Ectopic ACTH-producing neuroendocrine tumor occurring with large recurrent metastatic pheochromocytoma: a case report.

BACKGROUND: Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases. CASE PRESENTATION: We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with 123I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-ß-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. CONCLUSIONS: We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.

Colorectal paragangliomas with immunohistochemical deficiency of succinate dehydrogenase subunit B.

Recent progress in paraganglioma (PGL) revealed genotype-phenotype relationship, especially succinate dehydrogenase complex subunit B (SDHB) gene mutation-related to the extra-adrenal origin and metastasis. SDHB-immunohistochemistry can detect all types of SDH-subunit mutations, and is a useful tool to detect SDH-mutation tumors. PGLs usually occur along with sympathetic, and parasympathetic chains, however, colorectal paraganglioma is extremely rare. We have experienced one sigmoid colon PGL and one rectal PGL. These colorectal PGLs: a sigmoid colon PGL measuring 25 mm associated with a gastrointestinal stromal tumor (GIST) of the stomach, and a rectal PGL measuring 75 × 45 mm with elevated norepinephrine level were analyzed by immunohistochemistry for INSM1, chromogranin A, synaptophysin, tyrosine hydroxylase, dopamine-beta-hydroxylase, and SDHB and SDHA. The tumors were strongly positive for above markers, however, negative for SDHB. Both PGLs negative for SDHB immunohistochemistry were defined SDHB-deficient PGLs. Histologic grading of the PGLs by GAPP was well differentiated in sigmoid PGL versus poorly differentiated in rectal PGL. Although these PGLs were the same Stage II of TNM classification, the patient with sigmoid colon PGL had neither recurrence nor metastasis for 5 years after the operation, however, the patient with rectal PGL suffered the recurrent multiple metastases and expired 5 years after the operation. Herein, we compared these colorectal PGLs in regard to the patients' prognostic factors. Patient prognosis with these colorectal PGLs was mostly related to the tumor size and histologic grade under the same situation of SDH-deficiency.

A Study of Changes of Physical Functions According to Changes in Cognitive Functions in Community-Dwelling Elderly People Who Participated in an Exercise Program.

Although it is known that physical function differs depending on the state of cognitive function, there are no studies that consider changes in cognitive functions when evaluating physical functions of participants before and after an exercise program. In this study, it was observed changes in cognitive function and physical functions of elderly people who participated in a community-based exercise program for 6 months, and examined changes in physical functions that took into account changes in cognitive functions. Forty-nine participants, whose cognitive and physical functions were both measured before and after the exercise program, were included in the analysis. The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was used to assess participants' cognitive function and to determine whether they had mild cognitive impairment (MCI). To assess physical functions, a battery of physical tests was completed. Participants were classified into four groups (before/after; non-MCI/non-MCI, MCI/MCI, non-MCI/MCI, and MCI/non-MCI) according to the changes in cognitive functions after six months. There was no significant difference in the physical functions of the four groups before the start of the program. When changes in physical functions were examined in each group, some changes in physical functions were observed in the groups other than the non-MCI/MCI group. However, there was no significant difference in the physical functions between the four groups after the program. It was suggested that changes in physical functions of elderly people who participated in a community-based exercise program over a 6-month period were not different due to changes in cognitive functions.

Non-uniform distribution of passive muscle stiffness within hamstring.

Limited information is available on whether stiffness is different within and between the constituents of the hamstring, that is, the biceps femoris long head (BFlh), semitendinosus (ST), and semimembranosus (SM). Therefore, understanding of hamstring injuries and stretching effect on hamstring stiffness is difficult. The present study primarily aimed to identify whether passive muscle stiffness differs between the BFlh, ST, and SM and between the proximal, middle, and distal sites within each muscle. Secondly, the effect of stretching exercise on the heterogeneity in passive muscle stiffness was examined. In the lengthened hamstring positions by extending the knee joint or flexing the hip joint, passive muscle shear modulus (a measure of stiffness) at the proximal, middle, and distal sites of the BFlh, ST, and SM was measured by using ultrasound shear wave elastography. Furthermore, before and after five repetitions of 90-seconds static stretching for the hamstring, passive muscle shear modulus at the proximal and distal sites of the SM was measured. The shear modulus was significantly higher in the SM than in the BFlh and ST and higher at the distal site than the proximal site in all muscles. After the stretching, the higher shear modulus at the distal site of the SM compared to the proximal site was still observed (pre-stretching: +80%, post-stretching: +81%). These findings indicate that passive muscle stiffness varies within the hamstring regardless of performing stretching exercise and that passive muscle stiffness is not highest at the proximal site of the SM where a stretching-type hamstring strain typically occurs.

