Combined sepsis- and renal dysfunction-induced hypoglycaemia in an older patient taking cibenzoline.

Key Clinical Message: An 86-year-old geriatric patient with sepsis presented cibenzoline-induced hypoglycaemia, although within the boundary range of cibenzoline blood concentration. Abstract: An 86-year-old geriatric patient taking cibenzoline for ametropic hypertrophic cardiac tendinopathy was admitted to our hospital for the treatment of sepsis. Upon admission, blood cibenzoline levels of 400.1 ng/mL were observed. Antibiotic therapy was initiated and cibenzoline was discontinued. On Day 16, cibenzoline was administered orally at a reduced dose of 50 mg/day. Several days after restarting cibenzoline, the patient developed hypoglycaemia (64 mg/dL), prompting the administration of 20% glucose. The present case demonstrates a rational timeline for cibenzoline administration, considering the patient's renal dysfunction and sepsis. Clinicians should exercise caution when managing older patients with severe infections who are receiving cibenzoline, and should consider the possibility of blood glucose fluctuations regardless of cibenzoline blood levels. Further research is warranted to better understand and address the potential side effects of cibenzoline administration in geriatric populations.

Self-controlled Case Series Study for Acute Kidney Injury after Starting Proton Pump Inhibitors or Potassium-Competitive Acid Blocker in Patients with Cancer Using a Large Claims Database.

To investigate the risk of acute kidney injury (AKI) in patients with cancer following the initiation of proton pump inhibitors (PPIs) and potassium-competitive acid blocker (PCAB), considering sex and anti-cancer drug use. We conducted a self-controlled case-series study using the Japan Medical Data Center claims data from 12422 patients with cancer who were prescribed PPIs or PCAB between January 2017 and December 2019. Considering the timing of PPI or PCAB, control period (days -120 to -1), risk period 1 (days 0 to +30), and risk period 2 (days +31 to +365) were defined. To assess the incidence rate ratio (IRR) and 95% confidence interval (CI) as the risk ratio, we adjusted for anti-cancer drugs to assess the risk of AKI. Additionally, we also examined sex differences to identify the risk of AKI. AKI was observed in risk period 1 [2.05 (1.12-3.72), p = 0.0192], but a slight reduction was noted in risk period 2 [0.60 (0.36-1.00), p = 0.0481]. A sex-specific increase in the risk of AKI was observed only in males during risk period 1 [2.18 (1.10-4.32), p = 0.0260], with a reduction in risk period 2 [0.48 (0.26-0.89), p = 0.0200]. We identified an increased risk of AKI in patients with cancer starting PPIs or PCAB particularly in males within 30 d after PPI or PCAB initiation, emphasizing the need for vigilant monitoring and management of AKI in this patient population.

Identifying causative medications for agranulocytosis: A case report of an older adult with cerebral infarction.

Key Clinical Message: Most drugs that cause adverse events are difficult to identify in critically ill patients undergoing polypharmacy. We share our experience in identifying the causative drug among four suspect drugs administered during emergency treatment. Abstract: We present the case of a 93-year-old man who was admitted for the treatment of cerebrovascular events. The patient was initially prescribed dual antiplatelet therapy with aspirin and clopidogrel along with lansoprazole, Hange-koboku-toh, and elobixibat. On day 36 after admission, the patient was found to have developed agranulocytosis. To improve his cerebrovascular prognosis, we first discontinued medications other than the anticoagulant medicines and initiated filgrastim. We discontinued clopidogrel 9 days after the discontinuation of the other medicines considering his low white blood cell count. One day after the discontinuation of clopidogrel, the agranulocytosis was alleviated. Considering the time course, clopidogrel, lansoprazole, Hange-koboku-toh, and elobixibat were suspected as the culprit medicines. This case highlights the considerable challenges encountered in clinical practice when attempting to identify the drugs responsible for agranulocytosis, particularly in patients on intensive medication therapy.

