbios intra-hepáticos. Eles normalmente sugerem vasos tortuosos que se comunicam com a veia cava caudal na região do rim esquerdo. A forma congênita está associada a genética e uma das linhagens mais acometidas é a raça maltês. O presente relato de caso descreve o diagnóstico e tratamento de uma cadela maltês de oito meses de idade com Shunt portossistêmico extra-hepático. A paciente apresentava sinais de encefalopatia hepática, como: inquietação, locomoção apoiando-se nas paredes, compressão da cabeça contra a parede, tremores de cabeça e deficiência visual. Exames complementares constataram: glicemia pós-prandial próximo do valor inferior de referência, fosfatase alcalina (FA) e alanina aminotransferase (ALT) aumentadas e hipoalbuminemia. A ultra-sonografia revelou a presença de cálculo vesical e cálculo renal bilateral, fígado diminuído e aumento da ecogenicidade, vesícula biliar com conteúdo anecóico e alta celularidade podendo sugerir hepatopatia/ colangiohepatopatia e detectou DPS extra-hepático. O uso do Doppler auxiliou na localização do desvio identificando a comunicação e a turbulência certificando-se do DPS extra-hepático. Dieta com restrição protéica e antibioticoterapia com amoxicilina obtiveram bons resultados. Optou-se em fazer apenas o tratamento clínico e manter a qualidade de vida da paciente.

The present study aimed to determine the types of hemoglobin in Hampshire Down crossbreed sheep, and verify that this locus is in Hardy-Weinberg equilibrium. There have been collected 46 blood samples of healthy Hampshire Down crossbreed sheep. These samples were used to separate the hemoglobin per electrophoresis. The electrophoresis of the hemoglobin revealed a slow band characterized as hemoglobin A (HbAA), a fast band characterized as hemoglobin B (HbBB) and two bands in the heterozygous hemoglobin A and B (HbAB). The HbAB type was the most frequently one, followed by hemoglobin A (HbAA) and B (HbBB). The genotypic frequency of individuals BB, AB and AA were 36,95; 54,35 and 8,70% respectively. The allelic frequency of A and B were respectively 35,87% and 64,13%.. The qui square test (?2 = 0.859 and p = 0.6509) confirmed that the tested locus is in Hardy-Weinberg equilibrium.O presente trabalho teve como objetivo determinar os tipos de hemoglobinas em ovinos Hampshire Down e verificar se este locus encontra-se em equilíbrio de Hardy-Weinberg. Foram coletadas 46 amostras de sangue de ovinos Hampshire Down, considerados clinicamente sadios. Estas amostras foram utilizadas para a separação das hemoglobinas por eletroforese. A eletroforese das hemoglobinas revelou uma banda lenta caracterizada como hemoglobina B (HbBB), uma banda rápida caracterizada como hemoglobina A (HbAA) e duas bandas no heterozigoto para hemoglobinas A e B (HbAB). A variante HbAB foi a mais freqüentemente encontrada, seguida pela hemoglobina A (HbAA) e B (HbBB). A freqüência genotípica dos indivíduos BB, AB e AA foram 36,95; 54,35 e 8,70% respectivamente. A freqüência alélica de A e B foram respectivamente 35,87% e 64,13%. Pelo teste do qui-quadrado realizado (?2 = 0,859 e p=0,6509) confirmou-se que o locus testado está em equilíbrio de Hardy-Weinberg.

Diante da alta incidência de idosos que se encontram hospitalizados atualmente e as inúmeras necessidades apresentadas por eles, o presente estudo tem como objetivo descrever os diagnósticos de enfermagem mais comuns entre 50 iidosas hospitalizadas, as quais foram avaliadas considerando-se ser necessária a continuidade dos cuidados no domicílio. Os autores concluíram que as idosas apresentam diagnósticos em todos os padrões de resposta humana, com destaque para o déficit de conhecimento.