Post-allogeneic Hematopoietic Stem Cell Transplantation Portal Hypertension Not Associated with Liver Cirrhosis, Veno-occlusive Disease, or Graft-versus-host Disease: A Case Report.

We herein report a rare case of idiopathic portal hypertension (IPH)-like disease that developed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A 53-year-old woman who underwent allo-HSCT for acute myeloid leukemia showed portal hypertension with radiological and histopathological findings consistent with IPH, distinct from veno-occlusive disease (VOD) and graft-versus-host disease (GVHD) of the liver. This case highlights the importance of considering IPH-like disease as a potential cause of portal hypertension after allo-HSCT. Awareness of this complication can aid in the early diagnosis and appropriate management of patients post allo-HSCT.

Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS: We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS: Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS: Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.

Outcomes of Patients Who Undergo Transfusion of Fresh Frozen Plasma: A Prospective, Observational, Multicentre Cohort Study in Hiroshima, Japan.

PURPOSE: Given the chronic shortage of blood for transfusion in Japan, promotion of appropriate use of fresh frozen plasma (FFP) urgently needs to be addressed by the national blood project in Japan. Whether FFP transfusions are administered appropriately in Japan is currently unclear. In this study, we aimed to investigate the outcomes of patients who undergo FFP transfusion and the appropriateness of use of FFP. PATIENTS AND METHODS: This multicentre, prospective, observational cohort study was conducted from September 2017 to April 2019 at the 15 medical institutions in Hiroshima Prefecture that are the top providers of FFP. All patients who underwent FFP transfusion during the study period were included, relevant data being extracted from the medical records. The indications for FFP transfusion were classified in accordance with the Guidelines of the Ministry of Health, Labour and Welfare of Japan. Factors associated with patient outcomes at day 28 after FFP transfusion were subjected to multivariable logistic regression analysis. RESULTS: In total, data of 1299 patients were eligible for analysis. At least 63.8% of indications for FFP were in accordance with the guideline for FFP transfusions. The mortality rate at day 28 after FFP transfusion was 16.2%. Older age (65-74 years: adjusted odds ratio [AOR]=4.3, ≥75 years: AOR=4.1), non-perioperative use (AOR=4.5), coagulopathy associated with liver damage (AOR=2.7), large volume of FFP transfused (AOR=2.5), and lack of improvement in blood coagulation following FFP transfusion were independently and significantly associated with death within 28 days after FFP transfusion. CONCLUSION: Our findings do not support the simple conclusion that FFP transfusions contribute to prognosis. However, given that coagulopathy in patients with end-stage liver disease is infrequently improved by FFP transfusion, "inappropriate" use of FFP should be avoided. It is important to promote appropriate use of FFP so as not to waste blood resources.

LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH.

It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.

Safety and efficacy of sorafenib followed by regorafenib or lenvatinib in patients with hepatocellular carcinoma.

AIM: Sequential administration of sorafenib followed by regorafenib or lenvatinib is effective against advanced hepatocellular carcinoma (HCC). In this study, we compared the safety profiles and anti-tumor effects of sequential sorafenib and regorafenib or lenvatinib therapy in patients with HCC. METHODS: We investigated adverse events, treatment responses and dose intensities in patients with HCC who were consecutively treated with sorafenib followed by regorafenib or lenvatinib at the individual level. RESULTS: Each group included 20 patients. The safety profiles of regorafenib and sorafenib were similar. The severity of hypophosphatemia, palmar-plantar erythrodysesthesia syndrome, and decreased neutrophil counts associated with regorafenib or sorafenib was similar in 12 patients. Conversely, the incidences and grades of adverse events differed between sorafenib and lenvatinib treatment. The anti-tumor effects of regorafenib and lenvatinib compared with sorafenib were significantly different for each patient. The response to treatment and progression-free survival were comparable for regorafenib and lenvatinib. The median relative dose intensities during the first 56 days of regorafenib and lenvatinib treatment were 83.6 and 80.0%, respectively. CONCLUSIONS: Similar adverse events were experienced by patients during consecutive treatment with sorafenib and regorafenib, which was not observed during treatment with sorafenib and lenvatinib. The obtained safety profile of sorafenib provided meaningful insights for selecting sequential therapy for patients with advanced HCC.

