Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD: We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS: More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION: Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Comparative study of MAFLD as a predictor of metabolic disease treatment for NAFLD.

A novel concept of Metabolic Associated Fatty Liver Disease (MAFLD) was proposed, incorporating metabolic abnormalities such as obesity and diabetes, which are risk factors that affect the prognosis. Non-Alcoholic Fatty Liver Disease (NAFLD), entails fat accumulation in the liver without alcohol consumption and is often linked to obesity, insulin resistance, and metabolic syndrome. However, the broad nature of the disease concept has hindered prognosis accuracy. In this study, we assess the contribution of the impact of diagnostic criteria for MAFLD on metabolic disease progression compared to conventional diagnostic criteria for NAFLD. A total of 7159 patient who were presented to the health screening center in Tokai University Hospital both in 2015 and 2020 were included in the study. Fatty liver was diagnosed using abdominal ultrasonography. The diagnostic criteria for NAFLD were consistent with the global guidelines based on alcohol consumption. The diagnostic criteria for MAFLD were based on the International Consensus Panel. Medications (anti-hypertensive, diabetic, and dyslipidemia medications) were evaluated by self-administration in the submitted medical questionnaire. A total of 2500 (34.9%) participants were diagnosed with fatty liver (FL +), 1811 (72.4%) fit both NAFLD and MAFLD diagnostic criteria (overlap), 230 (9.2%) fit only the NAFLD diagnostic criteria (NAFLD group) and 404 (16.1%) fit the MAFLD diagnostic criteria (MAFLD group) at 2015. Over the next 5 years, medication rates increased in the NAFLD group for anti-hypertensive, + 17 (7.4%); diabetes, + 3 (1.3%); and dyslipidemia, + 32 (13.9%). In contrast, the only-MAFLD group showed a more significant increase with + 49 (12.1%), + 21 (5.2%), and + 49 (12.1%), for the respective medications, indicating a substantial rise in patients starting new medications. Our analysis of repeated health check-ups on participants revealed that the diagnostic criteria for MAFLD are more predictive of future treatment for metabolic disease than conventional diagnostic criteria for NAFLD.

First reports of clinical effects of transjugular intrahepatic portosystemic shunt in four patients with cirrhotic ascites refractory to tolvaptan.

OBJECTIVE: Ascites in patients with decompensated cirrhosis can lead to abdominal distention and decrease quality of life. Tolvaptan, a vasopressin V2 receptor antagonist, is an effective agent in the treatment of ascites, whereas some patients are refractory to tolvaptan. The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) for these patients is not known. In this study, we performed TIPS for tolvaptan-refractory cirrhotic patients and analysed its efficacy and safety in these patients. DESIGN: This retrospective analysis included patients with liver cirrhosis who received TIPS for ascites or hydrothorax refractory to tolvaptan therapy along with conventional diuretics between January 2015 and May 2018 at Tokai University Hospital. We evaluated the efficacy and safety of TIPS. RESULTS: This study included four patients. All patients presented with Child-Pugh class B liver cirrhosis and model for end-stage liver disease-sodium scores were 10/12/14/16. TIPS was generated successfully without any major complications in all patients. The body weight decreased by a mean of 4.7 (SD=1.0) kg and estimated glomerular filtration rate improved from a mean of 38.2 (SD=10.3) to 59.5 (SD=25.0) mL/min/1.73 m2 in a month after TIPS procedure. CONCLUSION: TIPS is an effective potential treatment for ascites in patients with tolvaptan refractory condition. In appropriate patients who can tolerate TIPS, the treatment may lead towards renal function improvement.

A case of breast cancer with extensive colon metastasis.

Breast cancer is one of the most common malignancies in women worldwide. Although most breast cancers are curable, in cases of metastasis, many are often found in the lungs, bones, liver, and central nervous system; however, metastasis to the gastrointestinal tract is rare. Invasive lobular carcinoma, which represents only 5%-10% of breast cancers, has a higher risk of metastasis to the gastrointestinal tract than invasive ductal carcinoma. Here, we report a rare case of gastrointestinal metastasis of invasive lobular carcinoma that spread extensively to the colonic mucosa. Given the improved survival rates of breast cancer patients with current treatments, many rarer metastatic diseases, including gastrointestinal metastases, are likely to be increased in the future.

The prevalence and natural history of hepatic cysts examined by ultrasound: a health checkup population retrospective cohort study.

