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Abstract Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr]

Abstract Background Famotidine, a histamine2-receptor antagonist (H2Ras), is widely used to treat and prevent gastrointestinal symptoms during pregnancy. Although several studies have reported the use of H2Ras during pregnancy, limited data on famotidine were included in these reports. Therefore, we analyzed pregnancy outcome data to evaluate the effects of famotidine use during pregnancy on the fetus. Methods Pregnancy outcome data were used for females enrolled in two Japanese facilities that provided counseling on drug use during pregnancy between April 1988 and December 2017. For the primary endpoint, the incidence of congenital malformations was calculated from the data of live birth to pregnant women who took famotidine (n = 330) or drugs considered to exert no teratogenic risk (control, n = 1,407) during the first trimester of pregnancy. Considering secondary endpoints, the incidence of obstetric outcomes, including preterm delivery, was calculated from data on the use of famotidine (n = 347) and controls (n = 1,476) during the entire pregnancy. The crude odds ratios (cORs) for the incidence of congenital malformations were calculated using univariate logistic regression analysis, with the control group used as the reference. Adjusted ORs (aORs) were calculated using multivariate logistic regression analysis adjusted for various other factors. Results The incidences of congenital malformations in the famotidine and control groups were 3.9% and 2.8%, respectively. There was no significant difference between the famotidine and control groups (cOR: 1.40 [95% CI:0.68–2.71], aOR: 1.06 [95% CI:0.51–2.16]). Conversely, the preterm delivery rates were 8.1% and 3.8% in the famotidine and control groups, respectively, indicating a significant difference (cOR: 2.00 [95% CI:1.20–3.27]). However, the multivariate analysis eliminated famotidine use as a confounding factor. Conclusions This observational cohort study revealed that exposure to famotidine during the first trimester of pregnancy was not associated with an increased risk of congenital malformations in infants. Although a higher rate of preterm delivery was detected in famotidine users when compared with controls, this could be attributed to confounding factors, such as complications.

Abstract Background Augmented renal clearance (ARC) decreases the therapeutic concentration of drugs excreted by the kidneys in critically ill patients. Several ARC prediction models have been developed and validated; however, their usefulness in Japan has not been comprehensively investigated. Thus, we developed a unique ARC prediction model for a Japanese mixed intensive care unit (ICU) population and compared it with existing models. Methods This retrospective study enrolled a mixed ICU population in Japan from January 2019 and June 2022. The primary outcome was the development and validation of a model to predict ARC onset based on baseline information at ICU admission. Patients admitted until May 2021 were included in the training set, and external validation was performed on patients admitted thereafter. A multivariate logistic regression model was used to develop an integer-based predictive scoring system for ARC. The new model (the JPNARC score) was externally validated along with the ARC and Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) scores. Results A total of 2,592 critically ill patients were enrolled initially, with 651 patients finally included after excluding 1,941 patients. The training and validation datasets comprised 456 and 195 patients, respectively. Multivariate analysis was performed to develop the JPNARC score, which incorporated age, sex, serum creatinine, and diagnosis upon ICU admission (trauma or central nervous system disease). The JPNARC score had a larger area under the receiver operating characteristic curve than the ARC and ARCTIC scores in the validation dataset (0.832, 0.633, and 0.740, respectively). Conclusions An integer-based scoring system was developed to predict ARC onset in a critically ill Japanese population and showed high predictive performance. New models designed to predict the often-unrecognized ARC phenomenon may aid in the decision-making process for upward drug dosage modifications, especially in resource- and labor-limited settings.

Abstract Background Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting. Methods Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation. Results Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2–4.8 and 4.3–9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08–3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups. Conclusions This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms.

Abstract Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.

Abstract Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m2)-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2–4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14–0.86, P = 0.02 for all cycles; 0.26, 0.11–0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.

Abstract Regorafenib is the first multikinase inhibitor for treating metastatic colorectal cancer (mCRC). Proteinuria is a frequently encountered adverse effect, regardless of prior administration of vascular endothelial growth factor inhibitors. Herein, we aimed to assess the impact of baseline preexisting proteinuria on regorafenib-induced problematic proteinuria during real-world mCRC therapy. Patients with mCRC receiving regorafenib (n = 100) were retrospectively assessed and divided into control and preexisting proteinuria (baseline grade of 1–2) groups. The primary endpoint was the development of grade ≥ 2 (grade ≥ 3 in case of baseline grade 2 patients) proteinuria. Propensity score-matching was performed to confirm the robustness of primary analyses. Defined proteinuria occurred in 30.7 and 57.9% of patients in the control and preexisting proteinuria groups, respectively, with significant differences in the all-patient population (P = 0.01). The preexisting proteinuria group exhibited significant defined proteinuria development within 7 days of regorafenib initiation, grade ≥ 3 symptoms, and treatment suspension owing to proteinuria. Similar results were obtained in the propensity score-matched population. According to multivariate logistic regression analysis, baseline proteinuria was a singular risk factor for defined proteinuria development (adjusted odds ratio; 3.76, 95% confidence interval; 1.45–9.75, P = 0.007). Collectively, our study revealed that patients with preexisting proteinuria develop regorafenib-induced proteinuria degradation.

