Substitution of Glu to Lys at Codon 332 on the GFAP Gene Alone Is Causative for Adult-onset Alexander Disease.

A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.

Successful Rituximab Therapy for Skin Sclerosis and Myositis in a Patient With Systemic Sclerosis, Myositis and Sjögren's Syndrome Associated With Autoimmune Polyendocrine Syndrome Type 2.

Autoimmune polyendocrine (or polyglandular) syndrome (APS) is a relatively rare clinical condition characterized by functional impairment of multiple endocrine glands due to loss of immune tolerance. APS is broadly categorized as rare monogenic forms, such as autoimmune polyendocrine syndrome type 1 (APS-1), and a more common polygenic variety, autoimmune polyendocrine syndrome type 2 (APS-2). Although many autoimmune conditions including autoimmune rheumatic diseases can develop in APS-2, systemic sclerosis or myositis as a complication is quite rare and no treatment strategy has yet been established. A 25-year-old man who had been diagnosed as having type 1 diabetes developed finger stiffness. Although the subjective symptoms were relatively mild, extensive examinations including various autoantibodies, hormones and biopsy of the skin and minor salivary glands revealed that he had APS-2 (type 1 diabetes and autoimmune thyroid disease) accompanied by systemic sclerosis, myositis and Sjögren's syndrome. Rituximab therapy was initiated for the progressive skin sclerosis, and this resulted in significant alleviation of both the sclerosis and the myositis. In APS, early diagnosis and immunomodulatory therapy may arrest the autoimmune process before irreversible organ damage has occurred. This case report suggests that rituximab may be a promising therapy for autoimmune rheumatic diseases associated with APS-2.

Design, synthesis, and pharmacological evaluation of N-(3-carbamoyl-1H-pyrazol-4-yl)-1,3-oxazole-4-carboxamide derivatives as interleukin-1 receptor-associated kinase 4 inhibitors with reduced potential for cytochrome P450 1A2 induction.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical molecule in Toll-like receptor/interleukin-1 receptor signaling and an attractive therapeutic target for a wide range of inflammatory and autoimmune diseases as well as cancers. In our search for novel IRAK4 inhibitors, we conducted structural modification of a thiazolecarboxamide derivative 1, a lead compound derived from high-throughput screening hits, to elucidate structure-activity relationship and improve drug metabolism and pharmacokinetic (DMPK) properties. First, conversion of the thiazole ring of 1 to an oxazole ring along with introduction of a methyl group at the 2-position of the pyridine ring aimed at reducing cytochrome P450 (CYP) inhibition were conducted to afford 16. Next, modification of the alkyl substituent at the 1-position of the pyrazole ring of 16 aimed at improving CYP1A2 induction properties revealed that branched alkyl and analogous substituents such as isobutyl (18) and (oxolan-3-yl)methyl (21), as well as six-membered saturated heterocyclic groups such as oxan-4-yl (2), piperidin-4-yl (24, 25), and dioxothian-4-y (26), are effective for reducing induction potential. Representative compound AS2444697 (2) exhibited potent IRAK4 inhibitory activity with an IC50 value of 20 nM and favorable DMPK properties such as low risk of drug-drug interactions mediated by CYPs as well as excellent metabolic stability and oral bioavailability.

Tumor-to-tumor metastasis of colon cancer metastasizing to a pancreatic neuroendocrine tumor associated with von Hippel-Lindau disease: a case report.

Von Hippel-Lindau disease (VHL) is frequently associated with pancreatic neuroendocrine tumors (PNETs). Here, we report a case of tumor-to-tumor metastasis in a VHL patient in whom colon cancer metastasized to the interior of a PNET. A 65-year-old man had undergone bilateral adrenalectomy for pheochromocytomas in both adrenal glands in his 50 s. Genetic screening was performed considering his family history of pheochromocytoma, and he was diagnosed with VHL. PNET was detected, for which the patient was regularly monitored by follow-up imaging. One year ago, the patient underwent right hemicolectomy to remove a tumor in the ascending colon (pT3N0M0, pStage IIA). He was admitted to our department for detailed examination because the pancreatic tumor had grown, and thus, pancreaticoduodenectomy was performed. Diagnostic imaging and histological findings indicated tumor-to-tumor metastasis, in which the patient's previous colon cancer had metastasized to and proliferated within the PNET. Colon cancer metastasizing to a PNET is extraordinarily rare and has never been reported in the literature. Thus, practitioners should be vigilant for tumor-to-tumor metastasis when performing imaging surveillance of PNETs.

[A case of meningeal melanomatosis diagnosed by immunostaining of cerebrospinal fluid].