Nivolumab exerts therapeutic effects against metastatic lesions from early gastric adenocarcinoma with a small proportion of neuroendocrine carcinoma after gastrectomy: a case report.

Gastric neuroendocrine carcinoma (NEC) is an aggressive disease with high metastatic ability. Gastric cancer has intra-tumoral and intra-patient heterogeneity and may contain NEC. We discuss the case of a 75-year-old man who underwent distal gastrectomy for early gastric cancer. Tumor pathology revealed that nearly all of the tumor (> 95%) was well-differentiated adenocarcinoma, with NEC detected in a small area (< 5%) at the invasion front. No metastasis was identified in the dissected lymph nodes (LN). Multiple liver metastases were detected 3 months after surgery. The metastatic lesion was resistant to both chemotherapy regimens; namely, SOX (S-1 combined with oxaliplatin) and ramucirumab combined with paclitaxel. However, tumor regression was detected after nivolumab treatment. The tumor regression continued for 26 cycles (13 months). Irinotecan treatment was then administered. After 18 irinotecan treatment cycles for 11 months, the para-aortic LN rapidly enlarged. Following biopsy, the swollen para-aortic LN was diagnosed as the recurrence of NEC components of the gastric cancer. Treatment with carboplatin combined with etoposide has been effective and continued. We report a case of NEC para-aorta LN metastases from early gastric cancer with a low proportion of NEC (< 5%). A partial response of the distant metastatic lesions was observed with nivolumab therapy.

Comparative analysis of liver functional reserve during lenvatinib and sorafenib for advanced hepatocellular carcinoma.

AIM: Most patients with advanced hepatocellular carcinoma (HCC) have underlying chronic liver disease, which potentially deteriorated the liver functional reserve that often affects the patients' clinical course. We investigated and compared the changes in liver functional reserve during lenvatinib or sorafenib therapy in patients with advanced HCC. METHODS: We prospectively collected medical information about patients with advanced HCC with a Child-Pugh score of 5-7 to compare the liver functional reserve during treatment in those who were treated with lenvatinib or sorafenib. We also evaluated the effect of the change in the liver functional reserve on patients' outcome. Moreover, we analyzed the contributing factors for maintaining the liver functional reserve during treatment. RESULTS: Patients were treated with lenvatinib (n = 45) or sorafenib (n = 157). Forty-five patients in the lenvatinib group and 135 patients in the sorafenib group were selected through a propensity score matching analysis. More patients treated with lenvatinib had a Child-Pugh score that was maintained or improved after 4 and 12 weeks compared with those treated with sorafenib (P = 0.048, P = 0.036, respectively). Lenvatinib was identified as one of the variables that was associated with maintaining Child-Pugh scores. Multivariate analysis revealed that a worsened Child-Pugh score after 4 weeks was an independent unfavorable predictive factor for overall survival. CONCLUSIONS: More patients treated with lenvatinib for advanced HCC maintained their liver functional reserves compared with those treated with sorafenib. Maintaining the liver functional reserve contributed to better outcomes for patients with advanced HCC.

Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to reduction in liver fibrosis scores during the course of nonalcoholic fatty liver disease (NAFLD) development. We will test our hypothesis that lowering glucose and increasing insulin reduce liver fibrosis in NAFLD. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels and sulfonylureas increase insulin levels, while both lower glucose levels. METHODS: This study is a 48-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily 20 mg tofogliflozin or 0.5 mg glimepiride. The sample size was calculated to be 14 in each group with a significance level of 0.05 and power of 0.90. The design required 40 evaluable patients in this study. The primary endpoint of this study will be the improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. The secondary efficacy endpoints in the present study include organ-specific insulin sensitivity, insulin/glucagon secretion, ectopic fat accumulation, bioelectrical impedance analysis, sympathetic nerve activity, comprehensive gene expression analyses in the liver and blood cells, and gut microbiota profiling. PLANNED OUTCOMES: Recruitment into this study started in November 2015 and will end in September 2020, with 40 patients randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by the end of 2022. The findings of this trial will be disseminated through peer-reviewed publications and international presentations. TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000020544) and ClinicalTrials.gov (NCT02649465).