Background: The KIT receptor tyrosine kinase and its ligand, stem cell factor (SCF), control proliferation and survival of mast cells. Thus, targeting KIT signaling may show promise for the treatment of allergic diseases involving mast cells. Recently, we discovered a new compound, MOD000001, as a potential small-molecule KIT kinase inhibitor by using an in silico approach. Objective: We sought to determine whether MOD000001 is highly selective to KIT, inhibits KIT signaling in mast cells, and affects IgE-mediated mast cell activation. Methods: The interaction of MOD000001 with 468 human kinases and its inhibitory activity against KIT were profiled and evaluated by using KINOMEscan (Discover X/Eurofins Corporation, Fremont, Calif) and cell-free kinase assays, respectively. The effects of MOD000001 on SCF-dependent signaling were examined by using primary mouse and human mast cells. The effects of MOD000001 on SCF-induced degranulation and passive cutaneous anaphylaxis reaction were examined in mice. Results: MOD000001 interacted with KIT and inhibited KIT kinase activity with high selectivity. MOD000001 suppressed SCF-induced KIT signaling in mouse and human mast cells and in mice. Passive cutaneous anaphylaxis reaction was suppressed in mice treated with MOD000001 both for a short-term (1 week) and for a long-term (7 weeks). Mice treated with MOD000001 for a long-term, but not for a short-term, showed skin mast cell reduction. Conclusions: MOD000001 is a highly selective KIT inhibitor that can suppress IgE-mediated mast cell activation in vivo. MOD000001 may do so by reducing tissue mast cell numbers or by other unknown mechanisms. The findings suggest potential benefits of MOD000001 for allergic diseases involving IgE-mediated mast cell activation.

Introduction: Mycophenolate mofetil (MMF), an inactive prodrug of mycophenolic acid (MPA), is an immunosuppressive drug used widely in the treatment of lupus nephritis. In this case report, the area under the blood concentration time curve (AUC) of MPA was significantly decreased by the concomitant use of sacubitril/valsartan. Case Presentation: The patient was a man in his 40s with a diagnosis of lupus nephritis class IVa/c+V. MMF dose was 1.5 g/day at admission, and AUC of MPA on day 14 was 25.1 μg⋅h/mL. Owing to poor blood pressure control, sacubitril/valsartan was initiated at 97/103 mg/day on day 29. On day 37, AUC of MPA was significantly decreased to 8.7 μg⋅h/mL, suggesting drug interaction with the newly initiated sacubitril/valsartan. Sacubitril/valsartan was decreased to 49/51 mg/day, and AUC of MPA on day 67 was 37.6 μg⋅h/mL, achieving the target range. The final MMF dose was set at 1.75 g/day. A possible mechanism of drug interaction between sacubitril/valsartan and MPA involves an organic anion transporting polypeptide (OATP). The inhibition of OATPs by sacubitril may have interrupted the enterohepatic circulation of MPA, resulting in a lower plasma concentration. Conclusion: Since lupus nephritis is often associated with hypertension, the drug interaction observed in this report may also occur in other cases. However, it is impossible to conclude that the decrease in plasma MPA levels was due to the concomitant use of sacubitril/valsartan, and more cases and basic findings are needed.

The global incidence of dementia has been rising for the past several years, posing significant health challenges regarding its management and prevention. Dementia is associated with a substantial burden on patients and their families. Therefore, effective, evidence-based preventive strategies are required for dementia. To achieve this, the predisposing factors for dementia and their relationship with other diseases need to be determined. Japan has a universal health insurance system and these data have been stored in their respective databases since 2008. Herein we explored the influence of clinical history on the occurrence of dementia based on data collected by the National Health Insurance in Japan and Municipal Care Certification Survey over the past 10 years. Multivariate logistic regression analysis was used to determine the factors from clinical history that affect the risk of dementia development. A significant odds ratio was observed for the development of dementia in 5-year data, involving the clinical history of osteoporosis, depression, internal carotid artery occlusion, schizophrenia, and Parkinson’s disease. In addition, a significant odds ratio was observed for the development of dementia in 10-year data, involving the clinical history of osteoporosis, cataracts, and schizophrenia.

Abstract Treatment using docetaxel (DOC) and ramucirumab (RAM) is an effective regimen in second or later line advanced non-small cell lung carcinoma (NSCLC) treatment. However, it induces severe adverse effects, resulting in treatment reduction such as dose reduction and/or discontinuation. This study aimed to reveal the factor(s) associated with treatment reduction in DOC + RAM. We retrospectively evaluated patients with advanced NSCLC (n = 155). Treatment reduction of the second course due to severe adverse effects was conducted in 25.8% of the participants, and relative dose intensity at the second course was 95.7 ± 8.4% for DOC and 91.9 ± 24.8% for RAM. Multivariate logistic regression analyses identified that baseline anemia and prophylactic granulocyte colony-stimulating factor (G-CSF) administration are preventive factors for the reduction (adjusted odds ratio, 0.29; 95% confidence interval, 0.12–0.66; P = 0.004 for baseline anemia, 0.18; 0.08–0.42; P

Abstract The occurrence of cisplatin (CDDP)-induced nephrotoxicity (CIN) has decreased with advancements in supportive care. In contrast, we reported that baseline diabetes mellitus (DM) complications significantly worsen CIN. This study aimed to determine further risk factors associated with CIN development in DM patients. Patients with thoracic cancer requiring DM pharmacotherapy, who received CDDP (≥ 60 mg/m2)-containing regimens using the short hydration method (n = 140), were enrolled in this retrospective multicenter observational study. The primary endpoint of the present study was the elucidation of risk factors (patient factors, DM medication influence, and treatment-related factors) associated with CIN development in patients with DM. Cisplatin-induced nephrotoxicity occurred in 22.1% of patients with DM. The median worst variation of serum creatinine levels and creatinine clearance (worst level − baseline level) was 0.16 mg/dL (range: − 0.12–1.41 mg/dL) and − 15.9 mL/min (− 85.5–24.3 mL/min), respectively. Multivariate logistic regression analyses identified female sex as the singular risk factor for CIN development in the DM population (adjusted odds ratio; 2.87, 95% confidence interval; 1.08–7.67, P = 0.04). Diabetes mellitus medication and treatment-related factors did not affect CIN development. In conclusion, our study revealed that female sex is significantly associated with CIN development in patients with DM and thoracic cancer.