Apple Pomace Extract Improves MK-801-Induced Memory Impairment in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease that involves progressive cognitive decline accompanied by synaptic degeneration and impaired neurotransmission. Recent studies revealed that apple pomace, a waste byproduct of the apple processing industry, has beneficial health properties, but its potential to prevent and treat AD has not been determined. Herein, we examined the effects of apple pomace extract on N-methyl-D-aspartate receptor antagonist MK-801-induced memory impairment in mice. Repeated treatment with apple pomace extract for 7 days reversed the MK-801-induced impairment of associative memory and recognition memory. RNA sequencing revealed that repeated treatment with apple pomace extract altered the gene expression profile in the hippocampus of mice. Real-time PCR showed that apple pomace extract induced upregulation of the mRNA expression for Zfp125 and Gstp1. Furthermore, gene sets related to synapse and neurotransmission were upregulated by apple pomace extract. These findings indicate that apple pomace extract may be useful for the prevention and treatment of AD.

Current perspectives on the diversification of endoscopic ultrasound-guided fine-needle aspiration and biopsy.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) has undergone significant advancements since it was first reported in 1992. Initially focused on the pancreas, EUS-guided fine-needle aspiration (FNA) has now been extended to encompass all organs proximal to the gastrointestinal system. Recently, a novel fine-needle biopsy (FNB) needle with an end-cut tip was developed, allowing for the collection of specimens suitable for histological assessment, a feat hard to achieve with traditional needles. The FNB needle holds promise for applications in immunohistochemistry staining and genetics evaluation, and it has the potential to yield specimens of comparable quality to core needle biopsy during percutaneous puncture, especially for lesions beyond the pancreas, such as lymph nodes. This review focuses on the efficacy of EUS-FNA/FNB for extended target regions, specifically lymph nodes, spleen, adrenal gland, and ascites. The indications for EUS-FNA have greatly expanded beyond the pancreas over the years, and future improvements and innovations in puncture needles will allow for the collection of higher-quality specimens, which is expected to play a significant part in personalized cancer treatment.

Transient EDTA-dependent pseudothrombocytopenia and ulcerative colitis recurrence during chemotherapy: A case of misleading platelet count results attributable to a laboratory artifact.

Key Clinical Message: EDTA-dependent pseudothrombocytopenia as well as myelosuppression should be suspected when thrombocytopenia occurs in patients with autoimmune disease during chemotherapy. Abstract: A patient with pancreatic cancer and ulcerative colitis developed transient ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia with exacerbation of ulcerative colitis during chemotherapy. Unfortunately, pseudothrombocytopenia could not be immediately detected because thrombocytopenia was masked by a reasonable time course of adverse events associated with chemotherapy and ulcerative colitis recurrence. When thrombocytopenia occurs during chemotherapy, especially in patients with autoimmune diseases, EDTA-dependent pseudothrombocytopenia and bone marrow suppression caused by anti-cancer agents should be suspected.

A super-geriatric patient with gastrostomy underwent life-threatening prothrombin time-international normalized ratio prolongation by warfarin following fasting and antibiotic therapy.

Key Clinical Message: A 97-year-old woman with gastrostomy had a drastic enhancement for PT-INR after starting antibiotic therapy. Possible causes include (1) vitamin K deficiency due to fasting and (2) a combination of warfarin and antibiotics. Abstract: Geriatric and Asian-descent patients are more sensitive to the effects of warfarin, a key anticoagulant drug. In this report, we present a 97-year-old bedridden woman being treated with warfarin for cardiogenic cerebral infarction and femoral neck replacement as part of in-home medical care with a gastrostomy and was admitted to our hospital after developing pneumonia. We discontinued warfarin and started antibiotics, and her pneumonia-related symptoms improved. Eleven days after restarting warfarin, the patient's PT-INR surpassed the upper limit for measurement (over 10). We considered the mechanism might be triggered by (1) fasting, low nutrition status; and (2) antibiotics secondary to risk factors such as gastrostomy and being a super-geriatric woman. We recommend careful monitoring of PT-INR in patients treated with warfarin and antibiotics, especially in the setting of gastrostomy or older persons.

Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset.

Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.

Dilemma Facing Patients Aged 75 Years and Older on Fluid Restriction When Drug Package Inserts Advise Use of a Lot of Water: A Cross-Sectional, Descriptive, and Hypothesis-Generating Study Using a Large Claims Database.

