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Masao Ichiki,1 Hiroshi Wataya,2 Kazuhiko Yamada,3 Nobuko Tsuruta,4 Hiroaki Takeoka,1 Yusuke Okayama,1 Jun Sasaki,1 Tomoaki Hoshino3 1Department of Respiratory Medicine, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 2Division of Internal Medicine, Saiseikai Fukuoka General Hospital, Fukuoka City, 3Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University, Kurume City, 4Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka City, Fukuoka, Japan Purpose: Diarrhea and oral mucositis induced by afatinib can cause devastating quality of life issues for patients undergoing afatinib treatment. Several studies have shown that hangeshashin-to (TJ-14) might be useful for chemotherapy-induced diarrhea and oral mucositis. In this study, we investigated the prophylactic effects of TJ-14 for afatinib-induced diarrhea and oral mucositis and minocycline for afatinib-induced skin rash.Patients and methods: First- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have become the standard first-line treatment in patients with EGFR-mutated non-small cell lung cancer. The incidence of diarrhea was higher with afatinib than with gefitinib, and we conducted a single-arm Phase II study with afatinib. Patients who had previously undergone treatment with afatinib were ineligible. Both TJ-14 (7.5 g/day) and minocycline (100 mg/day) were administered simultaneously from the start of afatinib administration. The primary end point was the incidence of ≥ grade 3 (G3) diarrhea (increase of ≥7 stools/day over baseline) during the first 4 weeks of treatment. The secondary end points were the incidence of ≥ G3 oral mucositis (severe pain interfering with oral intake) and ≥ G3 skin toxicity (severe or medically significant but not immediately life-threatening).Results: A total of 29 patients (nine men and 20 women; median age, 66 years; performance status, 0/1/2: 18/10/1) were enrolled from four centers. Four patients had undergone prior treatment with chemotherapy, including gefitinib or erlotinib. In all, 20 (68.9%) patients and one (3.4%) patient had diarrhea of any grade and ≥ G3, respectively. One (3.4%) patient had ≥ G3 oral mucositis; no patients had ≥ G3 skin rash. A total of 18 (62%) of the 29 patients achieved a partial response.Conclusion: The present study indicated a trend in which TJ-14 reduced the risk of afatinib-induced diarrhea and minocycline reduced the risk of afatinib-induced skin rash. Keywords: epidermal growth factor receptor, hangeshashin-to, afatinib, adverse events

The aim of this study was to evaluate the usefulness of technetium-99m (Tc-99m) pertechnetate scintigraphy with lemon juice stimulation in the diagnosis of Warthin's tumor and its correlation with Tc-99m uptake, tumor size, and histologic subtype. Tc-99m pertechnetate scintigraphy before and after lemon juice stimulation and pathologic specimens of 34 Warthin's tumors and 47 non-Warthin's lesions were retrospectively evaluated. Tc-99m uptake of Warthin's tumors before and after stimulation was visually graded as follows: absent; indeterminate; low grade; definite; and strong. Tumor size was defined as maximum diameter of the tumor measured from the surgical specimen. Warthin's tumors were classified into three histologic subtypes according to the ratio of epithelial and lymphoid stromal components: predominant epithelial; intermediate; and low-grade epithelial types. Eighteen of 34 (53%) Warthin's tumors and one benign lymphoepithelial cyst showed higher uptake than that of the normal parotid gland on Tc-99m scintigraphy before lemon juice stimulation. Thirty-two of the 34 (94%) Warthin's tumors, one benign lymphoepithelial cyst, one pleomorphic adenoma, and one oncocytoma revealed higher uptake than that of the normal parotid gland on Tc-99m scintigraphy after lemon juice stimulation. The mean size was 37 mm in strong uptake Warthin's tumors, 24 mm in definite uptake tumors, 19 mm in low-grade uptake tumors, and 12 mm in low-grade uptake tumors excluding those tumors with large cystic component. There was a significant correlation between tumor size and degree of Tc-99m uptake after lemon juice stimulation. However, there was no correlation between histologic subtype and Tc-99m uptake, and histologic subtype and tumor size in Warthin's tumors. Our study concludes that Tc-99m pertechnetate scintigraphy with lemon juice stimulation is useful for the detection and diagnosis of Warthin's tumor. The degree of uptake in Warthin's tumor on Tc-99m scintigraphy with lemon juice stimulation depends mainly on tumor size and the presence of large cystic component in it. [ABSTRACT FROM AUTHOR]

Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non-small-cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow-up. The median age of the Japanese patients was 73 years (range 63-88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment-naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment-related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment-related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Mass vaccination is the most important strategy to terminate the coronavirus disease 2019 (COVID-19) pandemic. Reports suggest the potential risk of the development of new-onset or relapse of minimal change disease (MCD) following COVID-19 vaccination; however, details on vaccine-associated MCD remain unclear. A 43-year-old man with MCD, who had been in remission for 29 years, developed nephrotic syndrome 4 days after receiving the third dose of the Pfizer-BioNTech vaccine. His kidney biopsy revealed relapsing MCD. Intravenous methylprednisolone pulse therapy followed by oral prednisolone therapy was administered, and his proteinuria resolved within 3 weeks. This report highlights the importance of careful monitoring of proteinuria after COVID-19 vaccination in patients with MCD, even if the disease is stable and no adverse events occurred during previous vaccinations. Our case report and literature review of COVID-19 vaccine-associated MCD indicated that MCD relapse tends to occur later after vaccination and slightly more often following the second and subsequent vaccine doses than new-onset MCD., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Occasionally, patients undergoing dialysis develop acute severe hypotension that requires interruption of dialysis within minutes of initiating every dialysis session. Although the underlying causes of recurrent intradialytic hypotension are evaluated extensively, including dialysis-associated allergic reactions or other possible causes, the definitive cause is sometimes missed. Dialysis is a life-sustaining procedure; therefore, prompt identification and management of the underlying cause of dialysis intolerance are crucial. Herein, we report three cases of patients undergoing dialysis who presented with hypereosinophilia-associated acute intradialytic hypotension. All three patients developed acute severe hypotension within minutes after the start of every dialysis session. The prescriptions for dialysis were changed, but episodes of intradialytic hypotension persisted. Pretreatment with methylprednisolone given intravenously before the dialysis session was also ineffective. All patients had hypereosinophilia (> 1500/μL) of different etiology. Eosinophil-lowering therapy with 0.5 mg/kg of prednisolone given orally daily was initiated, and all of them could restart dialysis without any hypotensive episodes within a few days. Our case report and literature review indicated that hypereosinophilia, regardless of its etiology, could result in severe acute hypotension shortly after the start of dialysis session. The oral administration of prednisolone daily was highly effective on hypereosinophilia-associated intradialytic hypotension, while pretreatment with intravenous corticosteroid therapy just before dialysis had no effect. Hypereosinophilia-associated acute intradialytic hypotension is an under-recognized condition; therefore, clinicians need to be aware of this clinical entity and initiate effective treatment strategies. We also provide a brief summary of previously published cases., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Background: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy., Materials and Methods: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17., Results: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] =  0.67, 95% confidence interval [CI]: 0.51-0.88, p =  0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p =  0.0011) and OS (p  < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively)., Conclusion: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

To investigate the relationship between white blood cell (WBC) count and incidence of hyper-low-density lipoprotein (LDL) cholesterolemia in a population-based longitudinal study. This is a retrospective study using data of annual health check-ups for residents of Iki City, Japan. A total of 3312 residents (≥ 30 years) without hyper-LDL cholesterolemia at baseline were included in this analysis. Primary outcome was incidence of hyper-LDL cholesterolemia (LDL cholesterol levels ≥ 3.62 mmol/L and/or use of lipid lowering drugs). During follow-up (average 4.6 years), 698 participants development of hyper-LDL cholesterolemia (incidence 46.8 per 1000 person-years). Higher incidence of hyper-LDL cholesterolemia was observed among participants with higher leukocyte count (1st quartile group: 38.5, 2nd quartile group: 47.7, 3rd quartile group: 47.3, and 4th quartile group: 52.4 per 1,000 person-years, P = 0.012 for trend). Statistically significant relation was observed even after adjustment for age, gender, smoking, alcohol intake, leisure-time exercise, obesity, hypertension and diabetes: hazard ratio 1.24 (95% confidence interval 0.99 to 1.54) for 2nd quartile group, 1.29 (1.03-1.62) for 3rd quartile group and 1.39 (1.10-1.75) for 4th quartile group, compared with 1st quartile group (P for trend = 0.006). Increased WBC count was related to incidence of hyper-LDL cholesterolemia in general Japanese population., (© 2023. The Author(s).)

