Histological differentiation between sporadic and colitis-associated intestinal cancer in a nationwide study: A propensity-score-matched analysis.

BACKGROUND AND AIM: Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS: We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS: A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION: CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

Pretreatment asthma control test score as a predictive score for clinical remission after bronchial thermoplasty in younger patients with severe asthma and preserved lung function.

OBJECTIVE: Bronchial thermoplasty (BT) decreases the incidence of asthma exacerbations, emergency room visits, and hospitalizations among patients with severe asthma. Predictors of BT effectiveness remain unclear as its mechanism of action and invasiveness remain obscure. This study aimed to identify factors that could predict BT outcomes. METHODS: Two respiratory physicians treated 20 consecutive patients with severe asthma using BT. The patients were assigned to groups based on clinical remission following an expert consensus proposed in 2020. Predictors of clinical remission were analyzed using asthma control test (ACT) score, pulmonary function and blood tests, and fractional exhaled nitric oxide. RESULTS: At baseline, the median age was 44 years (interquartile range [IQR], 31.0-52.8), and pre-bronchodilator (pre-BD) percent predicted forced expiratory volume in one second (%FEV1) was 85.9% (IQR, 74.8-100.5). Six (30%) patients achieved clinical remission. Among the patients treated with biologics, 20% had clinical remission, and 20% discontinued biologic therapy. The pre-BT ACT score was significantly lower in the group with than without remission (11.0 [IQR, 8.0-14.5] vs. 15.0 [IQR, 11.0-17.3], p = .016). Adverse events did not significantly differ between the groups. CONCLUSIONS: To the best of our knowledge, this is the first study to use clinical remission as a criterion for evaluating BT efficacy. The pre-BT ACT score might a the predict response to BT in younger adult patients with severe asthma and pre-BD %FEV1 ≥ 70%.

Association Between Sense of Coherence, Disease-Specific Symptoms, and Health-Related Quality of Life Among Japanese Patients with Ulcerative Colitis: A Cross-Sectional Study.

INTRODUCTION: We examined the associations among disease-related symptoms, health-related quality of life (HRQOL), and sense of coherence (SOC) in Japanese patients with ulcerative colitis (UC). METHODS: This cross-sectional survey involved patients and physicians at 23 hospitals specializing in UC treatment in Japan (December 2019-December 2020). Multiple linear regression analysis was performed using scores on the Mental Health and General Health subscales of the Medical Outcomes Study 36-Item Short-Form Health Survey as outcomes and SOC as the main independent variable. Scores on the Inflammatory Bowel Disease Questionnaire (IBDQ) and Fecal Incontinence Quality of Life Scale (FIQL) were used to measure the effect of disease-related symptoms. The moderating effect of symptoms on the association between HRQOL and SOC was also tested. RESULTS: SOC was positively and independently associated with HRQOL (Mental Health: ß = 0.43, 95% confidence interval [CI] = 0.24-0.61, P < 0.001; General Health: ß = 0.41, 95% CI = 0.23-0.59, P < 0.001). The association of SOC with Mental Health scores did not differ by symptoms, whereas its association with General Health was attenuated by symptoms (interaction term of IBDQ by SOC: ß = -0.0082, 95% CI = -0.017 to 0.00064, P = 0.07; that of FIQL by SOC: ß = -0.0052, 95% CI = -0.011 to 0.0010, P = 0.10). CONCLUSIONS: SOC affected mental health independently, and its protective association with general health perception was affected by symptoms. Further research is required to determine the most effective use of SOC in interventions to improve HRQOL in patients with UC.

Efficacy of cefmetazole in immunocompetent patients with uncomplicated colonic diverticulitis: A propensity score matching analysis.

INTRODUCTION: The incidence of colonic diverticulitis is increasing in Japan. Although antimicrobial chemotherapy is a treatment option, Japanese guidelines for diverticulosis do not recommend any antibiotic in particular and antibiotic selection is left to the discretion of the prescribing physician, who often selects antibiotics with anti-pseudomonal activity. Therefore, this study compared the efficacy of cefmetazole (CMZ) with that of tazobactam/piperacillin (TAZ/PIPC) in hospitalized Japanese immunocompetent patients with uncomplicated colonic diverticulitis. PATIENTS AND METHODS: This retrospective study included Japanese immunocompetent patients hospitalized for colonic diverticulitis between April 2019 and March 2022. Participants were divided into the CMZ and TAZ/PIPC groups. After propensity score matching, the intergroup differences in clinical outcomes, including adverse events, mortality, and re-admission rate, were ascertained. RESULTS: During the study period, 142 Japanese patients were hospitalized with community-onset colonic diverticulitis; 124 of these patients were immunocompetent. Of the 124 patients, 42 were excluded, and the CMZ and TAZ/PIPC groups comprised 62 and 20 patients, respectively. After propensity score matching, there were 16 patients in each group. There was no significant intergroup difference in the mortality and re-admission rates; however, the incidence of liver dysfunction was significantly higher (p = 0.018) in the TAZ/PIPC group. CONCLUSION: In patients with colonic diverticulitis, CMZ therapy should be selected because of the adequate clinical outcomes and lower incidence of adverse events, as this would reduce broad-spectrum antibiotic use and minimize antibiotic-resistant bacteria.