Abstract Oral mucositis (OM) is a common adverse effect of docetaxel-containing treatment. This study aimed to assess whether dexamethasone (DEX) dose-dependently attenuates docetaxel-induced OM and dysgeusia. We retrospectively analyzed medical records of patients with breast cancer receiving docetaxel-containing regimens at Hokkaido University Hospital between June 2015 and June 2022. The patients were divided into low-dose and high-dose groups (DEX 4 or 8 mg/day on days 2–4, respectively), and incidence of OM and dysgeusia, and risk factor(s) for OM incidence were evaluated. The incidence of all-grade OM in the first cycle was 57.8% in the low-dose group and 19.2% in the high-dose group (P = 0.0002), which met our primary endpoint. The incidence of OM in all treatment cycles was also significantly lowered by DEX-dose increase (P = 0.01). In contrast, the incidence of dysgeusia was similar between the two groups in the first and all cycles (P = 0.50 and P = 0.28, respectively). These results were also confirmed in a propensity score-matched population. Multivariate logistic regression analysis also suggested that lower DEX dosage was a singular risk factor for all-grade OM incidence. In conclusion, our study suggests that DEX dose-dependently reduces the incidence of OM in docetaxel-containing regimens for breast cancer treatment.

Abstract Docetaxel-induced fluid retention (DIFR) cumulatively occurs and is one of the most troublesome adverse effects. This study aimed to determine whether high dose dexamethasone (DEX) could prevent DIFR during breast cancer treatment. Breast cancer patients receiving docetaxel (75 mg/m2)-containing regimens were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2–4 and retrospectively assessed. Incidence of greater than or equal to grade 2 DIFR was significantly lower in the 8 mg group (13.0%) compared to the 4 mg group (39.6%, P = 0.001). All-grade DIFR was also less in the 8 mg group (P = 0.01). Furthermore, the maximum variation of body weight was significantly lower in the 8 mg group (P = 0.0003). These results were also confirmed in the propensity score-matched population. Additionally, time-related DIFR incidence was also significantly delayed in the 8 mg group (P = 0.0005). Our study revealed that high dose DEX prevents DIFR. Therefore, further studies on its management are required for less onerous chemotherapy provision with better DIFR control.

Immune checkpoint inhibitors have drastically improved cancer treatment. However, they may induce immune-related adverse events (irAEs). Here, we report a case of significantly delayed rheumatic irAEs (Rh-irAEs) with prior possible temporary neutropenic irAEs in a patient with atezolizumab-treated non-small-cell lung cancer and its management. A man in his sixties received atezolizumab monotherapy as the sixth-line treatment. He experienced an infusion-related reaction (fever) during the first cycle. On day 22 of cycle 2, grade 4 neutropenia suddenly appeared, but it disappeared on the next day. Cycle 3 was initiated after seven days; the patient did not exhibit any symptoms for approximately 500 days. However, on day 534 (day 1 of cycle 21), the patient complained of pain in the shoulders, back, and wrists. On day 644, the shoulder and back pain worsened with obvious swelling of the fingers. We thus suspended treatment and consulted a rheumatologist. A diagnosis of polyarthritis with active tenosynovitis was made based on joint ultrasound and laboratory tests. Prednisolone 15 mg attenuated the symptoms, allowing suspension of analgesics; however, dose reduction from 15 mg/day was difficult because of symptom flares. Finally, iguratimod 25 mg twice daily was initiated on day 764; prednisolone was reduced to 10 mg without flares, and its dosage was slowly reduced to 5 mg/day. Although irAEs exhibit multisystem features, delayed development of polyarthritis with active tenosynovitis after possible temporary neutropenic irAEs is rare. Thus, irAEs need to be monitored for a long time in patients with suspected irAE development even if it appears transiently.

Here, we describe a case of temporary severe neutropenia after atezolizumab monotherapy and its treatment course. Atezolizumab monotherapy was introduced as a 6th-line treatment for a man in his late 60s, who was diagnosed with stage Ⅳ lung adenocarcinoma. The first treatment cycle was administered during hospitalization, and the patient presented with a fever of 37.8°C on the first day. The fever resolved after the administration of acetaminophen and naproxen, and the white blood cell count, neutrophil count, and other white blood cell fractions were normal. However, grade 3 leukopenia and grade 4 neutropenia appeared at the beginning of the third cycle, and treatment was discontinued. After treatment, monocyte count in the leukocyte fraction increased from approximately 10% to 25.6%. Lenograstim 100 μg subcutaneous injection and oral levofloxacin 500 mg once daily were started of onset of neutropenia, and he was hospitalized the next day. Laboratory findings upon admission showed a significant improvement to 5,300/µL for leukocytes and 3,376/µL for neutrophils. Lenograstim was discontinued, with no further decrease in the neutrophil count. Atezolizumab therapy was resumed, and there was no further reduction in leukocyte, neutrophil, or leukocyte fractions over about a 2-year period. Concomitant drugs were maintained during the atezolizumab treatment, suggesting that they did not induce neutropenia. In conclusion, we observed temporary severe neutropenia during atezolizumab monotherapy. Neutrophil recovery with cautious monitoring has enabled longer efficacy. We should consider temporary symptom occurrence in cases of haematological immune-related adverse events.

