Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis.

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in plasma adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of plasma ACTH and serum cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in plasma ACTH and serum cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in plasma ACTH and serum cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9­48.3) (pre) to 64.4 (46.5­106.2) (peak) pg/mL (1.72­fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in plasma ACTH and serum cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of plasma ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of plasma ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, plasma ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.

Treatment preferences among Japanese patients and physicians for epidermal growth factor receptor-mutant non-small cell lung cancer.

INTRODUCTION: Evidence is limited on preferences of Japanese patients and physicians in treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Several oral or intravenous novel agents for EGFR exon 20 insertions are under development. The aim of our study was to investigate which attributes of novel treatments influenced selection of oral or intravenous agents among treated patients and treating physicians in Japan. METHODS: The study was designed by board-certified oncologists, patient representatives, and analytics specialists. Eligible participants completed an online survey with a discrete choice experiment presenting two treatment profiles described by attributes: mode of administration (oral or intravenous); frequency of administration; overall response rate (ORR); average progression-free survival (PFS); chance of experiencing severe side effects (SEs); mild-moderate gastrointestinal SEs; mild-moderate skin-related SEs; and patient out-of-pocket costs. RESULTS: Fifty-four patients (all self-reported EGFR-mutant) and 74 physicians participated from December 2021 to August 2022. All attributes being equal, there was greater preference for oral administration. However, there was greater preference for intravenous over oral, when ORR and PFS improved by 10% and 1 month, and severe SEs reduced by 10%. Physicians exhibited greater preference for PFS compared to patients (p < 0.01). Ranked order of attribute importance was as follows: (1) PFS; (2) ORR; (3) severe SEs, expressed by patients and physicians alike. CONCLUSIONS: Our study revealed Japanese physician and patient preferences in treatment options for EGFR-mutant NSCLC. Compared to the strong preference for a more efficacious drug, the preference of oral versus intravenous revealed a smaller impact.

The combination of doxazosin and metyrosine as a preoperative treatment for pheochromocytomas and paragangliomas.

PURPOSE: Preoperative medical management is critical to prevent intraoperative cardiovascular complications in patients with pheochromocytomas and paragangliomas (PPGLs). Initial treatment involves α-adrenergic receptor blockers. However, while the routine use of metyrosine alongside these blockers is not strongly recommended due to a lack of evidence supporting its efficacy and associated safety concerns, there are previous studies on combination therapy with phenoxybenzamine and metyrosine. There are few reports on combination therapy with the selective α1-adrenergic receptor blocker doxazosin. Therefore, we investigated this combination treatment, which theoretically can affect perioperative outcomes in patients with PPGLs. To our knowledge, this is the first such study. METHODS: This retrospective single-center observational study involved 51 patients who underwent surgical resection of PPGLs at Kobe University Hospital between 2014 and 2022. All patients received doxazosin at maximum doses. Fourteen patients received concomitant metyrosine, while 37 received doxazosin alone. Their perioperative outcomes were compared. RESULTS: No severe event, such as acute coronary syndrome, was observed in either group. Intraoperatively, the doxazosin + metyrosine group exhibited a lower median minimum systolic blood pressure (56 [54-60] vs. 68 [59-74] mmHg, P = 0.03) and required lower median remifentanil (P = 0.04) and diltiazem (P = 0.02) doses than the doxazosin-alone group. CONCLUSION: The combination of metyrosine and doxazosin as a preoperative treatment for PPGLs affects intraoperative circulatory hemodynamics, such as a reduced occurrence of blood pressure elevation during surgery. Further research is necessary to identify patients who will benefit most from this combination treatment.

Newer parameters of the octreotide test in patients with acromegaly.