Nasolacrimal Duct Obstruction Secondary to Eosinophilic Chronic Rhinosinusitis: A Case Report.

A 47-year-old Japanese woman presented with a 1-year history of right-sided epiphora. On initial consultation, the patient had a high right tear meniscus height. CT images revealed bilateral soft tissue opacification in the nasal cavity and maxillary, frontal, and ethmoid sinuses. The lesion in the right nasal cavity and maxillary sinus involved the right lacrimal sac and nasolacrimal duct. Blood test results showed elevated eosinophil count. Endoscopic sinus surgery and excisional biopsy of the nasolacrimal duct were performed. Histopathological examinations of the excised right nasolacrimal duct and nasal polyps from the nasal cavity and maxillary sinus showed high levels of eosinophilic inflammatory infiltrates. The definite diagnosis of eosinophilic chronic rhinosinusitis was made, based on clinical, radiological, and histopathological findings. At 1.5-year follow-up, tear meniscus height was normal, the lacrimal drainage system remained patent, and the rhinosinusitis did not recur.

Exacerbation rates in Japanese patients with obstructive lung disease: A subanalysis of the prospective, observational NOVELTY study.

BACKGROUND: Although clinical trials including asthma and COPD patients have revealed much about exacerbation frequencies, most studies are limited in that they recruited patients only with a clear diagnosis of one disease or the other, based on conventional diagnostic criteria, which may exclude many real-world patients with mixed symptoms. METHODS: NOVELTY is a global prospective observational study of patients with asthma and/or COPD from real-world practice. In this subanalysis, we compared patient characteristics of obstructive pulmonary diseases between the Japanese population (n = 820) and the overall population excluding Japanese patients (n = 10,406). RESULTS: The Japanese population had fewer exacerbations than the overall population across most of the physician-assessed disease severities and all diagnoses. The difference in exacerbation frequencies was more prominent in patients with COPD and asthma + COPD. The Japanese population was older, had higher former smoking rates, lower BMI, fewer respiratory symptoms, and better health-related quality of life compared with the overall population across all diagnoses. CONCLUSIONS: We clarified differences in patient characteristics among patients with asthma and/or COPD in Japan compared with non-Japanese patients. Importantly, we found that Japanese patients with asthma and/or COPD had significantly fewer exacerbations compared with patients overall. The results from our study may contribute to the development of precision medicine and guidelines specific to Japan.

Crohn's Disease-Associated Anorectal Cancer Has a Poor Prognosis With High Local Recurrence: A Subanalysis of the Nationwide Japanese Study.

INTRODUCTION: Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC. METHODS: A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables. RESULTS: Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local. DISCUSSION: Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.

Effect of Biologics on the Risk of Advanced-Stage Inflammatory Bowel Disease-Associated Intestinal Cancer: A Nationwide Study.

INTRODUCTION: The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set. METHODS: The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC. RESULTS: In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P < 0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% confidence interval, 0.034-0.356], P < 0.001). DISCUSSION: Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.

Home High-Flow Nasal Cannula Oxygen Therapy for Stable Hypercapnic COPD: A Randomized Clinical Trial.

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

Statistical tests for two-stage adaptive seamless design using short- and long-term binary outcomes.

The adaptive seamless design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In this article, we focus on a two-stage adaptive seamless design, for which treatment selection is based on the short-term binary endpoint and treatment comparison is based on the long-term binary endpoint. We thus propose an exact conditional test as a final analysis, based on the bivariate binomial distribution and given the selected treatment with the most promising short-term endpoint response rate from an interim analysis. Additionally, the mid- p $$ p $$ approach is incorporated to improve conservativeness for an exact test. Simulation studies were conducted to compare the proposed methods with a method based on the combination test. The proposed exact method controlled for type I error rate at the nominal level, regardless of the number of initial treatments or the correlation between short- and long-term endpoints. In terms of the treatment comparison power, the proposed methods are more powerful than that based on the combination test in the scenarios, with only one treatment being effective.

Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice.

Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.

