Influence of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine in adult patients receiving CHOP therapy.

PURPOSE: This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy. METHODS: Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration-time curves of VCR in the elimination phase (AUC1.5-25.5) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5-5.5 h) and terminal phase (5.5-25.5 h; t1/2γ) were determined according to the log-linear regression of the concentration-time data for at least 3 sampling points. RESULTS: A total of 41 adult patients were enrolled in this study. The median t1/2γ and AUC1.5-25.5 were significantly longer and higher in CYP3A5 non-expressers (CYP3A5*3/*3) than in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3) (21.3 vs 13.8 h, P = 0.005 and 35.5 vs 30.0 ngï½¥h/mL, P = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC1.5-25.5 (partial R2 = 0.212, P = 0.002 and partial R2 = 0.143, P = 0.010, respectively). CONCLUSION: The CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.

Newly diagnosed extranodal NK/T-cell lymphoma, nasal type, at the injected left arm after BNT162b2 mRNA COVID-19 vaccination.

Anti-SARS-CoV-2 vaccines were developed in response to the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the BNT162b2 mRNA vaccine is effective, adverse effects have been reported. Here, we report a case of extranodal NK/T-cell lymphoma, nasal type (ENKL), of the left arm following BNT162b2 mRNA vaccination. A 73-year-old male presented with a lump in the left arm, which was the site where he received the BNT162b2 mRNA vaccine 3 months prior. He was treated with topical corticosteroids and debridement, but the tumor progressed. Additionally, fever, night sweats, and general fatigue were observed. Laboratory findings included thrombocytopenia, elevated lactate dehydrogenase, and soluble interleukin-2 receptor levels. Skin biopsy led to a diagnosis of ENKL. The patient was treated with a 50% dose of SMILE therapy and radiotherapy, resulting in regression of the tumor. It seems that latent Epstein-Barr virus (EBV)-infected NK/T cells were reactivated by vaccination and contributed to the onset of ENKL. This is the first report of ENKL after BNT162b2 mRNA vaccination. The present case highlights the possible risk of development of malignant lymphoma, including ENKL at the injection site, after BNT162b2 COVID-19 vaccination.

The clinical and neuropathological picture of adult neuronal intranuclear inclusion disease with no radiological abnormality.

In typical adult neuronal intranuclear inclusion disease (NIID) with predilection for the basal ganglia or cerebral cortex, not only neurons but also glial cells harbor intranuclear inclusions. In addition, these inclusions are present in the peripheral autonomic nervous system, visceral organs and skin. In NIID cases with an expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of the Notch 2 N-terminal like C (NOTCH2NLC) gene, these repeats are located in an upstream open reading frame (uN2C) and result in the production of a polyglycine-containing protein called uN2CpolyG. Typically, patients with adult NIID show high-intensity signals at the corticomedullary junction on diffusion-weighted brain magnetic resonance imaging. We report a case of adult NIID in a 78-year-old Japanese male, who suffered from mild, non-progressive tremor during life but showed no radiographic abnormalities suggestive of adult NIID. Pathologically, ubiquitin-, p62- and uN2CpolyG-positive neuronal intranuclear inclusions were particularly frequent in the hippocampal formation, but were also seen in the enteric plexuses, kidney and cardiac muscles. By contrast, glial intranuclear inclusions were barely evident in the affected regions. The present case also had an immunohistochemical profile differing from that of typical adult NIID. The findings in this case suggest that adult NIID can show clinical, radiographic and pathological heterogeneity.

Impact of polymorphisms of pharmacokinetics-related genes and the inflammatory response on the metabolism of voriconazole.