Laparoscopic omental filling with intraoperative endoscopy for a perforated duodenal ulcer.

As a surgical treatment for a perforated duodenal ulcer, duodenal omental filling is effective. However, filling the perforation site with a sufficient amount of omentum is difficult in some situations. We herein report that we successfully filled a perforated duodenal ulcer with a sufficient amount of omentum using intraoperative endoscopy. The operation was performed with three ports, the operation time was 110 min, and the estimated blood loss was small. The postoperative course was good. No stenosis of deformity of the duodenum was observed on follow-up endoscopy. Laparoscopic surgery has a shorter operation time, shorter postoperative hospital stay, and less postoperative pain than open surgery. The combined use of intraoperative endoscopy with laparoscopic surgery is effective for a large perforation, and it can be expected to reduce the rate of conversion to open surgery. This combined procedure is considered useful as a laparoscopic omental filling operation.

Case of cecal volvulus successfully treated with endoscopic colopexy.

We herein report a case of cecal volvulus successfully treated with endoscopic colopexy. A 73-year-old man with a high fever and abdominal fullness was diagnosed with ileus caused by cecal volvulus. CT showed a dilated cecum and small intestine without bowel strangulation as well as acute pneumonia. Because the pneumonia increased the risk associated with general anesthesia, we attempted decompression of the bowel using endoscopy to avoid surgery. On day 1, a transanal ileus tube was inserted to the terminal ileum through the dilated cecum. On day 7, the bowel torsion spontaneously released. On day 8, we performed percutaneous endoscopic colopexy to fix the cecum on the abdominal wall and prevent re-twisting. The patient was discharged on day 15 without postoperative complications. Percutaneous endoscopic colopexy for cecal volvulus may be a treatment option when the risk associated with general anesthesia or surgery is high because of a comorbidity.

Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice.

Dieting often leads to body weight cycling involving repeated weight loss and regain. However, little information is available regarding rapid-response serum markers of overnutrition that predict body weight alterations during weight cycling. Here, we report the rapid response of serum leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine that induces insulin resistance in skeletal muscle, during diet-induced weight cycling in mice. A switch from a high-fat diet (HFD) to a regular diet (RD) in obese mice gradually decreased body weight but rapidly decreased serum LECT2 levels within 10 days. In contrast, a switch from a RD to a HFD rapidly elevated serum LECT2 levels. Serum LECT2 levels showed a positive correlation with liver triglyceride contents but not with adipose tissue weight. This study demonstrates the rapid response of LECT2 preceding body weight alterations during weight cycling in mice and suggests that measurement of serum LECT2 may be clinically useful in the management of obesity.

Post-progression survival and progression-free survival in patients with advanced hepatocellular carcinoma treated by sorafenib.

AIM: Although sorafenib is a standard drug for advanced hepatocellular carcinoma (HCC), little is known about a patient's clinical course after treatment. We investigated the effect of post-progression survival (PPS) and progression-free survival (PFS) on overall survival (OS) in patients whose advanced HCC was treated by sorafenib. METHODS: We searched in the PubMed database for reports with survival data of patients with HCC treated with sorafenib monotherapy, and selected reports with 20 or more patients each that provided data for both OS and PFS or time to progression (TTP). Median PPS (mPPS) was defined as the period obtained by subtracting median PFS or TTP (mPFS/TTP) from median OS (mOS). We identified 56 reports with 5803 patients. We investigated the correlation of mOS and either mPPS or mPFS/TTP using weighted linear regression. RESULTS: Median PPS correlated with mOS (r = 0.834) very strongly, whereas mPFS/TTP did not correlate with mOS as highly as PPS did (r = 0.546). When we stratified survival data by Child-Pugh classification, a significantly greater average percentage of mPPS to mOS was seen in Child-Pugh class A (54.4 ± 17.6%) than in Child-Pugh class B (32.0 ± 11.6%) (P = 0.015). CONCLUSION: PPS highly correlated with OS, and its importance should be more emphasized for advanced HCC patients treated after sorafenib therapy, whereas we need to take more care in interpreting the results of PFS to evaluate treatment efficacy in clinical trials of advanced HCC.