A 49-year-old woman was admitted to our hospital with suspected hypertensive encephalopathy. On the basis of MRI showing leptomeningeal enhancement and Class V cytology of the CSF, she was diagnosed as having leptomeningeal carcinomatosis. Although no primary site was detected, a few melanin granules were observed at the third CSF examination. The atypical cells in the CSF demonstrated immunoreactivity for HMB-45 and S-100, which are specific markers of malignant melanoma. There have been few reports of meningeal melanomatosis in Japan. This case illustrates that immunostaining is diagnostically useful in patients with leptomeningeal carcinomatosis from neoplasms with unknown primary sites.

Correction to: Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme.

The legends of Figs. 1 and 3 in the published original version of the above article are incorrect.

Primary Intracranial Malignant Epidermoid with Multiple Metastases in Internal Organs: A Rare Autopsy Case.

Primary intracranial malignant epidermoids are rare, with most cases developing from a pre-existing benign epidermoid cyst. We report a case involving a rare autopsy finding of a primary intracranial malignant epidermoid in the brainstem with cerebellopontine angle (CPA) involvement. A 53-year-old woman with double vision was diagnosed with right abducens palsy. At her visit to our hospital 3 months after the onset of the first symptom, she presented left hypoglossal nerve paralysis and truncal ataxia in addition to right abducens palsy. Magnetic resonance imaging (MRI) revealed a mass lesion (2-cm long and 3-cm thick) in the left CPA that exhibited gadolinium enhancement. Moreover, gadolinium-enhanced magnetic resonance imaging (MRI) revealed abnormal multiple brainstem and supratentorial mass lesions with partial enhancement. Whole-body computed tomography failed to identify any possible primary lesion. Following a tentative diagnosis of an epidermoid cyst with an assumption that the tumor was highly aggressive, we performed subtotal surgical resection of the CPA tumor. Histological findings revealed a malignant epidermoid in the CPA lesion. Although the patient underwent radiation and chemotherapy after the surgical resection, she died of respiratory failure 10 months after the onset of symptoms. Herein, we report the rare clinical course and autopsy data, and discuss the characteristic features of this rare condition.

Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme.

A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5-10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with three-tiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff's alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient's age (> 65 vs ≤ 65), lymph node and/or distant metastasis, and the two-tiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multi-institutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.

Tubulointerstitial nephritis with monotypic lympho-plasmacytic infiltrates in a patient with primary Sjögren's syndrome accompanied by IgA-type monoclonal gammopathy.

BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

Classic Chromophobe Renal Cell Carcinoma Incur a Larger Number of Chromosomal Losses Than Seen in the Eosinophilic Subtype.

Chromophobe renal cell carcinoma (chRCC) is a renal tumor subtype with a good prognosis, characterized by multiple chromosomal copy number variations (CNV). The World Health Organization (WHO) chRCC classification guidelines define a classic and an eosinophilic variant. Large cells with reticular cytoplasm and prominent cell membranes (pale cells) are characteristic for classic chRCC. Classic and eosinophilic variants were defined in 42 Swiss chRCCs, 119 Japanese chRCCs and in whole-slide digital images of 66 chRCCs from the Cancer Genome Atlas (TCGA) kidney chromophobe (KICH) dataset. 32 of 42 (76.2%) Swiss chRCCs, 90 of 119 (75.6%) Japanese chRCCs and 53 of 66 (80.3%) TCGA-KICH were classic chRCCs. There was no survival difference between eosinophilic and classic chRCC in all three cohorts. To identify a genotype/phenotype correlation, we performed a genome-wide CNV analysis using Affymetrix OncoScan® CNV Assay (Affymetrix/Thermo Fisher Scientific, Waltham, MA, USA) in 33 Swiss chRCCs. TCGA-KICH subtypes were compared with TCGA CNV data. In the combined Swiss and TCGA-KICH cohorts, losses of chromosome 1, 2, 6, 10, 13, and 17 were significantly more frequent in classic chRCC (p < 0.05, each), suggesting that classic chRCC are characterized by higher chromosomal instability. This molecular difference justifies the definition of two chRCC variants. Absence of pale cells could be used as main histological criterion to define the eosinophilic variant of chRCC.

Case of early-stage gastric cancer identified in the gastric mucosa with lanthanum phosphate deposition.

Background and study aims A 78-year-old man with Helicobacter pylori infection had been undergoing hemodialysis for chronic renal failure and receiving lanthanum carbonate preparations for 3 years. Endoscopy revealed fine white granular discoloration throughout the stomach, a moderately reddish depression on the lesser curvature of the gastric angle, and white granular discoloration in the surrounding area. A magnified image using narrow-band imaging showed that the depressed part had irregular vascular and pit structures. We established a diagnosis of intramucosal gastric cancer and performed endoscopic submucosal dissection. Histopathological examination revealed a well-differentiated adenocarcinoma that was confined to the mucosa of the depressed area. Moreover, using an electron probe microanalyzer-equipped electron microscope, we found that the degree of lanthanum deposition was lower in the tumor region than in the non-tumor region. Thus, the current case can help in understanding the relationship between lanthanum deposition and early-stage gastric cancer. Because gastric cancers can occur in lanthanum deposit-containing mucosa, esophagogastroduodenoscopy should be used carefully after understanding the characteristics of early- stage gastric cancer in such cases.