PURPOSE: Predicting the therapeutic effects of first-generation somatostatin receptor ligands (fg-SRLs) is important when assessing or planning effective treatment strategies in patients with acromegaly. The oft-used maximum growth hormone (GH) suppression rate parameter of the octreotide test has a suboptimal predictive value. Therefore, this study explored newer parameters of the octreotide test for predicting the therapeutic effect of long-acting fg-SRLs. METHODS: In this single-center retrospective study, the octreotide test parameters and the therapeutic effects of fg-SRL at 3 months were investigated in 45 consecutive treatment-naïve patients with acromegaly between April 2008 and March 2023. Additionally, the relationship between the octreotide test parameters and the therapeutic effects of fg-SRLs was investigated. Tumor shrinkage was evaluated based on changes in the longitudinal diameter of the macroadenomas. The area GH suppression rate-time under the curve (AUC) and the time to nadir GH level were calculated and compared with the maximum GH suppression rate. RESULTS: The AUC estimated reductions in serum insulin-like growth factor I, and tumor shrinkage. The time to nadir GH level predicted tumor shrinkage more robustly than the maximum GH suppression rate in patients with macroadenoma. CONCLUSION: The AUC and time to nadir GH level may potentially be newer parameters of the octreotide test for estimating the therapeutic effect of fg-SRLs.

Clinical features of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis: a new aspect of paraneoplastic autoimmune condition.

The pathogenesis of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis was gradually revealed as cases emerged. Our comprehensive analysis, including all reported cases, identified a new instance of anti-PIT-1 hypophysitis postimmune checkpoint inhibitor therapy. All 9 patients exhibited extremely low growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels; 2 had a slightly atrophic pituitary gland; 4 had thymoma, and 5 had malignant neoplasms of diffuse large B-cell lymphoma (DLBCL) and other origins. Patients with thymoma showed multiple autoimmune diseases. HLA-A*24:02 and/or A*02:06 were present in six and DR53 in 5 cases analyzed. High anti-PIT-1 antibody titers and ectopic PIT-1 expression in the cytosol and nucleus of the tumor tissues were observed in patients with thymoma or DLBCL, whereas it was exclusively observed in the nuclei of a bladder cancer patient. These findings provide new insights into the pathophysiology of paraneoplastic autoimmune hypophysitis.

Real-World Data About Treatment Outcomes for Patients with EGFR-Mutated NSCLC Resistance to Osimertinib and Platinum-Based Chemotherapy.

INTRODUCTION: Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor gene (EGFR) mutation. To facilitate future therapeutic developments in these patients after treatment with osimertinib and Pt-doublet, we estimated the outcomes of currently used post-treatment therapies. METHODS: Data of patients with NSCLC who received at least one medication after osimertinib and Pt-doublet between April 2008 and August 2021 were extracted from the Medical Data Vision claims database. The duration of treatment (DoT) (first treatment after osimertinib and Pt-doublet) and overall survival (OS) were estimated. The index date was the first day on which the medication was prescribed. RESULTS: In total, 731 patients (mean age 64 years) were screened. The most frequent post-treatments were docetaxel-based chemotherapy (30.2%), immune checkpoint inhibitor (ICI) alone or in combination (17.2%), first-/second-generation EGFR-tyrosine kinase inhibitors (16.7%), osimertinib (16.3%), and Pt-doublet (5.2%). The median DoT and OS (95% confidence interval) of all post-treatments were 3.5 (3.27, 3.77) and 10.3 (9.3, 12.1) months, respectively, reflecting the median DoT (3.8 months) and OS (10.0 months) of docetaxel-based chemotherapy. Among all post-treatment regimens, ICIs resulted numerically the shortest [2.77 (2.33, 3.00) months] and osimertinib the longest [4.40 (3.47, 5.67) months] median DoT. The median OS was shortest in patients post-treated with ICIs [7.07 (5.40, 9.90) months] and longest in patients rechallenged with Pt-doublet (12.27 months), followed by patients post-treated with osimertinib (11.70 months). In a subset analysis of patients who received first-line osimertinib and second-line Pt-doublet as well as Pt-doublet immediately after osimertinib, those post-treated with ICIs had the shortest median DoT. CONCLUSION: Given the limited real-world efficacy on EGFR-mutant NSCLC resistant to osimertinib and platinum-based chemotherapy, the development of more highly potent post-treatment therapies is warranted.

Frailty and Colorectal Surgery: Review and Concept of Cancer Frailty.