BACKGROUND: Several oral drugs are recommended to be taken with large amounts of water for reasons such as peptic ulcer prophylaxis. On the other hand, there are many patients with diseases that restrict water intake, and the actual frequency of patients receiving prescriptions in these conflicting situations is not clear. OBJECTIVE: Using a large claims database in Japan, this study aimed to determine the proportion of patients aged ≥ 75 years on fluid restriction who received drugs whose drug package insert mentioned "a large amount of water intake is needed when taking the drug". METHODS: We performed a prescription survey of older patients over 75 years of age using the Japan Medical Data Centre (JMDC) claims database. Out of approximately 8800 oral drugs used in Japan, we defined 29 drugs for which package inserts noted that a large amount of water intake is recommended during drug administration. We defined diagnosis codes for some common diseases for which restricted water intake is likely recommended: heart failure (NYHA class III or IV), liver cirrhosis with ascites, and chronic kidney disease stage 5, including dialysis patients. RESULTS: Of 5968 patients aged ≥ 75 years (men 47.7%), 320 (5.4%) patients with heart failure (2.8%, n = 170), liver cirrhosis (0.7%, n = 40), or chronic kidney disease (1.9%, n = 113), diagnoses likely associated with the need for fluid restriction, were prescribed drugs for which abundant fluid at intake was recommended. Among 29 identified drugs, 15 drugs were administered to older patients over 75 years with fluid restriction due to said diseases. CONCLUSIONS: Of patients 75 years and older with disease likely requiring water restriction, 5.4% faced the dilemma of following advice to restrict fluid intake due to their diagnoses or to adhere to instructions in drug package inserts to have abundant fluid intake when taking the drug. Our study raises awareness regarding the dilemma of water restriction and intake in clinical settings, highlighting the importance of considering individual patient needs. These real-world findings emphasize the need for information and guidelines to assist healthcare professionals in navigating this dilemma and making informed decisions for the benefit of their patients.

The risk of weekend biopsy: Impact of specimen source and fixation status on HER2 assessment in the treatment of advanced gastric cancer (The HER_WEEKEND study).

Accurate evaluation of human epidermal growth factor receptor type 2 (HER2) expression is crucial for determining chemotherapy regimens in gastric cancer. However, formalin fixation status has been identified as an important factor affecting HER2 assessment reliability. This retrospective cohort study aimed to investigate the correlation between sample collection day (weekday vs. weekend) and source (biopsy vs. surgical specimens) in assessing HER2 expression in patients with unresectable advanced/recurrent gastric cancer. Data were collected from gastric cancer patients who received chemotherapy at a single public hospital in Japan from 2008 to 2021. The analysis included 177 patients (109 men, 68 women) with a median age of 68.0 (21-88) years, and the primary outcome was the HER2 positivity rate. The overall HER2 positivity rate was 18.1%, with higher rates on weekdays (20.0%) compared to weekends (12.8%). Biopsies had higher positivity rates on weekdays (23.9%) but lower rates on weekends (11.1%) than surgical specimens. Significant differences were observed in formalin fixation times between weekdays and weekends for both biopsies and surgical samples. The study findings suggest that longer formalin fixation times on weekends may lead to underestimating HER2 expression, particularly in biopsies. Therefore, it is crucial to be cautious of excessive formalin fixation when collecting samples, especially during weekend biopsies.

Impact of Radar Chart-Based Information Sharing in a Multidisciplinary Team on In-Hospital Outcomes and Prognosis in Older Patients With Heart Failure.

Background: A multidisciplinary team (MDT) approach is crucial for managing older patients with heart failure (HF). We investigated the impact on clinical outcomes of implementation of a conference sheet (CS) with an 8-component radar chart for visualizing and sharing patient information. Methods and Results: We enrolled 395 older inpatients with HF (median age 79 years [interquartile range 72-85 years]; 47% women) and divided them into 2 groups according to CS implementation: a non-CS group (before CS implementation; n=145) and a CS group (after CS implementation; n=250). The clinical characteristics of patients in the CS group were assessed using 8 scales (physical function, functional status, comorbidities, nutritional status, medication adherence, cognitive function, HF knowledge level, and home care level). In-hospital outcomes (Short Physical Performance Battery, Barthel Index score, length of hospital stay, and hospital transfer rate) were significantly better in the CS than non-CS group. During the follow-up period, 112 patients experienced composite events (all-cause death or admission for HF). Inverse probabilities of treatment-weighted Cox proportional hazard analyses demonstrated a 39% reduction in risk of composite events in the CS group (adjusted hazard ratio 0.65; 95% confidence interval 0.43-0.97). Conclusions: Radar chart-based information sharing among MDT members is associated with superior in-hospital clinical outcomes and a favorable prognosis.