[A case of chordoma presenting as recurrent bacterial meningitis with cerebrospinal fluid leakage].

A 52-year-old man was admitted to our hospital because of two episodes of bacterial meningitis within a 6-month period. CSF examination showed neutrophilic pleocytosis with marked elevation of protein and hypoglycorrhachia, but the inflammatory reaction was mild and blood and CSF cultures were negative. At the time of the second admission, intermittent watery nasal discharge caused by CSF rhinorrhea was evident. CT and MR imaging revealed a tiny clival bone defect, and transnasal endoscopic repair was performed successfully. The pathological diagnosis was chordoma based on immunohistochemical staining for brachyury. Although chordoma presenting as recurrent bacterial meningitis occurs extremely rare, asking patients detailed questions about the CSF rhinorrhea must be essential for disclosing unclear infection sources.

Appearance of large scavenger receptor A-positive cells in peripheral blood: A potential risk factor for severe exacerbation of chronic obstructive pulmonary disease.

Fresh peripheral blood (PB) samples from 432 outpatients with stable chronic obstructive pulmonary disease (COPD) were examined. Patients were classified into Group A (large SRA+ cells were undetected) and Group B (large SRA+ cells were detected) and followed-up for 1 year. Patients were further subdivided according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Cox proportional hazard model had shown that Gold, Group, home oxygen therapy (HOT), and treatment were significant predictors of severe exacerbation. Six of 353 patients in Group A and 29 of 79 in Group B developed severe exacerbation. The rates of severe exacerbation were significantly higher in Group B patients, GOLD stage 2 than Group A, GOLD stage 2; in Group B, GOLD stage 3 than Group A, GOLD stage 3; and in all of Group B compared with in all of Group A. The Kaplan-Meier curves of Group B, GOLD stages 1-4, and of all of Group B showed significantly worse rates of severe exacerbation than those of Group A, Gold 1-4, and all of Group A, respectively. The appearance of large SRA+ cells in the PB of patients with stable COPD may represent a useful biomarker for severe COPD exacerbation.

A case of normotensive incidentally discovered adrenal pheochromocytoma.

Pheochromocytomas are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla. The clinical presentation includes headache, palpitation, and hypertension, but pheochromocytomas are sometimes clinically silent. The present case highlights the importance of biochemical testing for pheochromocytoma in patients with adrenal incidentaloma, even if they are completely normotensive and asymptomatic.

Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors.

Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.

Gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor: a case of a rare malignancy.

BACKGROUND: A gastric adenosquamous carcinoma (ASC) that produces granulocyte-colony stimulating factor (G-CSF) is an uncommon malignancy with a poor prognosis. Due to the rarity of this lesion, a standard treatment for the disease has not been established. CASE PRESENTATION: We describe a case of a 66-year-old male with a G-CSF-producing gastric ASC who presented with severe anemia and leukocytosis. A radical resection was performed, followed by a course of adjuvant chemotherapy. Histopathologic examination revealed that the tumor consisted of areas of both squamous cell carcinoma and adenocarcinoma. Immunohistochemical staining with an anti-G-CSF antibody was also positive. He was started on adjuvant capecitabine and oxaliplatin (CapeOX) 6 weeks after surgery. The patient stopped treatment after 3 months due to his own preference. Eight months following surgery, the patient was found to have diffuse lymph node, liver, and peritoneal metastases. CONCLUSIONS: G-CSF-producing gastric ASC is a rare and aggressive tumor. Because patients are usually diagnosed at an advanced stage, multidisciplinary evaluation and innovative treatments are needed. The rarity of this disease, with its aggressive features, poses a significant challenge in its treatment. In this brief case report, we summarize the management and outcomes of G-CSF-producing gastric ASC.

