Kagoshima University Hospital

OBJECTIVE: To investigate the physiologic effects of exogenous vasopressin as a potential alternative to traditional high-dose catecholamine therapy for septic patients with vascular hyporeactivity to catecholamines. DESIGN: Prospective, case-controlled study. SETTING: Intensive care unit of a university hospital. PATIENTS: Vasopressin was infused in 16 critically ill septic patients who remained persistently hypotensive despite infusions of pharmacologic doses of catecholamines. INTERVENTION: Continuous intravenous infusion of vasopressin at 0.04 units/min for 16 hrs, in place of escalating the amount of catecholamines being infused. MEASUREMENTS AND MAIN RESULTS: After administration of vasopressin, systemic vascular resistance and mean arterial pressure were immediately and significantly increased in comparison with the values obtained just before vasopressin. When the vasopressin infusions were discontinued, mean arterial pressure decreased immediately and dramatically. We did not detect any obvious adverse cardiac effects during the vasopressin infusions. Vasopressin had no effect on other hemodynamic parameters or any of the metabolic parameters studied, including measures of oxygenation, plasma glucose, or electrolytes. Urine output increased significantly during the administration of vasopressin, although this effect may be nonspecific. Lactate concentrations decreased, particularly in the survival group, but the decreases were not significant. Overall survival was 56%. CONCLUSIONS: Low-dose vasopressin infusions increased mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock and hyporesponsiveness to catecholamines. The data indicate that low-dose vasopressin infusions may be useful in treating hypotension in these patients.

RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4(+) lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4(+) lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES-28G, occurred at an allele frequency of approximately 17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES-28G mutation increases transcription of the RANTES gene. Taken together, these data suggest that the RANTES-28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.

BACKGROUND: A warm-water bath (WWB) or sauna bath (SB) has generally been considered inappropriate for patients with severe congestive heart failure (CHF). However, a comprehensive investigation of the hemodynamic effects of thermal vasodilation in CHF has not been previously undertaken. METHODS AND RESULTS: To investigate the acute hemodynamic effects of thermal vasodilation in CHF, we studied 34 patients with chronic CHF (mean age, 58 +/- 14 years). Clinical stages were New York Heart Association functional class II in 2, III in 19, and IV in 13 patients. Mean ejection fraction was 25 +/- 9%. After a Swan-Ganz catheter was inserted via the right jugular vein, the patient had a WWB for 10 minutes at 41 degrees C or an SB for 15 minutes at 60 degrees C. Blood pressure, ECG, echo-Doppler, expiration gas, and intracardiac pressures were recorded before, during, and 30 minutes after each bath. Oxygen consumption increased mildly, pulmonary arterial blood temperature increased by 1.2 degrees C, and heart rate increased by 20 to 25 beats per minute on average at the end of WWB or SB. Systolic blood pressure showed no significant change. Diastolic blood pressure decreased significantly during SB (P < .01). Cardiac and stroke indexes increased and systemic vascular resistances decreased significantly during and after WWB and SB (P < .01). Mean pulmonary artery, mean pulmonary capillary wedge, and mean right atrial pressures increased significantly during WWB (P < .05) but decreased significantly during SB (P < .05). These pressures decreased significantly from the control level after each bath (P < .01). Mitral regurgitation associated with CHF decreased during and 30 minutes after each bath. Cardiac dimensions decreased and left ventricular ejection fraction increased significantly after WWB and SB. In an additional study, plasma norepinephrine increased significantly during SB in healthy control subjects and in patients with CHF and returned to control levels by 30 minutes after SB. CONCLUSIONS: Hemodynamics improve after WWB or SB in patients with chronic CHF. This is attributable to the reduction in cardiac preload and afterload. Thus, thermal vasodilation can be applied with little risk if appropriately performed and may provide a new nonpharmacological therapy for CHF.

BACKGROUND: The value of pancreatoduodenectomy (PD) with extended lymphadenectomy for pancreatic cancer has been evaluated by many retrospective studies and 3 randomized controlled trials (RCT). However, the protocols used and the results found in the 3 RCTs were diverse. Therefore, a multicenter RCT was proposed in 1998 to evaluate the primary end point of long-term survival and the secondary end points of morbidity, mortality and quality of life of patients undergoing standard versus extended lymphadenectomy in radical PD for pancreatic cancer. METHODS: From March 2000 to May 2003, 112 patients with potentially curable pancreatic head cancer were enrolled and intraoperatively randomized to a standard or extended lymphadenectomy group. No resected patients received any adjuvant treatments. RESULTS: A hundred and one eligible patients were analyzed. Demographic and histopathological characteristics of the two groups were similar. The mean operating time, intraoperative blood loss and number of retrieved lymph nodes were greater in the extended group, but the other operative results were comparable. CONCLUSIONS: Although this multicenter RCT was conducted in a strict setting, extended lymphadenectomy in radical PD did not benefit long-term survival in patients with resectable pancreatic head cancer and led to levels of morbidity, mortality and quality of life comparable to those found after standard lymphadenectomy.