The effects of inflammatory responses and polymorphisms of the genes encoding cytochrome P450 (CYP) (CYP2C19 and CYP3A5), flavin-containing monooxygenase 3 (FMO3), pregnane X receptor (NR1I2), constitutive androstane receptor (NR1I3), and CYP oxidoreductase (POR) on the ratio of voriconazole (VRCZ) N-oxide to VRCZ (VNO/VRCZ) and steady-state trough concentrations (C0h ) of VRCZ were investigated. A total of 56 blood samples were collected from 36 Japanese patients. Results of multiple linear regression analyses demonstrated that the presence of the extensive metabolizer CYP2C19 genotype, the dose per administration, and the presence of the NR1I2 rs3814057 C/C genotype were independent factors influencing the VNO/VRCZ ratio in patients with CRP levels of less than 40 mg/L (standardized regression coefficients (SRC) = 0.448, -0.301, and 0.390, respectively; all p < .05). With regard to the concentration of VRCZ itself, in addition to the above factors, the presence of the NR1I2 rs7643645 G/G and rs3814055 T/T genotypes were found to be independent factors influencing the VRCZ C0h in these patients (SRC = -0.430, 0.424, -0.326, 0.406 and -0.455, respectively; all p < .05). On the contrary, in patients with CRP levels of at least 40 mg/L, no independent factors were found to affect VNO/VRCZ and VRCZ C0h . Inflammatory responses, and CYP2C19 and NR1I2 polymorphisms may be useful information for the individualization of VRCZ dosages.

Immune-mediated thrombocytopenia induced with durvalumab after chemoradiotherapy in a non-small cell lung cancer patient: A case report.

We describe a case of a 60-year-old man with a prolonged thrombocytopenia during a durvalumab maintenance therapy after chemoradiotherapy for locally advanced non-small cell lung carcinoma. Bone marrow specimen was normoplastic with the marked megakaryocyte depletion, which was assumed to be an acquired amegakaryocytic thrombocytopenic purpura. Although hematological disorders as immune-related adverse events (irAE) are rare, we should pay more attention to hematological disorders with durvalumab especially after concurrent chemoradiotherapy.

Leptomeningeal and intraventricular myelomatosis manifesting an aggressive form of communicating hydrocephalus.

Leptomeningeal myelomatosis (LMM) is a fatal complication that occurs in < 1% of patients with multiple myeloma. Many patients with LMM present with neurologic symptoms referable to cranial neuropathies, while the manifestation of communicating hydrocephalus has been underrecognized. A Japanese man with Bence Jones protein-κ multiple myeloma developed fever and headache at age 54 years. He then became somnolent and went into a coma. Neuroimaging analyses identified rapidly progressive communicating hydrocephalus due to meningitis. He died 83 days after the onset of headache without any response to treatment at age 55 years. No symptoms or signs associated with cranial nerves were found during the course of illness. Postmortem examination revealed hydrocephalus and diffuse infiltration of myeloma cells into the subarachnoid space of the cerebrum, cerebellum, and brainstem. In addition, the interstitial tissue of the choroid plexuses was filled with myeloma cells. These myeloma cells were positive for CD156 and light chain κ. The Ki-67 labeling index in myeloma cells of the central nervous system (CNS) was 30-40%. Histopathological examination further revealed many myeloma cells on the surface of the lateral, third and fourth ventricles and at the area postrema of the medulla oblongata. Patients with LMM can develop an aggressive form of communicating hydrocephalus. Given that cerebrospinal fluid, produced by epithelial cells in the choroid plexuses of the ventricles, passes into the subarachnoid space through the third and fourth ventricles, myeloma cells may invade the CNS through the choroid plexuses.

Long-term maintenance of the mucosal healing induced by azacitidine therapy in a patient with intestinal Behçet's-like disease accompanied with myelodysplastic syndrome involving trisomy 8.

Myelodysplastic syndromes (MDSs) are a group of myeloid neoplasms characterized by blood cell deformation and dysfunction, and MDS with trisomy 8 is closely linked with intestinal Behçet's-like diseases. Intestinal Behçet's-like disease is refractory to conventional therapies, including prednisolone, immunomodulators, and anti-tumor necrosis factor α agents. Here, we describe a 56-year-old woman with intestinal Behçet's-like disease ascribed to MDS with trisomy 8 who had multiple intractable intestinal ulcers. She presented with periodic fever and abdominal pain. The genetic analysis showed a heterozygous E148Q mutation in the Mediterranean fever gene. The patient did not tolerate treatment with colchicine because of diarrhea; therefore, azacitidine therapy was initiated. One cycle of azacitidine therapy improved the multiple intestinal ulcers, and the periodic fever and abdominal pain gradually disappeared. After eight cycles of azacitidine therapy, ileocolonoscopy, histological assessment and capsule endoscopy revealed mucosal healing. Azacitidine therapy was continued, and mucosal healing was maintained for more than 2 years. This case suggests that azacitidine therapy which has immunoregulatory effects and epigenetic modulations, might control intestinal Behçet's-like disease associated with MDS involving trisomy 8.