COL5A1 rs12722 polymorphism is not associated with passive muscle stiffness and sports-related muscle injury in Japanese athletes.

BACKGROUND: Poor joint flexibility has been repeatedly proposed as a risk factor for muscle injury. The C-to-T polymorphism (rs12722) in the 3'-untranslated region of the collagen type V α1 chain gene (COL5A1) is reportedly associated with joint flexibility. Flexibility of a normal joint is largely determined by passive muscle stiffness, which is influenced by intramuscular collagenous connective tissues including type V collagen. The present study aimed to test the hypothesis that the COL5A1 rs12722 polymorphism influences joint flexibility via passive muscle stiffness, and is accordingly associated with the incidence of muscle injury. METHODS: In Study 1, we examined whether the rs12722 polymorphism is associated with joint flexibility and passive muscle stiffness in 363 healthy young adults. Joint flexibility was evaluated by passive straight-leg-raise and sit-and-reach tests, and passive muscle stiffness was measured using ultrasound shear wave elastography. In Study 2, the association of the rs12722 polymorphism with sports-related muscle injury was assessed in 1559 Japanese athletes. Muscle injury history and severity were assessed by a questionnaire. In both Study 1 and Study 2, the rs12722 C-to-T polymorphism in the COL5A1 was determined using the TaqMan SNP Genotyping Assay. RESULTS: Study 1 revealed that the rs12722 polymorphism had no significant effect on range of motion in passive straight-leg-raise and sit-and-reach tests. Furthermore, there was no significant difference in passive muscle stiffness of the hamstring among the rs12722 genotypes. In Study 2, rs12722 genotype frequencies did not differ between the muscle injury and no muscle injury groups. Moreover, no association was observed between rs12722 polymorphism and severity of muscle injury. CONCLUSIONS: The present study does not support the view that COL5A1 rs12722 polymorphism has a role as a risk factor for sports-related muscle injury, or that it is a determinant for passive muscle stiffness in a Japanese population.

SMARCB1/INI1/BAF47- deficient pleural malignant mesothelioma with rhabdoid features.

Malignant mesothelioma (MM) with rhabdoid features is an MM variant. Fifteen cases have been reported previously, all of which were combined with other types of MM. Herein, we report an autopsy case of pleural MM with monomorphic rhabdoid features. The patient was a 62-year-old male without a history of asbestos exposure. An autopsy revealed a soft, granular tumor that replaced the entire left pleura and had invaded to the diaphragm and lower lobe of the lung. The tumor cells, which had eosinophilic plump cytoplasm and eccentric nuclei, were loosely cohesive. Immunohistochemistry showed that the cells were diffusely positive for calretinin, D2-40, vimentin, CAM5.2, and AE1/AE3; and negative for WT-1, TTF-1, CK7, CEA, desmin, CD34, BCL-2, S100 protein, and p40. Neither homozygous deletion of p16 nor BAP-1 protein loss was observed. Loss of INI1/BAF47 protein, an indicator of malignant rhabdoid tumor, was observed. Therefore, MM with rhabdoid features was confirmed.

A Novel SDHB IVS2-2A>C Mutation Is Responsible for Hereditary Pheochromocytoma/Paraganglioma Syndrome.