Frailty is characterized by reduced physiological reserves across multiple systems. In patients with frailty, oncological surgery has been associated with a high rate of postoperative complications and worse overall survival. Further, given that cancer and frailty can co-exist in the same patient, cancer and cancer-related symptoms can rapidly accelerate the progression of baseline frailty, which we have termed "cancer frailty". This distinction is clinically meaningful because the prioritization of interventions and the treatment outcomes may differ based on health conditions. Specifically, in patients with cancer frailty, improvements in frailty may be achieved via surgical removal of tumors, while prehabilitation may be less effective, which may in turn result in delayed treatment and cancer progression. In this review, we focused on challenges in the surgical treatment of non-metastatic colorectal cancers in patients with frailty, including those related to decision making, prehabilitation, and surgery. Potential recommendations for treating patients with cancer frailty are also discussed.

Dietary Fish and n-3 Polyunsaturated Fatty Acid Consumption, and Renal Cell Carcinoma Risk in Japan: The Japan Public Health Center-Based Prospective Study.

BACKGROUND: Previous epidemiologic studies found inconsistent associations between fish consumption and renal cell carcinoma (RCC). Although the consumption of n-3 polyunsaturated fatty acids (PUFA) was reported to protect against the development of some types of cancer, little is known regarding its association with RCC. METHODS: We investigated the association between fish and n-3 PUFA consumption and RCC risk using the Japan Public Health Center-based Prospective Study. We examined data from 84,063 eligible Japanese participants aged 45 to 74 years who responded to a validated food frequency questionnaire for Cohort I in 1995 and Cohort II in 1998. The participants were followed-up until 2013. HRs and 95% confidence intervals (CI) were estimated using a multivariable-adjusted Cox proportional hazard model, and the exposure level was categorized into quartiles. RESULTS: Among the 1,272,298 person-years of follow-up, 262 cases of newly diagnosed RCC were identified. The multivariate-adjusted HRs for the highest vs. lowest quartile of fish, including shellfish, were (HR = 1.43; 95% CI, 0.98-2.07) and the individual marine n-3 PUFAs were (HR = 1.56; 95% CI, 1.07-2.28; Ptrend = 0.09) for eicosapentenoic acid, (HR = 1.81; 95% CI, 1.27-2.59; Ptrend = 0.01) for docosapentaenoic acid, and (HR = 1.56; 95% CI, 1.07-2.27; Ptrend = 0.09) for docosahexaenoic acid. RCC were further categorized on the basis of diagnosis methods and cancer stage, and the positive correlation did not change substantially. CONCLUSIONS: We demonstrated that high consumption of n-3 PUFA is associated with RCC risk. IMPACT: The positive association between n-3 PUFA and RCC risk was observed in Japanese who consume higher amounts of fish than Western populations.

Safety and Accuracy of Professional Continuous Glucose Monitoring in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Hyperglycemia in the early days following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-known risk factor for acute graft-versus-host disease (GVHD) and non-relapse mortality. The FreeStyle Libre Pro, a factory calibrated continuous glucose monitoring (CGM) device, has been used for the retrospective analysis of glucose testing in patients with diabetes. We assessed the safety and accuracy of the device in patients undergoing allo-HSCT. We recruited eight patients who underwent allo-HSCT between August 2017 and March 2020. They wore the FreeStyle Libre Pro on the day before or on the day of transplantation until 28 days after transplantation. Adverse events, especially bleeding and infection, were monitored to assess safety, and blood glucose levels were measured and compared with the device values. None of the eight participants experienced bleeding that was difficult to stop from the sensor site or local infection that required antimicrobial administration. The device value was well correlated with blood glucose (correlation coefficient r=0.795, P<0.01); however, the overall mean absolute relative difference was 32.1%±16.0%. Our study demonstrated the safety of FreeStyle Libre Pro in allo-HSCT patients. However, the sensor results tended to be lower than the blood glucose levels.

Serum leucine-rich alpha-2 glycoprotein and calprotectin in children with inflammatory bowel disease: A multicenter study in Japan.