[Effective Treatment of a Case of Acute Myeloid Leukemia with Advanced Esophageal Cancer].

A 72-year-old man was diagnosed with acute myeloid leukemia and advanced esophageal cancer(cT3N3M1, clinical Stage IV, high-moderately differentiated squamous cell carcinoma). He was started on remission induction chemotherapy and postremission therapy provided according to the Japan Adult Leukemia Study Group's AML201 protocols. His acute myeloid leukemia showed a complete response. After that, he was administered radiotherapy for esophageal cancer and showed a partial response. One year after treatment, he developed a local recurrence of esophageal cancer. A salvage operation was performed at another hospital, and his postoperative course was uneventful. A case of acute myeloid leukemia with advanced esophageal cancer is rare and has a poor prognosis, but we could improve the prognosis and quality of life.

Islet amyloid with macrophage migration correlates with augmented ß-cell deficits in type 2 diabetic patients.

AIMS: Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear. METHODS: From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA-) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients. RESULTS: ß-Cell volume density was nearly 40% less in DA+ and 20% less in DA- when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of ß-cell and α-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with ß-cells with oxidative stress-related DNA damage, characterized by γH2AX expression, and suppressed (pro)insulin mRNA expression. CONCLUSIONS: In Japanese type 2 diabetic patients, islet amyloid was more common with severe ß-cell loss and high BMI, associated with macrophage infiltration.

Age-associated changes of islet endocrine cells and the effects of body mass index in Japanese.

AIMS/INTRODUCTION: Impaired growth and premature death of ß-cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age-related changes of the islet structure in Japanese non-diabetic subjects and explored the underlying mechanism of the changes. MATERIALS AND METHODS: A total of 115 non-diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, ß- and non-ß-cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)-1, cell cycle inhibitor P16, and oxidative stress marker γH2AX were also examined. RESULTS: There was a gradual and marginal decline of volume densities of islets, ß- and non-ß-cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in ß-cell mass, but not on the other variables. Ki67 positivity and PDX-1 expressions were high in the young, but low after maturation, whereas expressions of P16 and γH2AX were elevated in the aged. CONCLUSIONS: Age-associated decline of ß-cell mass is marginal after maturation, and the reduction of ß-cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.

The effects of dipeptidyl-peptidase-IV inhibitor, vildagliptin, on the exocrine pancreas in spontaneously diabetic Goto-Kakizaki rats.

OBJECTIVES: The risk of adverse effects of dipeptidyl peptidase-4 inhibitors on the exocrine pancreas, particularly the high risk of pancreatitis, is controversial. In this study, we examined the exocrine pancreatic function and structure in spontaneously diabetic Goto-Kakizaki (GK) rats treated with a dipeptidyl peptidase-4 inhibitor. METHODS: Male GK rats and normal Wistar rats 4 weeks of age were treated with vildagliptin (VG; 30 mg/kg/d) for 18 weeks. Subsequently, exocrine pancreatic pathology and function in treated animals were compared to those in untreated animals. RESULTS: In GK rats, VG treatment suppressed elevated serum concentrations of amylase and lipase, reduced lymphocytic infiltration around ducts, around vessels, and in acinar areas, and reduced the frequency of apoptotic acinar cells and ductule formation (both of which occurred more frequently in GK rats than Wistar rats). However, VG treatment had no effect on the proliferation rate of pancreatic duct glandular cells (which was low in GK rats) and of cells in the main ducts, peripheral ducts, and acini (which was similar in all groups). CONCLUSIONS: Perturbations of exocrine pancreatic function and structure in GK rats are ameliorated by long-term VG treatment.

Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats.

Reduced ß cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence ß and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, ß and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. ß cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced ß and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet ß cell mass in GK rats by facilitating the proliferation of islet endocrine cells.

Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat.

BACKGROUND: Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. METHODS: Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1ß, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. RESULTS: Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. CONCLUSION: AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.