Lung adenocarcinoma and adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by heterozygous germline mutations in the tumor suppressor gene MEN1, which encodes a nuclear protein, menin. MEN1 is characterized by the combined occurrence of tumors involving the pituitary gland, pancreatic islets, and parathyroid glands. Additionally, patients with MEN1 often exhibit adrenal tumors. Although most MEN1-associated tumors are benign, malignant lesions arising in these endocrine organs have been reported. Additionally, malignant diseases of non-endocrine organs concomitant with MEN1 have also been reported. Here, we report a rare case of a MEN1 patient who exhibited adrenocortical carcinoma (ACC) and lung adenocarcinoma (LAC). A 53-year-old Japanese woman was diagnosed with genetically proven MEN1 that initially manifested as parathyroid, pancreatic, and adrenal tumors. During the course of the disease, she developed LAC harboring the epidermal growth factor receptor gene mutations and cortisol-secreting ACC. Both tumors were surgically resected. The tumor cells were immunohistochemically negative for menin. Studies have suggested a causative link between MEN1 gene mutations and ACC, and menin expression may decrease in MEN1-related ACCs. In contrast, there are few reports suggesting a specific role of MEN1 gene mutations in LAC. Menin is often inactivated in the LACs of patients without MEN1. Thus, our patient's ACC probably occurred as part of MEN1, whereas the latter had no evident etiological association with her LAC. This case demonstrates the need for physicians to consider the potential development of malignant diseases originating from both endocrine and non-endocrine organs in MEN1 patients.

Acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.

BACKGROUND: The pathophysiologic mechanisms underlying acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not fully understood. Few studies have examined autopsy findings in patients who have died from an acute exacerbation of IPF. The pathologic findings in systemic organs have not been described. METHODS: We retrospectively reviewed the autopsy findings in 12 patients who had died from an acute exacerbation of IPF and two of connective tissue disease- associated interstitial lung disease between 2005 and 2015. We recorded demographic and clinical characteristics, autopsy findings and cytologic findings in peripheral blood. RESULTS: The median age at autopsy was 68 years (range 45-87 years); 11 subjects (78.5 %) were men. High-dose corticosteroid, cyclophosphamide and oxygen therapy had been administered to all patients. Underlying lesions had the usual interstitial pneumonia pattern; diffuse alveolar damage and contraction band necrosis were observed in all cases. Large cells expressing scavenger receptor A (SRA+) had been observed in the systemic circulation of 11 of the 14 cases (78.6 %) before acute exacerbation, and cells expressing tumor necrosis factor-α (TNF-α+) were detected after its diagnosis in nine (64.3 %). Both were detected in all cases at autopsy. There was neutrophil and platelet accumulation predominantly in capillaries, and extensive capillary endothelial cells injury. CONCLUSIONS: Our findings suggest that acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.

Histopathological analysis of spontaneous large necrosis of adrenal pheochromocytoma manifested as acute attacks of alternating hypertension and hypotension: a case report.

BACKGROUND: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors. Hypertension secondary to pheochromocytoma is often paroxysmal, and patients occasionally present with sudden attacks of alternating hypertension and hypotension. Spontaneous, extensive necrosis within the tumor that is associated with catecholamine crisis is an infrequent complication of adrenal pheochromocytoma, but its pathogenesis remains unclear. CASE PRESENTATION: A 69-year-old Japanese man developed acute-onset episodic headaches, palpitations, and chest pains. During the episodes, both marked fluctuations in blood pressure (ranging from 40/25 to 300/160 mmHg) and high plasma levels of catecholamines were found simultaneously. Radiological findings indicated a 4-cm left adrenal pheochromocytoma. These episodic symptoms disappeared within 2 weeks with normalization of plasma catecholamine levels. Two months later, the patient underwent adrenalectomy. Microscopic examinations revealed pheocromocytoma with a large central area of coagulative necrosis. The necrotic material was immunohistochemically positive for chromogranin A. Granulation tissue was adjacent to the necrotic area, accompanied by numerous hemosiderin-laden macrophages and histiocytes with vascular proliferation. Viable tumor cells, detected along the periphery of the tumor, demonstrated pyknosis, and the Ki-67 labeling index was 2 % in the hot spot. No embolus or thrombus formation was found in the resected specimen harboring the whole tumor. The Pheochromocytoma of the Adrenal gland Scaled Score was 2 out of 20. The patient's postoperative course was unremarkable for > 7 years. CONCLUSIONS: Presumed causal factors for the extensive necrosis of adrenal pheochromocytoma in previously reported cases include hemorrhage into the tumor, hypotension induced by a phentolamine administration, embolic infarction, high intracapsular pressure due to malignant growth of the tumor, and catecholamine-induced vasoconstriction. In the present case, histopathological and clinical findings suggest that under conditions of chronic ischemia due to catecholamine-induced vasoconstriction, an acute infarction occurred after sudden attacks of alternating hypertension and hypotension. Over the subsequent 2 weeks, repetitive massive release of catecholamines from the infarcts into circulation likely accelerated infarction progression by causing repeated attacks of alternating hypertension and hypotension and resulted in the large necrosis. This case highlights the need for physicians to consider acute spontaneous tumor infarction accompanying episodic catecholamine crisis as a rare but severe complication of pheochromocytoma.