Pheochromocytomas and paragangliomas are neuroendocrine tumors which arise from adrenal medulla, and sympathetic or parasympathetic nerves, respectively. Hereditary cases afflicted by both or either pheochromocytomas and paragangliomas have been reported: these are called hereditary pheochromocytoma/paraganglioma syndromes (HPPS). Many cases of HPPS are caused by mutations of one of the succinate dehydrogenase (SDH) genes; mainly SDHB and SDHD that encode subunits for the mitochondrial respiratory chain complex II. In this study, we investigated mutations of SDH genes in six HPPS patients from four Japanese pedigrees using peripheral blood lymphocytes (from one patient with pheochromocytoma and five patients with neck paraganglioma) and tumor tissues (from two patients with paraganglioma). Results showed that all of these pedigrees harbor germline mutations in one of the SDH genes. In two pedigrees, a novel IVS2-2A>C mutation in SDHB, at the acceptor-site in intron 2, was found, and the tumor RNA of the patient clearly showed frameshift caused by exon skipping. Each of the remaining two pedigrees harbors a reported missense mutation, R242H in SDHB or G106D in SDHD. Importantly, all these mutations are heterozygous in constitutional DNAs, and two-hit mutations were evident in tumor DNAs. We thus conclude that the newly identified IVS2-2A>C mutation in SDHB is responsible for HPPS. The novel mutation revealed by our study may contribute to improvement of clinical management for patients with HPPS.

Contributions of Hamstring Stiffness to Straight-Leg-Raise and Sit-and-Reach Test Scores.

The passive straight-leg-raise (PSLR) and the sit-and-reach (SR) tests have been widely used to assess hamstring extensibility. However, it remains unclear to what extent hamstring stiffness (a measure of material properties) contributes to PSLR and SR test scores. Therefore, we aimed to clarify the relationship between hamstring stiffness and PSLR and SR scores using ultrasound shear wave elastography. Ninety-eight healthy subjects completed the study. Each subject completed PSLR testing, and classic and modified SR testing of the right leg. Muscle shear modulus of the biceps femoris, semitendinosus, and semimembranosus was quantified as an index of muscle stiffness. The relationships between shear modulus of each muscle and PSLR or SR scores were calculated using Pearson's product-moment correlation coefficients. Shear modulus of the semitendinosus and semimembranosus showed negative correlations with the two PSLR and two SR scores (absolute r value≤0.484). Shear modulus of the biceps femoris was significantly correlated with the PSLR score determined by the examiner and the modified SR score (absolute r value≤0.308). The present findings suggest that PSLR and SR test scores are strongly influenced by factors other than hamstring stiffness and therefore might not accurately evaluate hamstring stiffness.

Cardiac paraganglioma with a novel germline mutation of succinate dehydrogenase gene D.

A 58-year-old woman with a past medical history of a carotid body tumor, resected 4 months prior to presentation, was admitted to our hospital for treatment of a cardiac tumor that was identified on post-operative echocardiography and chest computed tomography. The cardiac tumor was surgically removed and identified pathologically as a paraganglioma, similarly to the carotid body tumor. Genetic analysis of both tumors identified a non-synonymous mutation in the succinate dehydrogenase (SDH) gene D, Exon4, c.320T>C, p.Leu107Pro showing co-segregation with paternal transmission and maternal imprinting among family members. This novel mutation appears to be the cause of familial paraganglioma in this patient.

Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl.

Germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene (SDHB) cause susceptibility to paragangliomas and pheochromocytomas; however, it is exceedingly rare in childhood and especially in sporadic cases. We report the first Japanese pediatric case of paraganglioma with a de novo mutation in the SDHB gene. A 6-year-old girl with convulsions and hypertension was found to have a paravertebral abdominal tumor. Urinary and blood examinations revealed markedly elevated levels of norepinephrine. Following treatment for hypertension, the tumor was removed completely and histological findings were consistent with paraganglioma. Immunohistochemistry studies demonstrated the absence of SDHB protein expression, indicating an underlying SDH mutation with high probability. Germline mutation analysis of the SDHB gene revealed a heterozygous splice site mutation in intron 4 (C.423 + 1G > A). Subsequently, a second somatic genetic change was confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis, showing that deletion of the wild-type allele resulted in loss of function of SDHB. No germline mutations in SDHB were detected in her parents. CONCLUSION: Genetic testing should be considered for pediatric patients with paragangliomas, even in the absence of familial history, as closer lifelong screening to detect the development of malignancy will be required for patients with SDHB mutations. WHAT IS KNOWN: Most sporadic cases of paraganglioma with SDHB mutations occur between adolescence and adulthood. Screening methods for carriers of SDHB mutations assessing recurrence and detecting developing metastases are yet to be standardized. WHAT IS NEW: The current case of an extra-adrenal paraganglioma with a de novo SDHB mutation had an onset at 6 years. We suggest much closer periodical observation for these high-risk children.