Dexamethasone to prednisolone rotation relieved hiccups in colorectal cancer patient continuing teleworking during anticancer therapy.

We present a case of chemotherapy-induced hiccups that were alleviated by steroid rotation. Hiccups are often overlooked, but they have an impact on the patient's quality of life. In the COVID-19 era, web-based teleworking has become an important tool, hiccups during a teleconference should be noted as a concern for patients.

Novel anti-reflux biliary metal stent with a distal tapered end for distal malignant biliary obstruction: a feasibility study.

Background and study aims We developed a self-expandable metallic stent (SEMS) with a distal tapered end to reproduce the physiological bile flow with a pressure gradient due to the difference in the diameter. We aimed to evaluate the safety and efficacy of the newly developed distal tapered covered metal stent (TMS) for distal malignant biliary obstruction (DMBO). Patients and methods This single-center, prospective, single-arm study was conducted in patients with DMBO. The primary endpoint was time to recurrent biliary obstruction (TRBO), and the secondary endpoints were the survival time and incidence of adverse events (AEs). Results Thirty-five patients (15 men, 20 women; median age, 81 years [range: 53-92]) were enrolled between December 2017 and December 2019. The primary diseases were pancreatic head cancer in 25 cases, bile duct cancer in eight cases, and ampullary cancer in two cases. TMS was successfully placed in all cases. Acute cholecystitis occurred as an early AE (within 30 days) in two cases (5.7 %). The median TRBO was 503 days, median survival time was 239 days. RBO was observed in 10 cases (28.6 %), and the causes were distal migration in six cases, proximal migration in two cases, biliary sludge in one case, and tumor overgrowth in one case. Conclusions Endoscopic placement of the newly developed TMS in patients with DMBO is technically feasible and safe, and the TRBO was remarkably long. The anti-reflux mechanism based on the difference in diameter may be effective, and a randomized controlled trial with a conventional SEMS is required.

Histological improvement in chronic hepatitis C-autoimmune hepatitis overlap syndrome by glecaprevir and pibrentasvir.

A 60-year-old man with type-2 diabetes and chronic hepatitis C (HCV) was diagnosed with single hepatocellular carcinoma (HCC) of 67 mm in the hepatic posterior right lobe. Lenvatinib 8 mg was initiated but discontinued because of grade 3 liver injury. The patient continued to have prolonged liver injury and persistently high immunoglobulin G levels. Antinuclear antibody titer increased from 1:40 to 1:320. Histopathological examination of a liver biopsy specimen revealed interface hepatitis with lymphocyte and plasma cell infiltration, rosette formation, and emperipolesis, suggesting the possibility of autoimmune hepatitis (AIH). First, treatment with prednisolone was initiated; however, the response was poor. After starting glecaprevir/pibrentasvir (GLE/PIB) as direct-acting antivirals (DAA), HCV RNA rapidly disappeared, and serological liver function improved. After confirmation of sustained virological response 24, HCC recurrence was observed, and partial hepatectomy was performed. Background liver findings showed that liver parenchymal inflammation improved compared with that before DAA treatment. This is the first case of HCV-AIH overlap syndrome treated with DAA using GLE/PIB. Liver function improved within a short treatment period of 8 weeks, as confirmed using serology and histology.

[Safety and Efficacy of Robot-Assisted Surgery for Early Uterine Cancer in Our Institution over Five Years Since Its Introduction].