Abstract Background Augmented renal clearance (ARC) is associated with lower blood plasma concentrations of renally excreted drugs; however, its time course is unknown. The current study aimed to determine the onset timing/duration of ARC, its risk factors, and its association with clinical outcomes by continuous monitoring of urinary creatinine clearance (CrCl) in critically ill patients. Methods Data were retrospectively obtained from the medical records of 2592 critically ill patients admitted to the intensive care unit (ICU) from January 2019 to June 2022 at a tertiary emergency hospital. Among these, patients with continuously measured urinary CrCl were selected and observed over time. We evaluated the onset timing and duration of ARC by plotting Kaplan–Meier curves. Furthermore, by multivariate analyses, factors associated with the onset and persistence of ARC were analyzed, and the association between the ARC time course and clinical outcomes was evaluated. Results The prevalence of ARC was 33.4% (245/734). ARC onset was within 3 days of admission in approximately half of the cases, and within 1 week in most of the other cases. In contrast, the persistence duration of ARC varied widely (median, 5 days), and lasted for more than a month in some cases. Multivariate analysis identified younger age, male sex, lower serum creatinine at admission, admission with central nervous system disease, no medical history, use of mechanically assisted ventilation, and vasopressor use as onset factors for ARC. Furthermore, factors associated with ARC persistence such as younger age and higher urinary CrCl on ARC day 1 were detected. The onset of ARC was significantly associated with reduced mortality, but persistent of ARC was significantly associated with fewer ICU-free days. Conclusions Despite the early onset of ARC, its duration varied widely and ARC persisted longer in younger patients with higher urinary CrCl. Since the duration of ARC was associated with fewer ICU-free days, it may be necessary to consider a long-term increased-dose regimen of renally excreted drugs beginning early in patients who are predicted to have a persistent ARC.

Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1) and S1P production in BAT. Treatment of wild-type brown adipocytes with exogenous S1P or S1P receptor subtype-selective agonists stimulated triglyceride (TG) breakdown only marginally, compared with noradrenaline. However, genetic deletion of Sphk1 resulted in hypothermia and diminished body weight loss upon cold exposure, suggesting that SphK1 is involved in thermogenesis through mechanisms different from receptor-mediated, extracellular action of S1P. In BAT of wild-type mice, SphK1 was localized largely in the lysosomes of brown adipocytes. In the brown adipocytes of Sphk1−/− mice, the number of lysosomes was reduced and lysosomal function, including proteolytic activity, acid esterase activity, and motility, was impaired. Concordantly, nuclear translocation of transcription factor EB, a master transcriptional regulator of lysosome biogenesis, was reduced, leading to decreased mRNA expression of the lysosome-related genes in Sphk1−/− BAT. Moreover, BAT of Sphk1−/− mice showed greater TG accumulation with dominant larger lipid droplets in brown adipocytes. Inhibition of lysosomes with chloroquine resulted in a less extent of triglyceride accumulation in Sphk1−/− brown adipocytes compared with wild-type brown adipocytes, suggesting a reduced lysosome-mediated TG breakdown in Sphk1−/− mice. Our results indicate a novel role of SphK1 in lysosomal integrity, which is required for TG breakdown and thermogenesis in BAT.

Autophagosome formation involves the sequential actions of conserved ATG proteins to coordinate the lipidation of the ubiquitin-like modifier Atg8-family proteins at the nascent phagophore membrane. Although the molecular steps driving this process are well understood, the source of membranes for the expanding phagophore and their mode of delivery are only now beginning to be revealed. Here, we have used quantitative SILAC-based proteomics to identify proteins that associate with the ATG12–ATG5 conjugate, a crucial player during Atg8-family protein lipidation. Our datasets reveal a strong enrichment of regulators of clathrin-mediated vesicular trafficking, including clathrin heavy and light chains, and several clathrin adaptors. Also identified were PIK3C2A (a phosphoinositide 3-kinase involved in clathrin-mediated endocytosis) and HIP1R (a component of clathrin vesicles), and the absence of either of these proteins alters autophagic flux in cell-based starvation assays. To determine whether the ATG12–ATG5 conjugate reciprocally influences trafficking within the endocytic compartment, we captured the cell surface proteomes of autophagy-competent and autophagy-incompetent mouse embryonic fibroblasts under fed and starved conditions. We report changes in the relative proportions of individual cell surface proteins and show that cell surface levels of the SLC7A5-SLC3A2 amino acid transporter are influenced by autophagy capability. Our data provide evidence for direct regulatory coupling between the ATG12–ATG5 conjugate and the clathrin membrane trafficking system and suggest candidate membrane proteins whose trafficking within the cell may be modulated by the autophagy machinery. Abbreviations: ATG, autophagy related; BafA1, bafilomycin A1; GFP, green fluorescent protein; HIP1R, huntingtin interacting protein 1 related; MEF, mouse embryo fibroblast; PIK3C2A, phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha; SILAC, stable isotope labelling with amino acids in culture; SQSTM1, sequestosome 1; STRING, search tool for the retrieval of interacting genes/proteins

Abstract Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m2)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62–11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.