Time lag between the initiation of adalimumab after methotrexate correlates with the efficacy of adalimumab in rheumatoid arthritis patients.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab (ADA) and methotrexate (MTX) in patients with rheumatoid arthritis (RA) and investigate critical factors associated with efficacy. METHODS: In this retrospective cohort study, patients received ADA at a single facility. Clinical outcome was retrospectively evaluated using the Disease Activity Score in 28 joints with Erythrocyte Sedimentation Rate (DAS28-ESR). RESULTS: Of the 122 patients undergoing treatment with ADA between July 2008 and April 2014, DAS28-ESR data after 6 months of treatment were available for 103 and 87 (84.5%) were treated with a combination of ADA and MTX. For combination therapy, time lag between MTX and the initiation of ADA significantly correlated with efficacy of ADA at 6 months, as well as prior use of biologics, but not disease duration. CONCLUSIONS: Clinical outcomes were correlated with the time lag between MTX and the initiation of ADA, not disease duration. Early initiation of ADA after MTX might improve clinical outcomes.

Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity-results from the ENCOURAGE study, a prospective, international, multicenter randomized study.

OBJECTIVES: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission. METHODS: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2). RESULTS: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation. CONCLUSIONS: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.

Phenobarbital reduces blood glucose and gluconeogenesis through down-regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression in rats.

The regulatory mechanism of phosphoenolpyruvate carboykinase (GTP) (EC 4.1.1.32) (PEPCK) gene expression and gluconeogenesis by phenobarbital (PB), which is known to induce drug-metabolizing enzymes, was investigated. Higher level of PEPCK mRNA was observed in spherical rat primary hepatocytes on EHS-gel than monolayer hepatocytes on TIC (type I collagen). We found that PB directly suppressed PEPCK gene expression in spherical hepatocytes on EHS-gel, but not in those on TIC. PB strongly suppressed cAMP-dependent induction of PEPCK gene expression. Tyrosine aminotransferase (TAT), another gluconeogenic enzyme, was induced by cAMP, but not suppressed by PB. Chronic administration of PB reduced hepatic PEPCK mRNA in streptozotocin-induced diabetic and nondiabetic rats, and PB reduced blood glucose level in diabetic rats. Increased TAT mRNA in diabetic rats was not suppressed by PB. These results indicated that PB-dependent reduction is specific to PEPCK. From pyrvate challenge test, PB suppressed the increased gluconeogenesis in diabetic rats. PEPCK gene promoter activity was suppressed by PB in HepG2 cells. In conclusion, we found that spherical hepatocytes cultured on EHS-gel are capable to respond to PB to suppress PEPCK gene expression. Moreover, our results indicate that hypoglycemic action of PB result from transcriptional repression of PEPCK gene and subsequent suppression of gluconeogenesis.

Ulcerated Stenosis of the Small Intestine Associated With Hepatic Portal Venous Gas After Treatment for Cytomegalovirus Enteritis: A Case Report.

Due to its rarity, cytomegalovirus (CMV) enteritis remains poorly described with regard to its endoscopic and radiological findings. A 75-year-old woman was admitted to our hospital with abdominal pain and was treated with an antiviral agent for CMV enteritis. She was readmitted to our hospital 10 days after discharge due to a recurrence of abdominal pain. Emergency computed tomography revealed hepatic portal venous gas (HPVG) and ileal dilatation involving focal stenosis of the ileum. The patient underwent laparoscopic partial resection of the small intestine and was finally diagnosed with ulcered stenosis of the small intestine after treatment for CMV enteritis. This report represents a valuable addition to the literature describing a rare case of ulcerated stenosis of the small intestine associated with HPVG after treatment for CMV enteritis.

Potassium-competitive acid blocker-associated gastric mucosal lesions.