Lacking experience of laparoscopic surgery against gynecologic malignancies, we started performing robot-assisted surgery for uterine cancer in September 2017. Here we compared the safety and efficacy of robot-assisted surgery with those of open surgery in early-stage uterine cancer patients. The surgical time was significantly longer and the blood loss and hospital stay were significantly shorter for robot-assisted versus open surgery. No recurrence was observed after robot-assisted surgery. Robot-assisted surgery can be safely performed even in general hospitals and is an effective treatment option for early-stage uterine cancer patients.

Current Status of the Diagnosis of Early-Stage Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) can be treated with surgery, chemotherapy, and radiotherapy. Despite medical progress in each field in recent years, it is still insufficient for managing PDAC, and at present, the only curative treatment is surgery. A typical pancreatic cancer is relatively easy to diagnose with imaging. However, it is often not recommended for surgical treatment at the time of diagnosis due to metastatic spread beyond the pancreas. Even if it is operable, it often recurs during postoperative follow-up. In the case of PDAC with a diameter of 10 mm or less, the 5-year survival rate is as good as 80% or more, and the best index for curative treatment is tumor size. The early detection of pancreatic cancer with a diameter of less than 10 mm or carcinoma in situ is critical. Here, we provide an overview of the current status of diagnostic imaging features and genetic tests for the accurate diagnosis of early-stage PDAC.

Quantitative analysis of tissue area of endoscopic ultrasound-guided liver biopsy specimens using 19-gauge fine-needle biopsy needle in patients with diffuse liver disease: A single-center retrospective study.

BACKGROUND/PURPOSE: Endoscopic ultrasound-guided liver biopsy (EUS-LB) is a novel liver biopsy technique. We aimed to evaluate the efficacy and safety of EUS-LB in comparison with percutaneous liver biopsy (PLB). METHODS: This retrospective study evaluated the safety and efficacy of EUS-LB using a 19-gauge fine needle biopsy (FNB) needle compared with PLB using a spring-loaded 16-gauge needle in patients with diffuse liver disease at our hospital from April 2017 to December 2020. The primary outcomes included the total hepatic tissue surface area and the total number of portal tracts. Secondary outcomes included the success and adverse event rates. RESULTS: Twenty patients each underwent EUS-LB and PLB. There was no statistical difference in the sum of liver tissue surface area (22 mm2 vs 22.6 mm2 , P = .910) and the total number of portal tracts (29 vs 25, P = .916). The success rate was 95% (19/20) for EUS-LB and 100% (20/20) for PLB (P = 1). There were two adverse events in the PLB group but none in the EUS-LB group (P = .487). CONCLUSIONS: Endoscopic ultrasound-guided liver biopsy using FNB has an optimal tissue yield and success rate and is safe compared to PLB. Thus, EUS-LB may be a new alternative to PLB.

Changes in intestinal bacteria and imbalances of metabolites induced in the intestines of pancreatic ductal adenocarcinoma patients in a Japanese population: a preliminary result.

BACKGROUND: The relationship between pancreatic ductal adenocarcinoma (PDAC) and the intestinal environment is not fully understood. The purpose of this study was to elucidate the characteristics of the intestinal environment in PDAC. METHODS: We performed a case-control study of 5 Japanese patients with unresectable PDAC located in the body or tail (PDAC-bt). The number of patients analyzed was limited for this preliminary study. We included 68 healthy subjects, herein control, of pre-printed study in the preliminary study. 16S rRNA amplicon sequencing and metabolomic analysis were performed using fecal samples from the subjects. RESULTS: There was no difference in the Shannon index and Principal Coordinate Analysis between PDAC-bt and the control. However, a significant increase in oral-associated bacteria (Actinomyces, Streptococcus, Veillonella, Lactobacillus) was observed. A significant decrease of Anaerostipes was demonstrated in the feces of PDAC-bt compared with the control. The intestinal propionic acid and deoxycholic acid were significantly lower in PDAC-bt compared with the control. CONCLUSIONS: We showed that the intestinal environment of PDAC-bt is characterized by an increase in oral-associated bacteria and an imbalance of metabolites but without changes in alpha and beta diversity of the gut microbiota profiles.Clinical Trial Registration: www.umin.ac.jp, UMIN 000041974, 000023675, 000023970.

Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis.

Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.