Stroke is a progressive disease with remissions and exacerbations; it significantly reduces the quality of life of patients and their family and caregivers. Primary prevention is necessary to reduce the growing incidence of stroke globally. In this study, we determined the risk factors for cerebral infarction in elderly Japanese residents and proposed a primary care strategy to prevent cerebral infarction. We investigated the relationship between the incidence of cerebral infarction and the results of checkups 10 years ago. Multivariate logistic regression analysis was performed to determine the variables related to the occurrence of cerebral infarction in biochemical tests and questionnaires administered ten years ago. Hypertension and abnormal creatinine levels were related to increased risk of cerebral infarction based on our findings of the health checkups conducted 10 years previously. Furthermore, weight gain or loss of >3 kg over the last year and habit of eating an evening meal within 2 h before going to bed were associated with an increased risk of cerebral infarction based on the questionnaire results from the specific health checkups. Long-term, large-scale prospective studies are required to determine the specific health items related to increased risk of cerebral infarction.

Abstract Oral mucositis (OM) is one of the most common complications associated with chemotherapy. Here, we evaluated whether systemic dexamethasone (DEX) dosage in prophylactic antiemetics affected the incidence of OM in anthracycline-containing regimens. Patients receiving anthracycline-containing regimens for breast cancer were divided into high- and low-DEX dose groups and retrospectively evaluated. The incidence of all-grade OM in the first cycle in the high- and low-dose groups was 27.3% and 53.5%, respectively, and was significantly lowered by increasing the DEX dose (P

Abstract The potential of steroid sparing from day 2 onward is reported in anthracycline-containing regimens for breast cancer treatment. We evaluated whether the reduction of dexamethasone (DEX) dose from 9.9 to 6.6 mg on day 1 is possible in anthracycline-containing treatments. Patients receiving anthracycline-containing regimens were divided into control (9.9 mg DEX on day 1) and reduced (6.6 mg DEX on day 1) groups, and retrospectively evaluated. The complete response (CR) rate and the incidence and severity of nausea, vomiting, anorexia, and fatigue were evaluated. The CR rate in the acute phase (day 1) was 63.1% and 38.1% in the control and reduced groups, respectively, with significant difference (P = 0.01) between the groups. However, no difference was found in the delayed phase (days 2–7). The incidence of anorexia and vomiting during treatment was not statistically different. Severity of nausea tended to, but not statistically, worsen while anorexia significantly worsened in the reduced group. Multivariate analysis suggested that patients

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most serious adverse effects of chemotherapy. We experienced carboplatin (CBDCA)-induced akathisia-like CIPN, which was significantly attenuated by pregabalin administration, and report its treatment. A man in his 40s was administered CBDCA + pemetrexed (PEM) as the third-line treatment for recurrent malignant pleural mesothelioma. He rarely experienced mild akathisia-like symptoms on his feet before the diagnosis. The patient claimed that he exhibited mild degradation of the symptoms in the previous cisplatin (CDDP) + PEM treatment without the need for pharmacotherapy. Symptoms notably worsened approximately 7 days after the first cycle of CBDCA + PEM and did not disappear. Furthermore, symptoms worsened during the daytime and became milder at night. Lorazepam (0.5 mg) was administered 3 times a day from day 14 but was not effective. Finally, we evaluated the symptoms to be derived from CBDCA-induced neuropathy as he experienced the same symptoms in CDDP + PEM and did not have suspicious pathology or medicines for akathisia development. We decided to administer 75 mg pregabalin twice daily, resulting in significant symptom improvement. He also complained that he felt the symptoms 10 h after the previous pregabalin dose, suggesting that pregabalin was effective, and its effect weakened or disappeared as time progressed. Akathisia-like symptoms caused by CBDCA-induced CIPN are rare, but they significantly reduce the quality of life. Pregabalin was significantly effective in this case; therefore, we suggest that a detailed symptom interview and selection of the medicine, based upon the action mechanism, are necessary.

Docetaxel (DOC) is one of the most effective agents for breast cancer treatment. Here, we report docetaxel-induced severe hypertriglyceridemia in a patient previously diagnosed with hyperlipidemia and corresponding therapeutic intervention. A postmenopausal woman, with previously controlled hyperlipidemia using rosuvastatin 5 mg daily, was diagnosed with stage IIB breast cancer with human epidermal growth factor receptor-2 overexpression; she received DOC (75 mg/m2), pertuzumab, and trastuzumab treatment as neoadjuvant chemotherapy. The serum triglyceride level was mildly higher than normal, and cholesterol level was normal at baseline. The serum triglyceride level was almost stable after chemotherapy initiation but suddenly increased to grade 3 (770 mg/dL) after the third cycle of the treatment without any symptoms. Sustained-release bezafibrate 400 mg was administered, resulting in a significant decrease to the baseline level; bezafibrate was discontinued on day 28 of the fourth chemotherapy as neoadjuvant chemotherapy was completed. The level was stable around the baseline level during adjuvant chemotherapy with pertuzumab and trastuzumab. Therefore, DOC-induced severe hypertriglyceridemia was strongly indicated in this case. The mechanism underlying the symptoms remains unclear; we speculate that it could be a resultant of a decrease in lipid metabolism as the patient had grade 2 diarrhea. Moreover, her backgrounds, such as mild hypertriglyceridemia, postmenopausal, diabetes, and obesity, in addition to DOC administration might have affected the outcome. Fibrate administration and cessation of treatment were as effective as in previous reports. DOC-induced hypertriglyceridemia presents with the possibility of severe complications. Elucidation of the exact mechanisms and epidemiological features is required for better management.