Post-COVID-19 interstitial lung disease presenting with profound hypoxemia: Report of three cases demonstrating a good response to high-dose corticosteroid therapy.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to critical pneumonia, although the clinical courses vary. In some cases, COVID-19 pneumonia causes secondary pulmonary fibrosis, which can retain radiological changes and prolong respiratory symptoms. Interstitial lung disease (ILD) secondary to COVID-19 is thought to be caused by multiple pathologies, such as excessive cytokines and abnormal repair processes elaborated by lung cells (epithelium, mesenchyme, and alveolar macrophages) after lung injury rather than viral invasion itself. Immunosuppression therapy may improve chronic respiratory symptoms and radiological changes in post-COVID-19 ILD, although the treatment is not yet established. Herein, we report three patients with post-COVID-19 ILD who presented with profound hypoxemia that had a good response to high-dose corticosteroid therapy. Further and larger studies are needed to establish post-COVID-19 ILD.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

[A fatal case intra-abdominal hemorrhage following self-removal of a percutaneous transhepatic gallbladder drainage tube].

A 92-year-old woman with gallstone pancreatitis and acute cholangitis was admitted to our hospital where endoscopic retrograde cholangiopancreatography was performed for emergency biliary drainage. Biliary cannulation was unsuccessful. Consequently, percutaneous transhepatic gallbladder drainage (PTGBD) was performed, and her symptoms improved. The PTGBD tube was removed by the patient on the third day of admission resulting in cardiopulmonary arrest two hours later. Cardiopulmonary resuscitation restored spontaneous circulation. Contrast computed tomography revealed intra-abdominal hemorrhage from the right hepatic artery by the removed part of the PTGBD tube. The patient died despite hemostasis by transcatheter artery embolization. PTGBD is generally effective and safe;however, it can cause fatal hemorrhage, especially if PTGBD tubes are removed by the patient. Thus, self-removal should be strictly prevented.

[Two Cases in Which Simultaneous Laparoscopic Surgery and Breast Cancer Surgery Using a Head-Mounted Monitor Were Useful].

Herein, we report on how we were able to reduce the operation time by simultaneously performing laparoscopic surgery and breast cancer surgery using a head-mounted monitor(HMS-3000MT, Sony corporation). Case 1: 60s, female. A 5.5 cm leiomyoma was found in the central thoracic esophagus, and a 1 cm breast cancer was found in the C region of the left mammary gland. Subtotal esophagectomy with right thoracotomy and laparoscopy and a left partial mastectomy were performed. For the abdominal surgery, HMS-3000MT was used under hand-assisted laparoscopy, and a left partial mastectomy was performed concurrently. Operation time was 367 minutes(simultaneous surgery for 56 minutes). Esophagus: leiomyoma, 50×45 mm; and mammary gland: 16×15 mm, pTis(DCIS), pN0(sn), cM0, and pStage 0. Case 2: 70s, female. A 3 cm sized GIST was found on the posterior wall of the middle gastric body, and a breast cancer of 1.3 cm was also found in the B region of the right mammary gland. Using HMS-3000MT, laparoscopic local resection of the stomach and right total glandectomy were performed concurrently. Operation time was 114 minutes(simultaneous surgery for 58 minutes). Stomach: GIST, 25×22 mm, and modified Flecher classification low risk; and mammary gland: invasive ductal carcinoma, 15×15 mm, pT1c, pN0(sn), cM0, and pStage Ⅰ. Conclusion: In 2 fields of surgery, simultaneous surgery using HMS-3000MT was considered to be a useful method to shorten the operation time.

[A Case of Ectopic Pheochromocytoma between the Abdominal Aorta and Inferior Vena Cava].

We report a case of ectopic pheochromocytoma which is relatively rare. A 50-year-old man was found to have an abdominal tumor on a medical examination, and contrast-enhanced computed tomography showed a retroperitoneal tumor between the abdominal aorta and the inferior vena cava. As a result of close examinations, an ectopic pheochromocytoma was suspected. He was asymptomatic and suspected infiltrating into great vessels, but possibility of a malignant neoplasm could not be ruled out for the tumor had a tendency to enlarge, the resection of the tumor was performed. During the operation, the invasion of the tumor into the great vessels was denied and the tumor was completely resected. Large fluctuation of the blood pressure was not observed during the operation. Histopathological evaluations of the resected specimen revealed the ectopic pheochromocytoma. A pheochromocytoma was newly defined as a tumor with malignant potential for metastasis in all cases by the WHO classification published in 2017. He was diagnosed as moderately malignant by GAPP score, therefore the careful follow-up was considered necessary in the future.