BACKGROUND AND AIM: Serum leucine-rich alpha-2 glycoprotein (LRG) and calprotectin have been studied as disease activity markers in adults with inflammatory bowel disease (IBD). We evaluated them in pediatric IBD patients. METHODS: Subjects under 17 years old undergoing care at 11 Japanese pediatric centers were retrospectively assigned to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illness. Serum LRG and calprotectin were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: We enrolled 173 subjects, including 74 with CD, 77 with UC, and 22 NC. Serum LRG concentrations in active CD (median, 200 µg/mL) were significantly greater than in remission (81 µg/mL; P < 0.001) or NC (69 µg/mL; P < 0.001). Serum calprotectin concentrations in active CD (2941 ng/mL) also were significantly greater than in remission (962 ng/mL; P < 0.05) or NC (872 ng/mL; P < 0.05). Serum LRG concentrations in active UC (134 µg/mL) were significantly greater than in remission (65 µg/mL; P < 0.01) but not significantly greater than in NC (69 µg/mL); serum calprotectin concentrations in active UC (1058 ng/mL) were not significantly different from those in remission (671 ng/mL) or NC (872 ng/mL). In receiver operating characteristic analyses of LRG, calprotectin, C-reactive protein, and erythrocyte sedimentation rate for ability to distinguish active IBD from remission, CD and UC showed areas under receiver operating characteristic curves for LRG (0.77 and 0.70, respectively), exceeding those for calprotectin, C-reactive protein, or erythrocyte sedimentation rate. CONCLUSIONS: In pediatric IBD, serum LRG may better reflect disease activity than serum calprotectin, particularly in CD.

Efficacy and Safety of Synbiotics in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Randomized, Double-blinded, Placebo-controlled Pilot Study.

Objective High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective treatment option for relapsed and refractory aggressive malignant lymphoma. However, patients frequently experience treatment-induced gastrointestinal symptoms. Synbiotics, including live microorganisms and nondigestible food ingredients, reportedly ameliorate chemotherapy-induced mucosal damage. In this study, we assessed the efficacy and safety of synbiotics in patients undergoing auto-HSCT. Methods This randomized, double-blinded study included patients with malignant lymphoma eligible for auto-HSCT. The patients were randomly assigned to either a synbiotic group receiving Bifidobacterium longum (BB536) and guar gum or a placebo group receiving a placebo containing dextrin. The supplements were administered twice daily from the start of conditioning chemotherapy up to 28 days after auto-HSCT. The primary endpoint was the duration of total parenteral nutrition (TPN). Results In total, 12 patients were included and randomized. The median duration of TPN was 15 (range, 12-33) days in the synbiotic group and 17.5 (range, 0-32) days in the placebo group. The median duration of grade ≥3 diarrhea was shorter in the synbiotic group than in then placebo group (2.5 vs. 6.5 days), as was the duration of hospital stay (31.5 vs. 43 days). The oral intake and quality of life regarding diarrhea and anorexia improved in the synbiotic group after engraftment. Synbiotic infections, including bacteremia, were not observed. Conclusion Synbiotics may reduce gastrointestinal toxicity, thereby reducing nutritional problems and improving the quality of life of patients undergoing auto-HSCT, without severe adverse events.

Serum Zinc and Selenium in Children with Inflammatory Bowel Disease: A Multicenter Study in Japan.