We discuss the editorial handling of two papers that were published in and then retracted from the *Journal of Radiological Protection* (JRP).^1,2^ The papers, which dealt with radiation exposure in Date City, were retracted because “ethically inappropriate data were used.”^3,4^ Before retraction, four Letters to the Editor pointing out scientific issues in the papers had been submitted to JRP. The Letters were all accepted or provisionally accepted through peer review. Nevertheless, JRP later refused to publish them. We examine the handling by JRP of the Letters, and show that it left the reader unapprised of a) the extent of the issues in the papers, which went far beyond the use of unconsented data, and b) the problems in the way the journal handled the matter. By its actions in this case, JRP has enabled unscientific, unfounded and erroneous claims to remain unacknowledged. We propose some countermeasures to prevent such inappropriate actions by academic journals in future.

We discuss the editorial handling of two papers that were published in and then retracted from the Journal of Radiological Protection (JRP). The papers dealt with radiation exposure in Date City, and were retracted because “ethically inappropriate data were used”. Before retraction, four Letters to the Editor pointing out scientific issues in the papers had been submitted to JRP. The Letters were all accepted or provisionally accepted through peer review. Nevertheless, JRP later refused to publish them. We examine the handling by JRP of the Letters, and show that it led to a cover-up of the grave issues in the papers and in handling them, which went far beyond the use of unconsented data. By its actions in this case, JRP has established a dangerous precedent that unscientific, unfounded and erroneous claims can remain unacknowledged. We propose some countermeasures to prevent such abuse of editorial power by academic journals.

Abstract Background Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and dexamethasone (DEX) in carboplatin-containing regimens. Moreover, because aprepitant is an expensive drug, confirming its effectiveness is very important from the medical cost perspective. In this study, we examined the efficacy of prophylactically administered aprepitant, palonosetron and DEX, in paclitaxel and carboplatin (TC) combination chemotherapy. Methods Patients with gynecologic cancer who were treated with paclitaxel (175 mg/m2) and carboplatin (area under the curve, AUC = 5–6) combination chemotherapy were retrospectively evaluated. The complete response (CR) rate, severity of nausea, and incidence of anorexia in the first course were compared between patients who did not receive aprepitant (control group) and those who received (aprepitant group). Results The 106 patients were divided into two groups, consisting of 52 and 54 the control and aprepitant groups, respectively, and the patient background showed no significant difference between both groups. The CR rate of the overall phase between the control and aprepitant groups was 73.1 vs. 74.1%, that in the acute phase was 98.1 vs. 100%, and in the delayed phase was 75.0 vs. 74.1%, respectively, without any significant difference. The severity of nausea and incidence of anorexia were also not significantly different between both groups. Conclusions The results of the study suggest that adding aprepitant to palonosetron and DEX does not prevent carboplatin-induced nausea and vomiting in gynecologic cancer patients. Therefore, adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.

Irinotecan hydrochloride (irinotecan) is a chemotherapeutic agent used in the treatment of solid tumors. In addition to severe neutropenia and delayed diarrhea, irinotecan causes cholinergic syndrome, characterized by abdominal pain and acute diarrhea. The latter symptoms are frequently observed during and after irinotecan treatment. Here, we have discussed the case of a patient who completely recovered from abdominal pain following the administration of loperamide hydrochloride (loperamide) at a dose of 2 mg, before infusing irinotecan. In contrast, anticholinergic drugs were not as effective in alleviating symptoms. A 28-year-old man with stage IV rectal cancer with peritoneal metastasis was prescribed with fluorouracil, irinotecan, and levofolinate calcium (FOLFIRI), in addition to cetuximab. Anticholinergic drugs, such as scopolamine butylbromide (scopolamine) or atropine sulfate (atropine), were administered to treat abdominal pain that was considered as irinotecan-induced cholinergic syndrome, but monotherapy was not effective. Thereafter, oral loperamide (2 mg) with atropine (0.25 mg) was prescribed before irinotecan infusion. Consequently, the patient did not experience any abdominal pain during and after irinotecan treatment. Loperamide is an opioid receptor agonist and decreases the activity of the myenteric plexus of the intestinal wall. It also inhibits the release of both acetylcholine and prostaglandins, resulting in decreased inhibition of peristaltic movement. We assumed that its mechanism solely or in combination contributed to symptom relief. We hypothesized that the synergistic anticholinergic interaction between loperamide and atropine resulted in marked suppression of irinotecan-induced cholinergic syndrome compared to loperamide alone. Thus, loperamide may improve abdominal pain attributed to irinotecan-induced cholinergic syndrome.