[Hepatic mucosa-associated lymphoid tissue lymphoma in a patient with chronic hepatitis B].

A 50-year-old woman with chronic hepatitis associated with hepatitis B virus was found to have a hypoechoic liver tumor of 20 mm in diameter on ultrasonography. Dynamic computed tomography and magnetic resonance imaging revealed multiple tumors in the liver. The portal vein passed through the tumor, which is not a typical feature of hepatocellular carcinoma. We subsequently performed tumor biopsy and diagnosed mucosa-associated lymphoid tissue (MALT) lymphoma of hepatic origin. Here we report this rare case of hepatic MALT lymphoma in a patient with chronic hepatitis B, and present a review of the literature.

Acute gastric volvulus in a patient with trisomy 21.

Acute gastric volvulus is a torsion of the stomach by more than 180° and a life-threatening condition. We present a 50-year-old male patient with acute abdominal pain who has Down syndrome/trisomy 21. Computed tomography showed a significant distended stomach with features of a severe gastric volvulus. Emergency operation in form of reduction and gastropexy was performed. We are not aware of any similar cases published in the English literature, where as gastric volvulus occurred in a patient with Down syndrome.

LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance.

Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.

A case of synchronous bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character.

We report a case of synchronous locally advanced bilateral breast cancer with different pathological responses to neoadjuvant chemotherapy with different biological character. The patient had presented bilateral breast cancer: the left breast cancer was hormone receptor negative, human epidermal growth factor receptor-2 (HER2) positive, and classified as T4bN1M0, stage IIIb, while the right was hormone receptor positive, HER2-negative, and classified as T4bN0M0, stage IIIb. We administered four cycles of anthracycline-based therapy followed by 12 weekly cycles of taxane with trastuzumab for neoadjuvant chemotherapy. We had achieved a significant left tumor reduction after each chemotherapy, but not right tumor. Bilateral modified radical mastectomies with axillary lymph-node dissection were performed. The therapeutic effect in the left was determined as a pathological complete response, in contrast to the right side. She has no recurrence for more than five years, though she had advanced cancer with oncologic emergency. This case could be an informative experience to understand the relation of tumor biology and response to systemic therapy.

Successful conservative treatment of pneumatosis intestinalis associated with intraperitoneal free air: report of a case.

While pneumatosis intestinalis (PI) is a rare condition associated with a wide variety of underlying diseases, PI with intraperitoneal free air and ascites is extremely uncommon and is difficult to distinguish from diffuse peritonitis. We herein describe the case of an 87-year-old male who was admitted to our hospital with abdominal pain, distension and nausea. Abdominal plain radiography and computed tomography revealed intramural air collection in the entire intestine, intraperitoneal free air and ascites. Although we first suspected bowel necrosis and perforation, his physical findings and the properties of the diagnostic abdominal paracentesis did not support this diagnosis. Therefore, we selected conservative management, and the intramural air, intraperitoneal free air and ascites disappeared 1 week later. Recognition of the possible presence of non-surgical PI and intraperitoneal free air, although it is extremely rare, is important to avoid a misdiagnosis and the associated unnecessary surgical intervention.

Abdominal dynamic CT in patients with renal dysfunction: contrast agent dose reduction with low tube voltage and high tube current-time product settings at 256-detector row CT.