BACKGROUND: Reports of zinc and selenium deficiencies accompanying inflammatory bowel disease (IBD) mostly have originated from Western countries and concerned adult patients. Whether Japanese children with IBD have similar deficiencies remained unclear. AIM: We aimed to elucidate differences in serum zinc and selenium concentrations in Japanese children between types of IBD. METHODS: Children under 17 years old undergoing care at 12 Japanese pediatric centers were retrospectively enrolled between November 2016 and February 2018 to 3 groups representing Crohn's disease (CD), ulcerative colitis (UC), and normal controls (NC) with irritable bowel syndrome or no illnesses. Serum zinc and selenium were measured by atomic absorption spectrophotometry. Zinc and selenium deficiencies were defined by serum concentrations < 70 µg/dL and < 9.5 µg/dL, respectively. RESULTS: Subjects included 98 patients with CD (median age, 13 years), 118 with UC (11 years), and 43 NC (11 years). Serum zinc and selenium were significantly lower in CD (median, 64 and 12.6 µg/dL respectively) than in UC (69 and 14.6; P < 0.05 and P < 0.001) or NC (77 and 15.7; P < 0.01 and P < 0.001). Zinc deficiency was significantly more prevalent in CD (60.2%) than in NC (37.2%; P < 0.05), but not than in UC (51.7%; P = 0.22). Selenium deficiency was significantly more prevalent in CD (15.3%) than in UC (5.9%; P < 0.05) or NC (0%; P < 0.01). CONCLUSIONS: In Japanese children under 17 years old, serum zinc and selenium were significantly lower in CD than in UC or NC. Zinc and selenium should be monitored, and supplemented when deficient, in children with IBD, especially CD.

Absent X-linked inhibitor of apoptosis protein expression in T cell blasts and causal mutations including non-coding deletion.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.

A Case of Luscan-Lumish Syndrome: Possible Involvement of Enhanced GH Signaling.

CONTEXT: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. CASE DESCRIPTION: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. CONCLUSION: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.

Impact of pH and protein hydrophobicity on norovirus inactivation by heat-denatured lysozyme.

Norovirus, the leading cause of non-bacterial food poisoning, is responsible for several outbreaks associated with bivalves and ready-to-eat food products worldwide. As norovirus is resistant to alcohol, which is commonly used in food manufacturing processes, sodium hypochlorite is used for its inactivation. However, sodium hypochlorite has two disadvantages: it cannot be added to foods, and its effect is significantly reduced in the presence of organic compounds. Thus, a novel disinfectant against norovirus is urgently required for food hygiene. Thermally denatured egg white lysozyme inactivates norovirus; however, the optimal inactivating conditions and the underlying mechanism are unclear. In the present study, the inactivating mechanism of heat-denatured lysozyme against norovirus was analyzed using murine norovirus strain 1 (MNV-1). We found that the inactivating effect was enhanced by adjusting the pH of the lysozyme solution before thermal denaturation to 6.5 or higher. The reaction of heat-denatured lysozyme and MNV-1 was irreversible, and norovirus was completely inactivated after exposure to heat-denatured lysozyme. Furthermore, it was found that lysozyme residues 5-39 contributed to the norovirus-inactivating effect. Notably, the hydrophobicity and positive charges in this region contributed to the norovirus-inactivating effect, as evidenced by the norovirus inactivation test using mutated residues 5-39. These findings are novel and highlight the possible application of heat-denatured lysozyme as a disinfectant against norovirus in a wide range of food processes.

Cardiac Myxoma Caused by Fumarate Hydratase Gene Deletion in Patient With Cortisol-Secreting Adrenocortical Adenoma.

CONTEXT: Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. CASE DESCRIPTION: A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. CONCLUSIONS: This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.

Antibodies to Crohn's disease peptide 353 as a diagnostic marker for pediatric Crohn's disease: a prospective multicenter study in Japan.

BACKGROUND: Various serologic markers such as anti-glycoprotein 2 antibodies and anti-Saccharomyces cerevisiae antibodies have been reported to be diagnostically useful in Crohn's disease. Mitsuyama et al. reported that antibodies to Crohn's disease peptide 353, a newly proposed serologic marker, were more useful in Japanese adults than anti-Saccharomyces. We addressed the same issue in Japanese children and adolescents. METHODS: Prospectively enrolled subjects under 17 years old assessed and treated at 12 pediatric centers in Japan included groups with Crohn's disease, ulcerative colitis, other intestinal diseases, or good health. The 3 serum markers were analyzed by enzyme-linked immunosorbent assays. RESULTS: Enrolled subjects, numbering 367, included 120 with Crohn's disease, 148 with ulcerative colitis, 56 with other intestinal diseases, and 43 healthy subjects. In Crohn's disease, anti-Crohn's disease peptide 353, anti-glycoprotein 2, and anti-Saccharomyces concentrations (median, 2.25, 3.0, and 8.9 U/mL) were significantly greater than in ulcerative colitis (1.1, 1.9, and 3.4; all P < 0.001), other intestinal diseases (1.1, 1.85, and 2.95; all P < 0.001), and healthy controls (1.1, 1.7, and 2.8; all P < 0.001), respectively. At 95% specificity, sensitivity of anti-Crohn's disease peptide (45.0%) was significantly higher than for anti-glycoprotein 2 (30.8%; P < 0.05) or anti-Saccharomyces (26.7%; P < 0.01). CONCLUSIONS: Anti-Crohn's disease peptide 353 proved more useful for diagnosis of Crohn's disease in Japanese children than the other 2 markers. To our knowledge, this is the first pediatric report to that effect.