Abstract Background Several studies have reported the implementation of nutrition therapy and rehabilitation for acute and critical illnesses. However, rehabilitation nutrition for elderly sarcopenia patients with extremely severe postoperative complications during hospitalization has not yet been established. Case presentation We report the case of a 70-year-old man with sarcopenia that developed as a postoperative complication of the surgical resection of perihilar cholangiocarcinoma and left the patient bedridden from prolonged malnutrition and muscle weakness. The patient’s general condition improved after a nearly 6-month intervention by our Nutrition Support Team (NST) that combined nutrition, exercise, and pharmacotherapy. Conclusions The appropriate timing and order of pharmacotherapy, nutrient administration, exercise therapy, and team collaboration may enable elderly patients with severe (secondary) sarcopenia and postoperative complications to regain self-sustained walking.

We had previously reported on S-1-induced hypertriglyceridemia. Here, we report fluorouracil-induced hypertriglyceridemia in a patient with capecitabine-induced hypertriglyceridemia and the corresponding therapeutic process. A woman in her forties who had experienced grade 3 hypertriglyceridemia due to oxaliplatin + capecitabine was administered fluorouracil ± oxaliplatin + levofolinate calcium + panitumumab; however, grade 4 hypertriglyceridemia occurred after the thirteenth administration. Bezafibrate normalized the elevation. Chemotherapy cessation resulted in its decrease to normal, and bezafibrate was stopped. Nine months after cessation, treatment with fluorouracil + irinotecan + levofolinate calcium + ramucirumab was initiated. After four cycles of treatment, her serum triglyceride levels increased again to grade 3, and then, fenofibrate was administered, resulting in a significant decrease to grade 1–2. Serum triglyceride levels significantly reduced after cessation of the prior fluorouracil-containing regimen, although its elevation was observed again following the latter treatment. Therefore, fluorouracil-induced hypertriglyceridemia was strongly speculated in this case. We have speculated that the most probable cause of tegafur and capecitabine-induced hypertriglyceridemia is fluorouracil or its metabolic enzymes since their end product is fluorouracil in the previous report. Results from this patient suggest that our supposition was correct. Fibrates administration, cessation of the treatment, and monitoring of serum triglyceride level was effective in this case as well as previous reports. Fluorouracil-induced hypertriglyceridemia is associated with the one caused by tegafur and capecitabine and presents the possibility of severe complications. Elucidation of its exact mechanism and epidemiological features is needed for better understanding.

Abstract The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) plays a crucial role in angiogenesis at least in part through participating in endocytosis and, thereby, endosomal signaling of several cell surface receptors including VEGF receptor-2 and TGFβ receptor in vascular endothelial cells (ECs). The Notch signaling cascade regulates many cellular processes including cell proliferation, cell fate specification and differentiation. In the present study, we explored a role of PI3K-C2α in Delta-like 4 (Dll4)-induced Notch signaling in ECs. We found that knockdown of PI3K-C2α inhibited Dll4-induced generation of the signaling molecule Notch intracellular domain 1 (NICD1) and the expression of Notch1 target genes including HEY1, HEY2 and NOTCH3 in ECs but not in vascular smooth muscle cells. PI3K-C2α knockdown did not inhibit Dll4-induced endocytosis of cell surface Notch1. In contrast, PI3K-C2α knockdown as well as clathrin heavy chain knockdown impaired endocytosis of Notch1-cleaving protease, γ-secretase complex, with the accumulation of Notch1 at the perinuclear endolysosomes. Pharmacological blockage of γ-secretase also induced the intracellular accumulation of Notch1. Taken together, we conclude that PI3K-C2α is required for the clathrin-mediated endocytosis of γ-secretase complex, which allows for the cleavage of endocytosed Notch1 by γ-secretase complex at the endolysosomes to generate NICD1 in ECs.

Abstract Background Ward pharmacists are required for the active implementation of therapeutic drug monitoring (TDM). This epidemiological study verified whether Japanese ward pharmacists contribute to improving the TDM implementation proportions of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents using the large health insurance claims database. Methods The patients who received intravenous anti-MRSA agents from April 2012 to March 2017 were enrolled. We defined ward pharmacy service as the “drug management and guidance fee” and/or “inpatient pharmaceutical services premium”. In addition, implementation of TDM was identified by “the specific drug treatment management fee”. We compared the proportions of TDM implementation for vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK) in the ward and non-ward pharmacy service groups. To avoid confounding, the propensity score method was employed. Moreover, the clinical variables affecting TDM implementation in each anti-MRSA agent were analyzed by using a multiple logistic regression model. Results The following number of patients were included in the study: VCM (n = 2138), TEIC (n = 596), and ABK (n = 142). After propensity score matching, the proportions of TDM implementation for VCM and TEIC were higher in the ward pharmacy service group than in the non-ward pharmacy service group (VCM: 69.2% vs 60.3%, TEIC: 51.4% vs 34.7%), while no significant difference was observed for ABK (21.2% vs 23.1%). As independent clinical variables affecting TDM implementation for VCM and TEIC, several clinical variables, including ward pharmacy services, were extracted. In contrast, no clinical variables were extracted for ABK. Conclusions We found that the ward pharmacy service is associated with the active implementation of TDM for anti-MRSA agents, such as VCM and TEIC.

We present a case in which serotonin syndrome developed immediately after the initiation of low-dose methadone following an increase in oxycodone dose and the initiation of duloxetine. The symptoms of serotonin syndrome were alleviated and later disappeared upon cessation of methadone alone. The case was a 47-year-old woman with a desmoid tumor. The administration of duloxetine (20 mg/day) was initiated while the patient took oxycodone sustained-release tablets (40 mg/day). The following day, excessive perspiration, chills, and tremors appeared after the initiation of 15 mg/day methadone. Discontinuation of methadone led to an alleviation of the symptoms which completely disappeared 3 days later. The results suggest that low-dose methadone can trigger serotonin syndrome as early as after the first dose. Thus, it is important to be aware of the risks and to immediately take action if symptoms appear.