To reliably estimate the prognoses of patients with hepatocellular carcinoma (HCC), both liver function and tumor-related factors should be accounted for. However, there are few worldwide staging systems that assess prognostic value in the context of selecting individual patients for randomized stratification in therapeutic and clinical trials. We investigated the value of known prognostic systems and verified the usefulness of the new scoring system proposed by the Cancer of the Liver Italian Program (CLIP), as determined from 662 Japanese patients. A retrospective analysis of the HCC diagnoses at 4 Japanese institutions from 1990 and 1998 was performed. Overall survival was the only end point used in the analysis. Discriminatory ability and predictive power of the CLIP score were compared with those of Okuda stage and AJCC TNM stage. Compared with the Okuda and AJCC staging systems, the CLIP score's enhanced discriminatory capacity, which was tested by the linear trend test and Harrels' c-index, revealed a class of patients with an impressively more favorable prognosis and another class with a relatively shorter life expectancy. Moreover, the likelihood ratio test showed that the CLIP score had additional homogeneity of survival within each score above that of the Okuda stage or the AJCC stage. This was true for 3 subgroups of patients who received surgery, transcatheter arterial chemoembolizations, and percutaneous ethanol injections. Collectively, these findings indicate that the CLIP score has the highest stratification ability with regard to prognosis in patients with HCC. The CLIP score could be used internationally to stratify randomization groups in therapeutic and clinical trials.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

PURPOSE: Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches. METHODS: Reflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology-Human T-Lymphotropic Virus and Related Retroviruses-in Tokyo, Japan, March, 2017, to review evidence for current clinical practice and to update the consensus with a new focus on the subtype classification of cutaneous ATL, CNS lesions in aggressive ATL, management of elderly or transplantation-ineligible patients, and treatment strategies that incorporate up-front allogeneic hematopoietic stem-cell transplantation and novel agents. RESULTS: As a result of lower-quality clinical evidence, a best practice approach was adopted and consensus statements agreed on by coauthors (> 90% agreement). CONCLUSION: This expert consensus highlights the need for additional clinical trials to develop novel standard therapies for the treatment of ATL.

INTRODUCTION: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. METHODS: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring >48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality. RESULTS: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected]. CONCLUSIONS: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00940654.

BACKGROUND/PURPOSE: It is important to predict the development of clinically relevant pancreatic fistula (grade B/C) in the early period after pancreaticoduodenectomy (PD). This study has been carried out as a project study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHPBS) to evaluate the predictive factors associated with clinically relevant pancreatic fistula (grade B/C). METHOD: The data of 1,239 patients from 11 medical institutions who had undergone PD between July 2005 and June 2009 were retrospectively analyzed to review patient characteristics and perioperative and postoperative parameters. RESULTS: A drain amylase level >4,000 IU/L on postoperative day (POD) 1 was proposed as the cut-off level to predict clinical relevant pancreatic fistula by the receiver operating characteristic (ROC) curve. The sensitivity, specificity, and accuracy of this cut-off level were 62.2, 89.0, and 84.8%, respectively. A multivariate logistic regression analysis revealed that male [odds ratio (OR) 1.7, P = 0.039], intraoperative bleeding >1,000 ml (OR 2.5, P = 0.001), soft pancreas (OR 2.7, P = 0.001), and drain amylase level on POD 1 >4,000 IU/L (OR 8.6, P < 0.001) were the significant predictive factors for clinical pancreatic fistula. CONCLUSION: The four predictive risk factors identified here can provide useful information useful for tailoring postoperative management of clinically relevant pancreatic fistula (grade B/C).

