Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Successful treatment of tuberculous meningitis in an Indian female under hemodialysis therapy.

Hemodialysis is a well-known risk factor for severe infection by putting patients under an immunocompromised state. Such patients are prone to opportunistic pathogen and present with atypical manifestations during infection. Tuberculous meningitis is a central nervous system infection of Mycobacterium tuberculosis, accounting for the highest mortality of all forms of tuberculosis. In fact, the mortality rate of tuberculous meningitis in hemodialysis patients is extremely poor because early clinical diagnosis is difficult. Here, we report a case of tuberculous meningitis in a 61-year-old Indian hemodialysis patient, who presented with fever of unknown origin and was successfully treated with empiric treatment with standard four-drug regimen against tuberculosis. Comprehensive screening of the origin of fever revealed only the positive results of interferon-gamma release assay, which led us to initiate an empiric therapy for tuberculosis, before making a definitive diagnosis by cerebrospinal fluid nested PCR. Soon after the initiation of the treatment, the fever immediately abated. Although the patient experienced a single episode of paradoxical worsening and severe liver injury, she recovered well without any complications. This report provides a clinical course of the disease in a hemodialysis patient, highlighting the importance of early clinical diagnosis and rapid initiation of empirical tuberculosis treatment.

A circulating subset of iNKT cells mediates antitumor and antiviral immunity.

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.

Borderline Case of TAFRO Syndrome and POEMS Syndrome.

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.

Study protocol for SPARED trial: randomised non-inferiority phase III trial comparing dexamethasone on day 1 with dexamethasone on days 1-4, combined with neurokinin-1 receptor antagonist, palonosetron and olanzapine (5 mg) in patients receiving cisplatin-based chemotherapy.

INTRODUCTION: Dexamethasone (DEX) is administered for multiple days to prevent chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy (HEC); however, its notorious side effects have been widely reported. Although our multicentre randomised double-blind comparative study verified non-inferiority of sparing DEX after day 2 of chemotherapy when combined with neurokinin-1 receptor antagonist (NK1-RA) and palonosetron (Palo) for patients receiving HEC regimen, DEX sparing was not non-inferior in patients receiving cisplatin (CDDP)-based HEC regimens in subgroup analysis. Recently, the efficacy of the addition of olanzapine (OLZ) to standard triple antiemetic therapy on HEC has been demonstrated by several phase III trials. This study aims to confirm non-inferiority of DEX sparing when it is combined with NK-1RA, Palo and OLZ in patients receiving CDDP-based HEC regimens. METHODS AND ANALYSIS: This is a randomised, double-blind, phase III trial. Patients who are scheduled to receive CDDP ≥50 mg/m2 as initial chemotherapy are eligible. Patients are randomly assigned to receive either DEX on days 1-4 or DEX on day 1 combined with NK1-RA, Palo and OLZ (5 mg). The primary endpoint is complete response (CR) rate, defined as no emesis and no rescue medications during the delayed phase (24-120 hours post-CDDP administration). The non-inferiority margin is set at -15.0%. We assume that CR rates would be 75% in both arms. Two hundred and sixty-two patients are required for at least 80% power to confirm non-inferiority at a one-sided significance level of 2.5%. After considering the possibility of attrition, we set our final required sample size of 280. ETHICS AND DISSEMINATION: The institutional review board approved the study protocol at each of the participating centres. The trial result will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000032269.

The µ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine.

AIMS: Opioids are commonly used analgesics for moderate to severe pain, but levels of drug effect vary among individuals. As for the mechanisms underlying these individual differences, there have been reports suggesting effects of polymorphisms in the gene encoding µ-opioid receptor (OPRM1). However, whether these polymorphisms affect the actions of µ-opioid receptor partial agonists has yet to be determined. This study aimed to assess differences in the pharmacological actions of buprenorphine, a µ-opioid receptor partial agonist, due to a polymorphism (A118G, rs1799971) in the OPRM1 gene in humans. MATERIALS AND METHODS: Ten healthy adult men (5 with OPRM1 c.118AA and 5 with OPRM1 c.118GG) received a single intravenous dose of buprenorphine hydrochloride at 0.001 mg/kg. Blood samples were collected up to 360 minutes after drug administration to assess the pharmacokinetics of buprenorphine. Nociceptive thresholds (temperature), digital symbol substitution test (DSST), and visual analog self-rating scale (VAS) for subjective symptoms were also evaluated over time to assess the pharmacodynamics. RESULTS: Nociceptive thresholds were significantly increased in the AA as compared to the GG group after buprenorphine administration (p = 0.025), while the DSST scores were significantly lower in the AA group (p < 0.001). The VAS scores for drowsiness (p < 0.001), malaise (p < 0.001), nausea (p < 0.001), and euphoria (p = 0.004) were higher in the AA than in the GG group. CONCLUSION: Levels of pharmacological actions of a µ-opioid receptor partial agonist vary in accordance with a polymorphism in the OPRM1 gene (A118G).