PURPOSE: To evaluate the feasibility of a low-contrast agent dose protocol at abdominal dynamic computed tomography (CT) with a low tube voltage high tube current-time product technique and a 256-detector row CT unit. MATERIALS AND METHODS: This prospective study received institutional review board approval; written informed consent to participate was obtained from all patients. The study included 151 patients; 117 had an estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m(2). These patients were examined with the conventional 120-kVp protocol. The other 34 patients underwent scanning with an 80-kVp tube voltage, a high tube current-time product, and a 40% reduction in contrast agent dose. Effective dose (ED), image noise, attenuation, contrast-to-noise ratio (CNR), and figure of merit of the aorta in the arterial phase and of the portal vein and hepatic parenchyma in the portal venous phase in the two groups were compared with the Student t test. RESULTS: Estimated ED was about 20% lower with the 80-kVp protocol than with the 120-kVp protocol. There were no significant differences in CNR in any region of interest between the 80-kVp protocol and the 120-kVp protocol (abdominal aorta: 36.9 ± 9.7 [standard deviation] vs 36.1 ± 8.1, P = .63; portal vein: 13.4 ± 3.2 vs 13.1 ± 3.2, P = .65; hepatic parenchyma: 6.4 ± 2.6 vs 6.7 ± 2.3, P = .51). CONCLUSION: Contrast dose at hepatic dynamic 256-detector row CT in patients with renal dysfunction can be decreased by 40% with this protocol by using the 80-kVp setting and a high tube current-time product.

Resectable gallbladder cancer presenting with acute pancreatitis caused by hemobilia.

A 79-year-old female was transferred to our hospital because of suspicion that her acute pancreatitis was caused by stone impaction in the common bile duct (CBD). Laboratory examination showed aspartate aminotransferase, 1645 U/l; alanine aminotransferase, 476 U/l; amylase, 1365 U/l; and white blood cells, 10700/µl. Computed tomography (CT) showed an enhanced tumor in the neck of the gallbladder, an abnormal CBD filled with a high-density area, and localized swelling in the head of the pancreas. Magnetic resonance cholangiopancreatography also showed a low-intensity area in the CBD. Endoscopic retrograde cholangiopancreatography showed coagulated blood discharged from the papilla of Vater. The diagnosis was acute pancreatitis caused by impaction of coagulated blood from a gallbladder tumor. A curative operation was performed 10 days after endoscopic bile duct drainage. Gallbladder cancer (GBCa) has no special symptoms and is usually diagnosed at an advanced stage; however, hemobilia and acute pancreatitis are unusual as an initial presentation of GBCa.

Trends in transmitted drug-resistant HIV-1 and demographic characteristics of newly diagnosed patients: nationwide surveillance from 2003 to 2008 in Japan.

The emergence and transmission of drug-resistant human immunodeficiency virus-1 (HIV-1) compromises antiretroviral treatment for HIV-1. Thus, testing for drug resistance is recommended at diagnosis and before initiating highly active antiretroviral treatment. We conducted an epidemiological study enrolling newly diagnosed patients between 2003 and 2008 in our nationwide surveillance network. In the 6-year study period, the prevalence of drug-resistant HIV-1 among 2573 patients, consisting mainly of Japanese men in their late-30s and infected through male-to-male sexual contacts, followed an increasing trend from 5.9% (16/273) in 2003 to 8.3% (50/605) in 2008. Nucleoside reverse transcriptase inhibitor-associated mutations predominated in each year, with T215 revertants being the most abundant. The predictive factor for drug-resistant HIV-1 transmission was subtype B (OR=2.36; p=0.004), and those for recent HIV-1 infection were male gender (OR=3.79; p=0.009), MSM behavior (OR=1.67; p=0.01), Japanese nationality (OR=2.31; p=0.008), and subtype B (OR=5.64; p<0.05). Continued activities are needed to raise awareness of the risks of HIV-1 infection and complications of drug-resistant strains. Continued surveillance is also needed to understand trends in the HIV-1 epidemic.