Abstract Background Piperacillin/tazobactam (PIPC/TAZ) and cefepime (CFPM) are commonly used for the treatment of nosocomial and healthcare-associated infections. Recent reports have suggested that the incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin (VCM) and PIPC/TAZ is higher than that in patients treated with CFPM. However, there have been few reports on a comparison of the incidences of AKI in patients treated with PIPC/TAZ monotherapy and patients treated with CFPM. In this study, we investigated whether the incidence of AKI in patients treated with PIPC/TAZ is higher than that in patients treated with CFPM. Methods This study was a single-center retrospective observational study. Patients who died during the therapeutic period, patients younger than 18 years of age, and patients undergoing hemodialysis were excluded. Primary outcomes were the incidence of AKI and the AKIN stages defined by the Acute Kidney Injury Network. Secondary outcomes were discontinuation and/or change of antibiotics and initiation of dialysis due to AKI. We also investigated the time to onset and the risk factors of AKI in this population. Results There were 163 patients in the PIPC/TAZ group and 103 patients in the CFPM group. The incidence of AKI in patients treated with PIPC/TAZ (8.6%) was significantly higher than that in patients treated with CFPM (0.9%) (odds ratio (OR), 9.53; 95% confidence interval (CI), 1.41–408; p= 0.011). AKI severity was mostly stage 1 in both groups. There was no discontinuation and/or changes of antibiotics and there was no initiation of dialysis in either group. The onset of AKI in the PIPC/TAZ group (median period of 4 days) was earlier than that in the CFPM group. PIPC/TAZ was determined to be an independent risk factor of AKI in multivariate analysis (adjusted OR, 9.56; 95% CI, 1.21–75.3; p = 0.032). Conclusions This study showed that the incidence of AKI in patients who received PIPC/TAZ was higher than that in patients who received CFPM. Furthermore, the onset of AKI was earlier in patients who received PIPC/TAZ than in patients who received CFPM. PIPC/TAZ was an independent risk factor of AKI in this study population.

Background & objectiveTheanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail.Main methodsAfter oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine.Key findingsPlasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions.SignificanceIncreased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

Artificial neural networks are the main tools for data mining and were inspired by the human brain and nervous system. Studies have demonstrated their usefulness in medicine. However, no studies have used artificial neural networks for the prediction of adverse drug reactions. We aimed to validate the usefulness of artificial neural networks for the prediction of adverse drug reactions and focused on vancomycin -induced nephrotoxicity. For constructing an artificial neural network, a multilayer perceptron algorithm was employed. A 10-fold cross validation method was adopted for evaluating the resultant artificial neural network. In total, 1141 patients who received vancomycin at Hokkaido University Hospital from November 2011 to February 2019 were enrolled. Among these patients, 179 (15.7%) developed vancomycin -induced nephrotoxicity. The top three risk factors of vancomycin -induced nephrotoxicity which are relatively important in the artificial neural networks were average vancomycin trough concentration ≥ 13.0 mg/L and concomitant use of piperacillin-tazobactam and vasopressor drugs. The predictive accuracy of the artificial neural network was 86.3% and that of the multiple logistic regression model (conventional statistical method) was 85.1%. Moreover, area under the receiver operating characteristic curve (AUROC) of the artificial neural network was 0.83. In the 10-fold cross-validation, the accuracy obtained was 86.0% and AUROC was 0.82. The artificial neural network model predicting the vancomycin -induced nephrotoxicity showed good predictive performance. This appears to be the first report of the usefulness of artificial neural networks for an adverse drug reactions risk prediction model.

Objectives. We evaluated the effect of the different carrier systems on early vascular response through histological analysis and scanning electron microscopy using a porcine model. Background. Although Synergy™ and Promus PREMIER™ share an identical stent material and drug elution (everolimus), they use different drug carrier systems: biodegradable abluminal coating polymer or durable conformal coating polymer, respectively. However, data regarding the impact of the different coating systems on vessel healing are currently limited. Methods. Twelve Synergy™ and Promus PREMIER™ were implanted in 12 swine. Histopathological analysis of the stented segments was performed on the 2nd and 14th days after implantation. Morphometric analysis of the inflammation and intimal fibrin content was also performed. Results. On the 2nd day, neointimal thickness, percentage of neointimal area, and inflammatory and intimal fibrin content scores were not significantly different between the two groups. On the 14th day, the inflammatory and intimal fibrin content scores were significantly lower in Synergy™ versus those observed in Promus PREMIER™. In Synergy™, smooth muscle cells were found and the neointimal layers were smooth. In contrast, inflammatory cells were observed surrounding the struts of Promus PREMIER™. Conclusions. These results demonstrate that termination of reactive inflammation is accelerated after abluminal coating stent versus implantation of conformal coating stent.

Sphingosine kinase (SphK) converts sphingosine into lipids, and is implicated in inflammation. Here the authors show that SphK1 functions as an acetyltransferase, regulates microglial phagocytosis and is reduced in a model of Alzheimer’s Disease, such that its restoration ameliorates pathology