Escherichia coli-induced granulomatous colitis in a cat.

CASE SUMMARY: A 10-year-old castrated male domestic shorthair cat presented with a 6 month history of diarrhoea that responded poorly to medical treatment. Ultrasonography revealed moderate thickening of the colonic wall (4.8 mm) and right colic and jejunal lymphadenomegalies. Endoscopic examination revealed partial circumferential narrowing of the transverse colon and friable colonic mucosa with multiple haemorrhagic regions. Histopathological and immunohistochemical examinations revealed a large number of Escherichia coli phagocytosed by periodic acid-Schiff-positive macrophages. Bacterial culture also yielded enrofloxacin-sensitive E coli. The cat was initially treated with prednisolone, which resulted in little improvement. Following histopathological examination and bacterial culture, treatment with enrofloxacin was commenced. Antibacterial therapy resulted in remission of the diarrhoea and an increase in body weight within 14 days. RELEVANCE AND NOVEL INFORMATION: Granulomatous colitis (GC) or histiocytic ulcerative colitis has been rarely described in cats. There has only been one previously published case study involving a cat, and the aetiology remains largely unknown. The current article describes the regression of E coli-related GC following antibacterial treatment in a cat. Clinical signs, histopathological appearance and response to enrofloxacin were similar to those in canine GC. The current findings suggest that E coli also plays an important role in the development of feline GC.

Question answering system using Q & A site corpus Query expansion and answer candidate evaluation.

Question Answering (QA) is a task of answering natural language questions with adequate sentences. This paper proposes two methods to improve the performance of the QA system using a Q&A site corpus. The first method is for the relevant document retrieval module. We proposed modification of measure of mutual information for the query expansion; we calculate it between two words in each question and a word in its answer in the Q&A site corpus not to choose the words that are not suitable. The second method is for the candidate answer evaluation module. We proposed to evaluate candidate answers using the two measures together, i.e., the Web relevance score and the translation probability. The experiments were carried out using a Japanese Q&A site corpus. They revealed that the first proposed method was significantly better than the original method when their accuracies and MRR (Mean Reciprocal Rank) were compared and the second method was significantly better than the original methods when their MRR were compared.

Effects of dosing interval on the pharmacokinetic and pharmacodynamic interactions between the oral adsorbent AST-120 and triazolam in humans.

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic interactions between the oral adsorbent AST-120 and triazolam. METHODS: In this randomized, cross-over study, 12 healthy volunteers received a single oral dose of triazolam 0.25 mg alone or with AST-120 2 g given 0, 30 or 60 min before triazolam administration. RESULTS: The area under the plasma triazolam concentration-time curve (AUC(0-∞)) significantly decreased with simultaneous AST-120 + triazolam (alone vs simultaneous: 10.9 ± 6.0 vs 6.4 ± 2.6 ng·h/mL, p = 0.003). Triazolam-induced impairment in psychomotor performance assessed by the digit symbol substitution test was significantly attenuated when AST-120 was administered simultaneously. No significant changes in pharmacokinetic and pharmacodynamic parameters were observed when AST-120 was given 30 or 60 min before triazolam administration. CONCLUSIONS: Administering AST-120 simultaneously with triazolam affects the pharmacokinetics and pharmacodynamics of triazolam. Dosing AST-120 at least 30 min before triazolam administration may avoid these interactions.

Protective effect of caffeine on streptozotocin-induced beta-cell damage in rats.

Many epidemiological studies have shown that coffee consumption reduces the risk of type 2 diabetes mellitus (T2D), although the reasons as to why remain unclear. In this study we investigated the effect of caffeine on pancreatic beta-cell damage in rats using the diabetogenic agent, streptozotocin (STZ). Wistar rats were given intraperitoneal injections of saline or caffeine (10, 50 or 100 mg kg(-1)). After 15 min, the rats were injected with a citrate buffer or 65 mg kg(-1) STZ. Three days after injection, an oral glucose tolerance test (OGTT) was performed on the rats. Furthermore, three days after the OGTT, the pancreas was isolated and homogenized, followed by determination of insulin content. STZ treatment significantly increased the plasma glucose level compared with the control at all times during the OGTT, which was significantly diminished by caffeine pretreatment at all doses. STZ treatment significantly decreased the plasma insulin level, however, which was not recovered by caffeine pretreatment. Pancreatic insulin content was significantly reduced by STZ treatment compared with the control, which was significantly recovered by caffeine pretreatment at a dose of 100 mg kg(-1) (P<0.01). We showed that caffeine protects pancreatic beta-cells against STZ toxicity. Further investigation will be required to understand the protective effect of caffeine against beta-cell destruction in T2D.