Higashi Nagoya National Hospital

Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10−9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.

Rationale: Patients with noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex pulmonary disease (MAC-PD) are treated intermittently three times per week, although no randomized controlled trials have been conducted comparing three times weekly with daily therapy. Objectives: To assess the tolerability, safety, and efficacy of intermittent versus daily treatment in patients with previously untreated noncavitary NB MAC-PD. Methods: In an open-label study, patients were randomly assigned to the intermittent therapy group receiving clarithromycin 1,000 mg, rifampicin 600 mg, and ethambutol 25 mg/kg (maximum 1,000 mg) three days per week or the daily therapy group receiving clarithromycin 800 mg, rifampicin 450 mg, and ethambutol 15 mg/kg (maximum 750 mg) daily for 1 year. The primary endpoint was the proportion of patients requiring modification of the initial treatment regimen. Results: Twenty-one Japanese hospitals participated in the study, enrolling 141 patients between May 2019 and December 2021. The full analysis set included 138 participants (intermittent therapy = 70; daily therapy = 68). There were no significant differences between the intermittent and daily therapy groups in terms of the regimen modification rate (20.0% [14 of 70] vs. 33.8% [23 of 68]; adjusted odds ratio, 0.48; 95% confidence interval, 0.22 to 1.05; P = 0.06) or culture conversion (70.3% vs. 80.0%; P = 0.53), time to culture conversion (28.0 vs. 28.5 d; P = 0.89), improvement in chest CT findings (60.9% vs. 71.0%; P = 0.30), or clarithromycin resistance development (1.4% vs. 0%; P = 1.00). Elevated aspartate aminotransferase (16.9% vs. 41.2%; P = 0.003) and alanine aminotransferase (18.3% vs. 44.1%; P = 0.002) were more common in the daily treatment group, whereas elevated bilirubin (11.3% vs. 1.5%; P = 0.04) and dysgeusia (14.1% vs. 1.5%; P = 0.01) were more common in the intermittent treatment group. The daily treatment group exhibited a greater absolute change in the 36-Item Short Form Health Survey physical aspect score (-2.5 points) than the intermittent treatment group (2.1 points) (P = 0.01). Conclusions: Intermittent treatment was not significantly better tolerated than daily treatment for noncavitary NB MAC-PD. However, further studies with larger numbers of patients are needed. Clinical trial registered with https://jrct.mhlw.go.jp/en-top (jRCTs031190008).

Mycobacterium avium subsp. hominissuis (MAH) causes mainly pulmonary infection in immunocompetent hosts, disseminated infection in immunocompromised hosts, such as individuals infected with human immunodeficiency virus (HIV), and infection in pigs. To examine the features of MAH isolates from different origins, we performed molecular epidemiological analysis and drug susceptibility testing using eight drugs, including clarithromycin, rifampicin, ethambutol, streptomycin, and amikacin. Phylogenetic analysis based on the allelic profile of whole-genome multi-locus sequence typing of 156 strains, including those from Japan, Europe, the United States, and Taiwan, revealed that 93.6% of isolates from patients with pulmonary MAH disease and 61.5% of isolates from HIV-positive patients formed clusters unique to Japanese strains, whereas the remaining isolates from HIV-positive patients and all isolates from pigs were included in other clusters formed by strains from Europe, the United States, and Taiwan. Thus, isolates from patients with pulmonary MAH disease and pigs were genetically distinct, and isolates from HIV-positive patients were classified into two distinct genetic types. Furthermore, isolates from patients with pulmonary MAH disease were significantly more resistant to seven drugs, excluding rifampicin, compared with other isolates. These results indicate that MAH isolates from three different origins in Japan have different genetic and drug susceptibility characteristics.

Progressive supranuclear palsy (PSP) manifests with the loss of skeletal muscle mass, but the longitudinal changes have not been investigated. We studied changes in body composition, including in skeletal muscle mass, in patients with PSP twice, approximately 1 year or more apart, and we compared these measurements with those of patients with Parkinson’s disease (PD). The total number of participants was 42: 10 men had PD, 13 men had PSP, 8 women had PD, and 11 women had PSP. Using a body composition analyzer, we measured such parameters as body mass index (BMI), skeletal muscle mass, basal metabolic rate (BMR), body fat percentage (BFP), and the ratio of extracellular water to total body water. We also calculated the skeletal muscle mass index (SMI). We measured the Barthel index to assess activities of daily living. The Barthel index was lower in patients with PSP than in those with PD at the first evaluation, and it worsened by the time of the second evaluation. In men with PSP, skeletal muscle mass was far more reduced than in those with PD, but no such changes were found among women with either disease. The SMI of men with PSP was correlated significantly with BMI, BMR, BFP, and the Barthel index. Skeletal muscle mass diminished faster in patients with PSP, especially in men, than in patients with PD, probably because of inactivity.