Background: The aim of the study was to identify factors related to the need for hospitalization due to acute alcohol intoxication., Methods: The data of 42 patients with acute alcohol intoxication who visited our hospital from April 1, 2014 to September 30, 2015 were available for analysis. Factors related to outcome included hospitalization or release to home, Glasgow coma scale (GCS), temperature, pulse rate, blood pressure, oxygen saturation of the peripheral artery (SpO 2 ), and respiratory rate. A retrospective survey was done that included estimated blood alcohol concentration, osmotic pressure, and serum lactate level. The following formula was used to estimate blood alcohol concentration: (measured osmotic pressure - estimated osmotic pressure × 4.6 mg/dL). Univariate analysis of each variable was done for the two outcome groups, hospital admission or release to home, then statistically significant items were subjected to multivariate analysis., Results: Of the 42 patients (average age 22.8 ± 8.6 years, 33 men, six women), 29 were admitted and 13 were released to home. There was a weak correlation between estimated blood alcohol concentration and GCS. There was no significant difference in alcohol concentration or GCS between the hospitalized and released to home groups. In multivariate analysis using the outcome as the objective variable, a serum lactate level of 26 mg/dL or higher was associated with the need for hospitalization (odds ratio: 6.7)., Conclusion: A serum lactate level of 26 mg/dL would be useful for deciding if hospitalization is necessary for patients with acute alcohol intoxication., Competing Interests: The authors declare that they have no conflict of interest., (Copyright 2023, Takeoka et al.)

Background: Vibrio vulnificus is typically present in seawater, fish, and shellfish, and is known to cause severe sepsis, particularly in patients with liver diseases such as cirrhosis. V. vulnificus is one of the most dangerous waterborne pathogens, and infection mainly occurs in western Japan during the summer, with an increased fatality rate. Herein, we report the case of a patient with primary biliary cholangitis and sepsis caused by V. vulnificus infection sustained through shrimp shelling., Case Presentation: An 82-year-old Japanese Asian woman with no medical history or underlying disease developed redness, swelling, and pain, which extended from the right fingers to the upper arm. A diagnosis of sepsis due to cellulitis was made. Blood culture detected V. vulnificus; thus, minocycline was administered in addition to meropenem. The disease course was uneventful, and the patient was discharged on day 28 of hospitalization. Symptoms in the right upper arm developed 1 day after the patient shelled a large number of shrimp; therefore, the infection route was assumed to be through wounds sustained during shrimp shelling. We suspected liver disease and measured serum anti-mitochondrial M2 antibody levels, leading to the diagnosis of primary biliary cholangitis., Conclusions: As in this case, small wounds caused by handling fish and shrimp are a potential source of infection. Patients with severe V. vulnificus infection should be thoroughly assessed for the presence of liver diseases such as primary biliary cholangitis., (© 2023. The Author(s).)

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder with genetic defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes, leading to recurrent severe infections and granuloma formation. Genitourinary involvement, including obstructive granulomas, infections, nephrotoxicity of anti-infective agents, and amyloidosis, is frequently observed in patients with CGD, whereas the clinical and pathological details of the less commonly reported glomerular disease remain obscure. Here, we report the case of a patient with CGD who developed rapidly progressive IgA vasculitis-associated nephritis (IgAVN) and review the literature on biopsy-proven glomerular diseases in patients with CGD. A 22-year-old male patient with CGD developed rapidly progressive glomerulonephritis (RPGN) following peripheral purpura and was diagnosed with crescentic IgAVN based on the renal biopsy evaluation. There was no evidence of active infections, and he received pulse intravenous methylprednisolone followed by oral prednisolone. His renal function returned to normal within 4 weeks, and his proteinuria and microhematuria finally resolved. The present case and literature review indicate that IgAVN and IgA nephropathy with RPGN are the most common causes of glomerular disease in patients with CGD. Clinicians should be aware of the possibility of these diseases as causes of RPGN in CGD, because delays in diagnosis and appropriate treatment may affect renal outcomes., (© 2021. Japanese Society of Nephrology.)