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, people have undermined their mental health. It has been reported that post-COVID conditions at a certain rate. However, information on the mental health of people with post-COVID conditions is limited. Thus, this study investigated the relationship between post-COVID conditions and mental health. METHODS: Design of the present study was an International and collaborative cross-sectional study in Japan and Sweden from March 18 to June 15, 2021. The analyzed data included 763 adults who participated in online surveys in Japan and Sweden and submitted complete data. In addition to demographic data including terms related to COVID-19, psychiatric symptoms such as depression, anxiety, and post-traumatic stress were measured by using the fear of COVID-19 scale (FCV-19S), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 item (GAD-7), and Impact of Event Scale-Revised (IES-R). RESULTS: Of the 135 COVID-19 survivors among the 763 total participants, 37.0% (n = 50/135) had COVID-19-related sequelae. First, the results of the Bonferroni-corrected Mann Whitney U test showed that the group infected SARS-CoV-2 with post-COVID conditions scored significantly higher than those without one and the non-infected group on all clinical symptom scales (P ≤ .05). Next, there was a significant difference that incidence rates of clinical-significant psychiatric symptoms among each group from the results of the Chi-squared test (P ≤ .001). Finally, the results of the multivariate logistic model revealed that the risk of having more severe clinical symptoms were 2.44-3.48 times higher among participants with post-COVID conditions. CONCLUSION: The results showed that approximately half had some physical symptoms after COVID-19 and that post-COVID conditions may lead to the onset of mental disorders. TRIAL REGISTRATION: The ethics committee of Chiba University approved this cross-sectional study (approval number: 4129). However, as no medical intervention was conducted, a clinical trial registration was not necessary.

BACKGROUND: The options for medical use of signaling molecules as stimulators of tissue regeneration are currently limited. Preclinical evidence suggests that fibroblast growth factor (FGF)-2 can promote periodontal regeneration. This study aimed to clarify the activity of FGF-2 in stimulating regeneration of periodontal tissue lost by periodontitis and to evaluate the safety of such stimulation. METHODOLOGY/PRINCIPAL FINDINGS: We used recombinant human FGF-2 with 3% hydroxypropylcellulose (HPC) as vehicle and conducted a randomized double-blinded controlled trial involving 13 facilities. Subjects comprised 74 patients displaying a 2- or 3-walled vertical bone defect as measured > or = 3 mm apical to the bone crest. Patients were randomly assigned to 4 groups: Group P, given HPC with no FGF-2; Group L, given HPC containing 0.03% FGF-2; Group M, given HPC containing 0.1% FGF-2; and Group H, given HPC containing 0.3% FGF-2. Each patient underwent flap operation during which we administered 200 microL of the appropriate investigational drug to the bone defect. Before and for 36 weeks following administration, patients underwent periodontal tissue inspections and standardized radiography of the region under investigation. As a result, a significant difference (p = 0.021) in rate of increase in alveolar bone height was identified between Group P (23.92%) and Group H (58.62%) at 36 weeks. The linear increase in alveolar bone height at 36 weeks in Group P and H was 0.95 mm and 1.85 mm, respectively (p = 0.132). No serious adverse events attributable to the investigational drug were identified. CONCLUSIONS: Although no statistically significant differences were noted for gains in clinical attachment level and alveolar bone gain for FGF-2 groups versus Group P, the significant difference in rate of increase in alveolar bone height (p = 0.021) between Groups P and H at 36 weeks suggests that some efficacy could be expected from FGF-2 in stimulating regeneration of periodontal tissue in patients with periodontitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00514657.

PURPOSE: A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. METHODS: Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients' or surgeons' wishes. RESULTS: Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36-0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment. CONCLUSION: Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days.

BACKGROUND: Surgical annuloplasty can potentially hoist the posterior annulus anteriorly, exaggerate posterior leaflet (PML) tethering, and lead to recurrent ischemic/functional mitral regurgitation (MR). Characteristics of leaflet configurations in late postoperative MR were investigated. METHODS AND RESULTS: In 30 patients with surgical annuloplasty for ischemic MR and 20 controls, the anterior leaflet (AML) and PML tethering angles relative to the line connecting annuli, posterior and apical displacement of the coaptation and the MR grade were measured by echocardiography before, early after, and late after surgery. Early after surgery, grade of MR and AML tethering generally decreased (P<0.01), whereas PML tethering significantly worsened (P<0.01). Nine of the 30 patients showed recurrent/persistent MR late after surgery. Compared with patients without late MR, those with the MR showed similar reduction in the annular area, significant re-increase in posterior displacement of the coaptation, and progressive worsening in PML tethering (P<0.05) late after surgery in comparison to the early phase. Both preoperative MR and late postoperative MR were significantly correlated with all tethering variables in univariate analysis. Although apical displacement of the coaptation was the primary determinant of preoperative MR (r2=0.60, P<0.0001), increased PML tethering was the primary determinant of late MR (r2=0.75, P<0.0001). CONCLUSIONS: Whereas both leaflets tethering is related to preoperative ischemic MR, both leaflets tethering but with predominant contribution from augmented and progressive PML tethering is related to recurrent/persistent ischemic/functional MR late after surgical annuloplasty.