The prognostic significance of absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) remains unclear in patients with postoperative pneumonia (POP). The study objectives were to investigate the prognostic effects of ALC and ANC in POP patients, and to evaluate the time courses of ALC and ANC during hospitalization. This post-hoc analysis of a single-center prospective observational study evaluated consecutive POP patients, and comparatively analyzed community-acquired pneumonia (CAP) patients to highlight features of POP. In total, 228 POP patients and 1027 CAP patients were assessed. Severe lymphopenia (ALC < 500 cells/μL) at diagnosis was associated with worse 90-day survival in both types of pneumonia. In POP patients, neutrophilia (ANC > 7500 cells/μL) was associated with better survival, whereas CAP patients with neutrophilia tended to have a lower survival rate. Prolonged lymphopenia and delayed increase in neutrophils were characteristic time-course changes of non-survivors in POP. The time courses of ALC and ANC between survivors and non-survivors in POP trended differently from those in CAP. Our study showed that ALC and ANC at pneumonia diagnosis can serve as prognostic factors in POP patients. Differences in time-course changes of ALC and ANC between survivors and non-survivors may provide important information for future immunological research in pneumonia.

Autologous stem cell transplantation (ASCT) remains an important therapeutic strategy for multiple myeloma; however, a proportion of patients fail to mobilize a sufficient number of peripheral blood stem cells (PBSCs) to proceed to ASCT. In the present study, we aimed to clarify the characteristics and outcomes of poor mobilizers. Clinical data on poorly mobilized patients who underwent PBSC harvest for almost 10 years were retrospectively collected from 44 institutions in the Japanese Society of Myeloma (JSM). Poor mobilizers were defined as patients with less than 2 × 106/kg of CD34+ cells harvested at the first mobilization. The proportion of poor mobilization was 15.1%. A sufficient dataset including overall survival (OS) was evaluable in 258 poor mobilizers. Overall, 92 out of 258 (35.7%) poor mobilizers did not subsequently undergo ASCT, mainly due to an insufficient number of PBSCs. Median OS from apheresis was longer for poor mobilizers who underwent ASCT than for those who did not (86.0 vs. 61.9 mon., p = 0.02). OS from the diagnosis of poor mobilizers who underwent ASCT in our cohort was similar to those who underwent ASCT in the JSM database (3y OS rate, 86.8% vs. 85.9%). In this cohort, one‐third of poor mobilizers who did not undergo ASCT had relatively poor survival. In contrast, the OS improved in poor mobilizers who underwent ASCT. However, the OS of extremely poor mobilizers was short irrespective of ASCT.

Skeletal muscle mass loss has been associated with decreased physical performance; however, the body composition characteristics in progressive supranuclear palsy (PSP) are not well understood. We investigated body composition parameters, focusing on skeletal muscle mass, in patients with PSP and compared them with those of healthy older adults. This retrospective cross-sectional study included 39 patients with PSP and 30 healthy older adults (control group). Using a multi-frequency bioelectrical impedance analysis, we measured the skeletal mass index (SMI), basal metabolism, extracellular water/total body water ratio (ECW/TBW), and body fat percentage and examined the relationship between SMI and age, body mass index (BMI) and other body composition parameters. The PSP group had a higher rate of low muscle mass (56.4%) than the control group (10.0%), although the ages and BMIs were similar. The leg SMI was lower for the PSP group, while the ECW/TBW was higher for the PSP group. The basal metabolism was lower for the PSP group than for the controls but only in the women. The basal metabolism and BMI showed a significant correlation with SMI in the PSP group. There was a significant correlation between SMI and age, ECW/TBW, and body fat percentage in the PSP group but only in the women. This study is the first to show that a high proportion of patients with PSP have low muscle mass. We showed differences in terms of sex in muscle mass loss in women with PSP, which was associated with inactivity and aging.

6070 Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]