Background: MET exon 14 skipping is an oncogenic driver occurring in 3-4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib., Methods: In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned., Results: As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months' follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable [ne]), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients' quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively)., Conclusions: Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable., (© The Author(s) 2021. Published by Oxford University Press.)

The differentiation between major histological types of lung cancer, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC), and small-cell lung cancer (SCLC) is of crucial importance for determining optimum cancer treatment. Hematoxylin and Eosin (H&E)-stained slides of small transbronchial lung biopsy (TBLB) are one of the primary sources for making a diagnosis; however, a subset of cases present a challenge for pathologists to diagnose from H&E-stained slides alone, and these either require further immunohistochemistry or are deferred to surgical resection for definitive diagnosis. We trained a deep learning model to classify H&E-stained Whole Slide Images of TBLB specimens into ADC, SCC, SCLC, and non-neoplastic using a training set of 579 WSIs. The trained model was capable of classifying an independent test set of 83 challenging indeterminate cases with a receiver operator curve area under the curve (AUC) of 0.99. We further evaluated the model on four independent test sets-one TBLB and three surgical, with combined total of 2407 WSIs-demonstrating highly promising results with AUCs ranging from 0.94 to 0.99.

Background: Infection, such as by human immunodeficiency virus (HIV), has been reported to cause atherosclerosis by inducing inflammation. Because human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus, as is HIV, we investigated the possible influence of HTLV-1 on the pathogenesis of atherosclerosis by use of established atherosclerosis parameters., Methods: The study was done on Iki Island, Fukuoka, an area endemic for HTLV-1. The data of 1,424 residents who reported to an annual health check were available for analysis. Anti-HTLV-1 antibody status and factors associated with atherosclerosis were examined, including maximum intima-media thickness (Max-IMT) and brachial-ankle pulse wave velocity (PWV)., Results: HTLV-1 positive participants had significantly higher Max-IMT (1.15 ± 0.55 vs. 1.08 ± 0.61 mm, P = 0.04) and PWV (1,760.6 ± 414.5 vs. 1,657.1 ± 425.5 cm/s, P < 0.01) values than did those negative. Moreover, in multiple regression analysis (odds ratio: 1.39, P < 0.01) of participants with Max-IMT 1.1 mm or over, HTLV-1 was extracted as an independent factor for the development of atherosclerosis., Conclusion: Our results indicate that HTLV-1 infection confers a high risk of atherosclerosis, although its opposite relation is also possible. It is important to carefully follow the health status of HTLV-1 carriers., Competing Interests: None to declare., (Copyright 2021, Takeoka et al.)

Background: When using rapid antigen test kits for the diagnosis of influenza, false-negative results may occur if done too soon after the onset of symptoms. The purpose of this study was done to determine clinical laboratory items other than rapid antigen testing are useful for diagnosing influenza., Methods: The subjects were 915 patients who visited the outpatient clinic of hospital between April 2010 and March 2017 during the influenza epidemic seasons, from December to April, and had both fever of 37.0 degrees or more and cold symptoms., Results: Of the 214 patients who met the inclusion criteria, 176 had influenza. Multivariate analysis extracted patient consultation within four days of onset, fever of 37 degrees or higher, posterior pharyngeal lymphoid follicles, CRP of 0.77 mg/dL or less, and a lymphocyte count of 900/μL less as independent variables., Conclusion: In previous study, lymphoid follicles on the posterior pharyngeal wall and decreased lymphocyte count were reported as influenza-specific findings. Both were confirmed with high specificity in our study, indicating that both would be useful when patients with influenza-like symptoms were false-negative for the rapid antigen test., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2021 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)