The prevalence of hepatic cysts in the general population and their natural history are largely unknown. This study aimed to assess the prevalence and natural history of hepatic cysts by investigating health checkup participants. Ultrasonographic data of health checkup participants (n = 38,842) were retrospectively evaluated to calculate its prevalence. In addition, we assessed the changes in the size and characteristics of hepatic cysts over 10 years (n = 7709). We found the prevalence of hepatic cysts was 21.9%. Older age, female sex, and presence of kidney cysts or pancreatic cysts were associated with the occurrence of hepatic cysts. Younger age, female sex, and the existence of multiple hepatic cysts were associated with cyst enlargement. Among 126 individuals who had hepatic cysts with a diameter of 30 mm or larger at the first visit, two (1.6%) required treatment. Remain 124 cases showed four patterns: 44 cases with enlargement, 47 stable, 11 regression after enlargement, and 22 regression. Hyperechoic fluid inside the cysts was observed in 54.5% (18 of 33), which was significantly higher than 6.6% (6 of 91) of the non-regression (OR = 17.0). The appearance of intracystic hyperechoic fluid by ultrasound may predict subsequent regression of the hepatic cyst.

Successful endoscopic hemostasis compared to transarterial embolization in patients with colonic diverticular bleeding.

Transarterial embolization (TAE) is performed in patients with colonic diverticular bleeding after difficult endoscopic hemostasis or rebleeding. A total of 375 patients with hematochezia at our hospital from 1 April 2016 to 31 March 2020 were retrospectively analysed. Firstly, we compared the group in which hemostasis was achieved by endoscopy alone with the group that eventually underwent TAE. Secondly, we compared the group in which hemostasis was achieved by endoscopy alone, with the group switched to TAE after endoscopic hemostasis failed. The group that eventually underwent TAE had a higher shock index and lower Alb and PT% than the endoscopic hemostasis group. The shock index was correlated with Alb and PT%. When the cut-off value for the shock index was defined as more than 0.740, an OR of 9.500, a positive predictive value (PPV) of 40.0%, a negative predictive value (NPV) of 93.4%, and an accuracy of 80.3% were obtained for predicting a switch to TAE treatment. The greatest risk for TAE was the presence of shock and extravasation on contrast-enhanced CT. A switch to TAE treatment was likely when the shock index was more than 0.740. TAE should be considered in cases with a high shock index and showing extravasation on contrast-enhanced CT.

Eosinophilic Cholecystitis Associated with Eosinophilic Granulomatosis with Polyangiitis.

We report a case of eosinophilic cholecystitis associated with eosinophilic granulomatosis with polyangiitis (EGPA) complicated by cerebral hemorrhage. A 60-year-old man presented to a local hospital with a diagnosis of acute cholecystitis, with persistent fever and epigastric pain for 2 weeks. His symptoms persisted despite 3-week hospitalization; therefore, he was transferred to our hospital for further evaluation. Laboratory investigations upon admission showed white blood cells 26,300/µL and significant eosinophilia (eosinophils 61%). Abdominal computed tomography revealed no gallbladder enlargement but a circumferentially edematous gallbladder wall. Additional blood test results were negative for antineutrophil cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies; however, immunoglobulin (Ig)G and IgE levels were high at 1,953 mg/dL and 3,040/IU/mL, respectively. He improved following endoscopic transnasal gallbladder drainage for cholecystitis and was diagnosed with EGPA and received corticosteroid and immunosuppressant combination therapy. The eosinophil count decreased immediately after treatment, and abdominal pain and numbness resolved. He returned with left-sided suboccipital hemorrhage likely attributed to EGPA 6 months after discharge. EGPA is characterized by inflammation of small blood vessels and clinically manifests with an allergic presentation of bronchial asthma, as well as renal dysfunction, interstitial pneumonia, enteritis, and cerebral hemorrhage. Few reports have described cholecystitis as a presenting symptom of EGPA. We report a rare case of such a presentation with added considerations.

Brønsted acid-controlled [3 + 2] coupling reaction of quinone monoacetals with alkene nucleophiles: a catalytic system of perfluorinated acids and hydrogen bond donor for the construction of benzofurans.

We have developed an efficient Brønsted acid-controlled strategy for the [3 + 2] coupling reaction of quinone monoacetals (QMAs) with nucleophilic alkenes, which is triggered by the particular use of a specific acid promoter, perfluorinated acid, and a solvent, fluoroalcohol. This new coupling reaction smoothly proceeded with high regiospecificity in regard with QMAs for introducing π-nucleophiles to only the carbon α to the carbonyl group, thereby providing diverse dihydrobenzofurans and derivatives with high yields, up to quantitative, under mild conditions in short reaction times. The choice of Brønsted acid enabled us to avoid hydrolysis of the QMAs, which gives quinones, and the formation of discrete cationic species from the QMAs. Notably, further investigations in this study with regard to the acid have led to the findings that the originally stoichiometrically used acid could be reduced to a catalytic amount of 5 mol % loading or less and that the stoichiometry of the alkenes could be significantly improved down to only 1.2 equiv. The facts that only a minimal loading (5 mol %) of perfluoroterephthalic acid is required, readily available substrates can be used, and the regioselectivity can be controlled by the acid used make this coupling reaction very fascinating from a practical viewpoint.