Since the introduction of vonoprazan, a potassium-competitive acid blocker (P-CAB), it has been demonstrated to reversibly inhibit gastric acid secretion by engaging in potassium-competitive ionic binding to H+/K+-ATPase. In contrast, proton pump inhibitors (PPIs) achieve H+/K+-ATPase inhibition through covalent binding to cysteine residues of the proton pump. Reported cases have indicated an emerging trend of P-CAB-related gastropathies, similar to those associated with PPIs, as well as unique gastropathies specific to P-CAB use, such as the identification of web-like mucus. Pathologically, parietal cell profusions, which show a positively correlated with hypergastrinemia, have a higher incidence in P-CAB users compared to PPI users. Thus, this review aims to summarize the endoscopic and pathological findings reported to date concerning P-CAB-related gastric mucosal lesions. Additionally, it seeks to discuss the differences between the PPIs and P-CABs in terms of the formation and frequency of associated gastropathies. This review highlights the evident differences in the mechanism of action and potency of acid inhibition between P-CABs and PPIs, notably contributing to differences in the formation and frequency of associated gastropathies. It emphasizes the necessity to distinguish between P-CAB-related and PPI-related gastropathies in the clinical setting.

Emergency Endoscopic Hemostasis Using the Endoscopic Mucosal Resection Technique for Severe Bleeding From Early Gastric Cancer: A Case Report.

Bleeding from gastric cancer may lead to severe anemia and hypovolemic shock, and can be a life-threatening condition in affected patients; thus, achieving hemostasis is essential to improving their clinical course. While endoscopic hemostasis is recommended as the hemostatic modality of first choice, endoscopic hemostasis involving the endoscopic mucosal resection (EMR) technique is also being used, though under-reported. An 85-year-old man diagnosed with bleeding from gastric cancer was raced to our hospital for hemostasis. Emergency esophagogastroduodenoscopy (EGD) revealed a 45 mm-sized elevated lesion involving the coagula due to dripping bleeding from the surface of the posterior wall of the gastric lower body. EMR was performed without any technical difficulty, and hemostasis was achieved immediately. The patient was discharged without rebleeding. This case appears to support the usefulness of EMR as an emergency endoscopic hemostatic modality for severe bleeding from early gastric cancer.

A Case of Duodenal Adenocarcinoma Effectively Highlighted by Linked Color Imaging and Confirmed by Histopathology.

While the differential diagnosis of duodenal adenocarcinoma versus adenoma remains the key to determining treatment strategies in patients with suspected duodenal adenocarcinoma, the role of linked color imaging (LCI) in their differential diagnosis remains insufficiently documented. In this case, esophagogastroduodenoscopy (EGD) was performed on a 67-year-old man for anemia, which revealed a 20-mm-sized, whitish, partially reddish, pedunculated lesion located in the duodenal bulb on white light imaging. Using LCI, the lesion was highlighted as a whitish, pedunculated lesion with its central and inferior areas depicted as orangish and reddish, respectively. Endoscopic mucosal resection was performed on the suspicion of an adenocarcinoma for biopsy and endoscopic diagnosis. Histological examination revealed the lesion to be an adenocarcinoma contained in an adenoma: papillary, type 0-Ip, measuring 20x20 mm, pTis (M), involving no lymphovascular invasion. This case appears to underpin the usefulness of LCI in the differential diagnosis of duodenal adenocarcinoma.

Mixed invasive mucinous and non-mucinous adenocarcinoma of the lung with hematogenous metastases to multiple organs.

Mixed invasive mucinous and non-mucinous adenocarcinoma is a rare variant of lung adenocarcinoma. In pure invasive mucinous adenocarcinoma, multilobar and bilateral involvement are common, and extrathoracic metastasis is rare. Here, we report a case of mixed invasive mucinous and non-mucinous adenocarcinoma with distant metastasis to multiple organs without marked enlargement of the primary lung lesion. The pathological findings indicated high tumor invasiveness and the patient died 10 months after diagnosis despite chemoimmunotherapy. Further investigations are necessary to elucidate the clinical characteristics and appropriate management of mixed invasive mucinous and non-mucinous adenocarcinoma.