Efficacy of preoperative amino acid supplements on postoperative physical function and complications in open heart surgery patients: A study protocol for a randomized controlled trial.

BACKGROUND: Elderly patients undergoing cardiac surgery often show poor nutritional status, muscle wasting, and sarcopenia, which are reported to affect postoperative functional recovery and incidence of complications. Amino acids are essential in maintaining nutritional status, synthesizing muscle protein, and promoting beneficial energy balance of the heart muscle. ß-Hydroxy ß-methylbutyric acid (HMB) is a leucine metabolite known to increase muscle protein synthesis and inhibit protein catabolism; it has been used to more effectively support patients with muscle wasting due to wearing diseases. However, the efficacy of amino acid administration comprising HMB in patients undergoing open heart surgery remains unclear. This study aims to examine whether preoperative short-term aggressive amino acid administration helps support postoperative recovery of physical function and prevent complications. METHODS: This is a single-center prospective randomized controlled trial (UMIN000030490). Patients aged ≥65 years who will be hospitalized for medical examination before cardiac surgery will be recruited. The participants will be randomly assigned to the experimental or control group. The experimental group will be administered with an amino acid supplement with HMB 1200mg, l-glutamine 7000mg, and l-arginine 7000mg once or twice per day depending on the degree of renal dysfunction, for 14-28 days preoperatively. The control group will not receive any nutritional intervention. The main outcome will be a change in the 6-min walking test distance pre- and postoperatively as a sign of functional recovery. Secondary outcomes such as the incidence of complications; physical, nutritional, and psychological states; mortality; and length of hospital stay will also be evaluated. CONCLUSION: This clinical study will determine the effects of preoperative short-term oral amino acid supplementation with HMB, l-glutamine, and l-arginine on postoperative physical function in elderly patients undergoing cardiac surgery.

KCTD12 is negatively regulated by Kit in gastrointestinal stromal tumors.

Our group has previously demonstrated that pfetin, encoded by the KCTD12 gene, is a strong prognostic biomarker for gastrointestinal stromal tumors (GISTs). However, the underlying mechanisms that control pfetin expression remain unknown. To elucidate the regulatory mechanisms of KCTD12 in GIST, in addition to a possible association between KCTD12 alterations and protein expression, we examined 76 patients with GISTs for KCTD12 mutations by PCR-direct sequence, and compared these results with clinicopathologic data. The function of pfetin in GIST progression was also revealed using GIST T1 cells. In this series, pfetin expression was not observed in 15 cases, and loss of pfetin expression was associated with higher mitotic rate (>5/50HPFs: p = 0.029). There was also a trend between presence of necrosis and loss of pfetin expression but this was not statistically significant (p = 0.09). KCTD12 mutations were frequently observed in 22 out of 76 GISTs (28.9%); however, they did not affect protein expression and were not associated with patients' prognosis. KCTD12 in vitro knockdown resulted in the accelerated growth of GIST T1 cells, confirming that pfetin functions as a tumor suppressor. KIT knockdown significantly inhibited cellular growth and upregulated the expression of pfetin at both the mRNA and protein level. These findings suggest that GISTs with loss of pfetin expression has proliferative advantage and that higher pfetin expression in GISTs may be indicative of lower expression levels of KIT. This relationship confirms that pfetin is a useful prognostic marker in GISTs.