The role of calcium-binding protein S100g (CalbindinD-9K) and annexin A10 in acute pancreatitis.

BACKGROUND: We reported that the pancreas of the interferon-regulatory factor (IRF) 2 knock-out (KO) mouse represents an early phase of acute pancreatitis, including defective regulatory exocytosis, intracellular activation of trypsin, and disturbance of autophagy. The significantly upregulated and downregulated genes in the IRF2 KO pancreas have been reported. The catalogue of gene transcripts included two types of calcium-binding proteins (S100 calcium binding protein G [S100g] and Annexin A10 [Anxa10]), which were highly upregulated in the IRF2 KO pancreas. As the intracellular calcium signal plays a pivotal role in regulatory exocytosis and its disturbance is related to pancreatitis, we then evaluated the role of S100g and Anxa10 in acute pancreatitis. METHOD: We induced cerulein-pancreatitis in wild-type mice and examined the changes in the expression of these genes by qPCR and immunohistochemistry. We constructed S100g-overexpressing or Anxa10-overexpressing AR42J cells (AR42J-S100g, AR42J-Anxa10). We examined the changes in amylase secretion, intracellular calcium ([Ca2+]i), and cell viability in these cells, when incubated with cholecystokinin (CCK). RESULTS: The expression of S100g and Anxa10 was increased in cerulean-induced pancreatitis. The acini were patchily stained for S100g and the cytosol of acini was evenly but weakly stained for Anxa10. Stimulation with 100pM CCK-8, decreased amylase secretion and inhibited the [Ca2+]i increase in AR42J-S100g cells. These effects were weak in AR42J-Anxa10 cells. Cell viability was not changed by incubation with cerulein. CONCLUSION: In cerulean pancreatitis, the expression of S100g and Anxa10 was induced in the acini. S100g may work as a Ca2+ buffer in acute pancreatitis.

Sperm enter glands of preovulatory bovine endometrial explants and initiate inflammation.

We previously reported that sperm binding to cultured monolayers of bovine uterine epithelial cells induces an acute inflammatory response involving the Toll-like receptor (TLR2) signaling pathway. This response serves to clear the uterus of sperm and thereby prepares the endometrium for implantation. The endometrium is lined by surface epithelial cells; however, epithelial cells also line uterine glands. To investigate the source of the immune response, we used an explant model. Explants of bovine endometrium were incubated with bull sperm illuminated by JC1 fluorescent labeling in their mitochondria. The sperm glided over the surface epithelium until they encountered and entered uterine glands, where they remained. Scanning electron microscopy of explants revealed polymorphonuclear neutrophils (PMNs) in uterine glands along with sperm. In the absence of sperm, PMNs were not seen in glands. The incubation of sperm with explants resulted in an acute inflammatory response, seen as the upregulation of mRNA expression of IL8, TNFA, IL1B, PGES and TLR2 in whole explants, as well as increased TNFA protein expression in uterine glands. TLR1/2 antagonist reduced sperm numbers in the glands and inhibited the increase of TNFA. Our observations suggest that uterine glands serve as a site where sperm interact with the uterine epithelium to trigger the innate immune response to clear excess sperm from the uterus.

Toll-like receptor 2 mediates the immune response of the bovine oviductal ampulla to sperm binding.

We previously reported that sperm binding to cultured bovine oviduct epithelial cells induces an anti-inflammatory immune response. Now we have developed a differentiated explant model to focus on the oviductal ampulla, where fertilization occurs, and to study the effect of sperm capacitation on the immune response. We used heparin to stimulate bovine sperm capacitation. Fluorescence imaging showed that 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide-labeled sperm pretreated with (Hep(+) ) or without (Hep(-) ) heparin rapidly attached to the explant ciliated epithelium in similar numbers. However, only Hep(+) sperm upregulated explant messenger RNA (mRNA) transcription of TLR2, IL8, TGFB1, and PGES, without changes in TNFA and IL-10 expression, while Hep(-) sperm only upregulated PGES. The responses were primarily anti-inflammatory, with a greater response produced by Hep(+) sperm, which also produced a substantial increase in TLR2 protein expression in the epithelium. The addition of TLR1/2 (toll-like receptor 1/2) antagonist to the Hep(+) and (Hep(-) ) sperm-explant coincubations reduced sperm attachment to the epithelium and inhibited TLR2 protein expression and some of the Hep(+) sperm-induced mRNA transcription. Our observations suggest that the ampullar epithelium immunologically reacts more strongly to sperm that have undergone heparin stimulation of capacitation. This anti-inflammatory response could serve to protect capacitated sperm as they approach the oocyte in the ampulla.

Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03).

PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.