PURPOSE This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m 2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m 2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Although Tax protein is the main target of cytotoxic T lymphocyte (CTL) on human T-cell lymphotropic virus type I (HTLV-I)-infected cells, and Tax peptide 11 through 19 binding to HLA-A*02 has been shown to elicit a strong CTL response, there are patients with adult T-cell leukemia (ATL) bearing HLA-A*02. To explore whether there is genetic variation in HTLV-I tax that can escape CTL recognition during the development of ATL, the HTLV-I tax gene was sequenced in 55 patients with ATL, 61 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 62 healthy carriers, and it was correlated with the presence of HLA-A*02. First, a premature stop codon in the 5' half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL. This stop codon was revealed to emerge after the viral transmission to the patient from sequence analysis in family members with ATL. Second, amino acid change in Tax peptide 11-19 was observed in 3 patients with ATL. CTL assays demonstrated that this altered Tax 11-19 peptide, observed in ATL patients with HLA-A*02, was not recognized by Tax 11-19-specific CTL. Two patients with ATL had large deletions in tax by sequencing, and 5 patients with ATL had deletions in HTLV-I by Southern blotting. These findings suggest that at some stage of ATL development, HTLV-I-infected cells that can escape the host immune system are selected and have a chance to accumulate genetic alterations for further malignant transformation, leading to acute ATL.

BACKGROUND: The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). METHODS: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. RESULTS: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. CONCLUSION: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. TRIAL REGISTRATION: JapicCTI-173646.

amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. We evaluated the efficacy and safety of valemetostat, a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor, in treating relapsed or refractory (R/R) ATL. This multicenter phase 2 trial enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. The primary end point was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Secondary end points included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Twenty-five patients (median age, 69.0 years) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. The primary end point was met with a centrally reviewed ORR of 48.0% (90% confidence interval [CI], 30.5-65.9), including 5 complete and 7 partial remissions. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). IEAC-assessed median DOR was not reached (NR) (95% CI, 1.87 to NR; months). Treatment-emergent adverse events (TEAEs) were manageable. TEAEs that occurred in ≥20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Grade ≥3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. This trial was registered at www.clinicaltrials.gov as #NCT04102150.

OBJECTIVE: Fasting plasma ghrelin levels play an important role in the pathophysiology of the eating disorder anorexia nervosa. Bulimia nervosa (BN) also has been associated with abnormal neuroendocrine regulation. Thus, we examined the relationship between body mass index (BMI) and plasma ghrelin concentrations in patients with BN for the first time. METHODS: The subjects included 15 female BN patients and 11 female healthy volunteers (controls). Fasting blood samples were collected from all subjects. RESULTS: The plasma ghrelin concentrations in all subjects demonstrated a significantly negative correlation with BMI. Mean plasma ghrelin level in BN patients was significantly higher than that in the controls, though mean BMIs between the groups were not significantly different. CONCLUSION: These findings suggest that not only BMI but also abnormal eating behaviors with habitual binge eating and purging may have some influence on circulating ghrelin level in BN.

OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics of interstitial lung disease (ILD) patients with anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies. Patients and Methods We examined 14 ILD patients with anti-ARS autoantibodies between 2004 and 2007 and retrospectively investigated their clinical, radiographic, and pathological findings. RESULTS: Anti-Jo-1 antibodies were the most common (10 of 14), followed by anti-OJ, anti-KS, and anti-EJ (1 each for 3 patients); 1 patient with polymyositis had both anti-Jo-1 and anti-PL-12 antibodies. Ten patients had a chronic clinical course, whereas 4 presented with subacute deterioration. Of 8 patients with myositis, 1 (12.5%) had myositis-preceding ILD, 3 (37.5%) had ILD-preceding myositis, and 4 (50%) had simultaneous onset. Chest high-resolution computed tomography frequently showed lung-base predominant ground glass opacities (GGO) with volume loss. The results of surgical lung biopsies indicated that 4 patients had nonspecific interstitial pneumonia (NSIP) and/or organizing pneumonia (OP) patterns. All but 1 received corticosteroid therapy, and 6 patients were also given cyclosporin. The mean duration of follow-up was 22 months (range, 5-47 months). ILD improved in 9 patients and stabilized in 3; however, in 1 patient, it initially improved during 6 months, then progressively worsened despite treatment, and finally resulted in death. CONCLUSION: These results indicate that ILD patients with anti-ARS antibodies usually have a chronic clinical course, lung-base predominant GGO with volume loss, NSIP and/or OP patterns, and a good response to corticosteroid treatment; however, some have a rapidly worsening course and recurrence, despite therapy.