Development of an umbilical cord blood transplantation-specific nonrelapse mortality risk assessment score.

ABSTRACT: Higher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation-specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Personalized medicine with germline pathogenic variants: Importance of population- and region-wide evidence.

Rare germline pathogenic variants in cancer-predisposing genes have a high impact and potential for clinical utility. In the last 30 years, based on evidence of cancer risk associated with germline pathogenic variants, several measures have been suggested for personalized medicine, including the development of novel treatments, treatment stratification, risk reduction by surgical measures, chemoprevention, removal of environmental factors, and surveillance for early detection among specific high-risk individuals. However, this evidence is mainly based on evaluations of European populations. Our large-scale analyses of more than 100,000 individuals, including 14 disease cases and non-cancer controls in the Japanese population, suggest some discrepancies in the associations between cancer-predisposing genes and diseases, expansion of the targeted diseases of BRCA1 and BRCA2, and a potential novel risk-reduction measure for gastric cancer. They are likely to be explained by population and region variations; therefore, more population-wide and region-wide research could provide improved personalized medicine as well as a better understanding of disease mechanisms. This review summarizes current personalized medicine and discusses the potential use of germline pathogenic variants.

Trends in non-Hodgkin lymphoma mortality rate in Japan and the United States: A population-based study.

Characterizing trends in mortality rates with consideration of trends in incidence rates at the population level could help identify unmet needs in public health and provide essential indicators of cancer control. In the late 20th century, the arrival of the first molecular targeted agent, rituximab, for non-Hodgkin lymphoma (NHL) led to a paradigm shift in NHL treatment. However, the public health impact of this arrival has not been fully clarified. Here, we evaluated trends in the mortality and incidence rates of NHL in Japan and the United States. Age-standardized rates of mortality reversed after the introduction of rituximab, around 2000, beginning to decline significantly with annual percent changes (95% confidence interval) of -2.6% (-3.6% to -1.6%) in Japan and - 3.9% (-4.2% to -3.5%) in the United States. Despite an increase in incidence, the mortality in all age groups weakened the upward trends or decreased in both countries. From a long-term perspective, the trends in mortality rates differed between the countries. In the United States, the mortality rate has declined continuously since the introduction of rituximab, with a declining incidence rate. In contrast, in Japan, the mortality rate stopped declining and the incidence rate increased remarkably. The introduction of rituximab has had a substantial impact at the population level across a wide range of individuals. To reduce the disease burden in terms of mortality, elucidating risk factors that lead to a decreasing incidence rate is warranted for NHL, as well as further development of novel treatments.

Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.

BACKGROUND: Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated. METHODS: We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). RESULTS: Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]). CONCLUSIONS: H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Association between early corticosteroid administration and long-term survival in non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.

Non-infectious pulmonary complications (NIPCs) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with poor outcomes. It is important to maximize the effectiveness of primary treatment because secondary treatment has not been established. We analyzed data from 393 patients who underwent allogeneic HSCT during a 10-year period. Thirty-seven were diagnosed with NIPCs, which consisted of idiopathic pneumonia syndrome, bronchiolitis obliterans, and interstitial lung disease including cryptogenic organizing pneumonia. Among these, 18 died (Dead group) while 19 remained alive (Alive group) during the study period. The median time between NIPC diagnosis and first administration of ≥ 1 mg/kg/day corticosteroids (prednisolone dose equivalent) was significantly longer in the Dead group than the Alive group, at 9 days versus 4 days (p = 0.01). We further divided these cases into those who received prednisolone within seven days and after 8 days. We found that the ≤ 7 days group were more likely to survive after their NIPC diagnosis compared to the ≥ 8 days group (p = 0.06). Our analysis showed that early initiation of corticosteroid therapy is associated with long-term survival in NIPCs.

Association between germline pathogenic variants in cancer-predisposing genes and lymphoma risk.

The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. We identified 309 pathogenic variants among 4,850 variants in the 27 cancer-predisposing genes. Pathogenic variants in the following four cancer-predisposing genes were associated with a high risk of lymphoma: ATM (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25-5.51; p = 1.06 × 10-2 ), BRCA1 (OR, 5.88; 95% CI, 2.65-13.02; p = 1.27 × 10-5 ), BRCA2 (OR, 2.94; 95% CI, 1.60-5.42; p = 5.25 × 10-4 ), and TP53 (OR, 5.22; 95% CI, 1.43-19.02; p = 1.23 × 10-2 ). The proportion of carriers of these genes was 1.6% of lymphoma patients. Furthermore, pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma (OR, 21.57; 95% CI, 7.59-61.26; p = 8.07 × 10-9 ). These results provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment, such as other neoplasms.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants.

Importance: The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines. Objective: To evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types. Design, Setting, and Participants: This case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021. Main Outcomes and Measures: Germline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Results: A total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives. Conclusions and Relevance: The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.

Autologous or allogeneic hematopoietic cell transplantation for relapsed or refractory PTCL-NOS or AITL.

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53-1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46-0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT.

Association between germline pathogenic variants and breast cancer risk in Japanese women: The HERPACC study.

Approximately 5%-10% of breast cancers are hereditary, caused by germline pathogenic variants (GPVs) in breast cancer predisposition genes. To date, most studies of the prevalence of GPVs and risk of breast cancer for each gene based on cases and noncancer controls have been conducted in Europe and the United States, and little information from Japanese populations is available. Furthermore, no studies considered confounding by established environmental factors and single-nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) together in GPV evaluation. To evaluate the association between GPVs in nine established breast cancer predisposition genes including BRCA1/2 and breast cancer risk in Japanese women comprehensively, we conducted a case-control study within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (629 cases and 1153 controls). The associations between GPVs and the risk of breast cancer were assessed by odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models adjusted for potential confounders. A total of 25 GPVs were detected among all cases (4.0%: 95% CI: 2.6-5.9), whereas four individuals carried GPVs in all controls (0.4%). The OR for breast cancer by all GPVs and by GPVs in BRCA1/2 was 12.2 (4.4-34.0, p = 1.74E-06) and 16.0 (4.2-60.9, p = 5.03E-0.5), respectively. A potential confounding with GPVs was observed for the GWAS-identified SNPs, whereas not for established environmental risk factors. In conclusion, GPVs increase the risk of breast cancer in Japanese women regardless of environmental factors and GWAS-identified SNPs. Future studies investigating interactions with environment and SNPs are warranted.

Possible prognostic impact of WT1 mRNA expression at day + 30 after haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide for patients with myeloid neoplasm: a multicenter study from the Okayama Hematological Study Group.

BACKGROUND: Previous studies have revealed that relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be predicted by monitoring Wilms' tumor 1 (WT1) mRNA expression. However, only a few studies have investigated patients who received human leukocyte antigen-haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCY-haplo). In this study, we investigated the relationship between WT1 mRNA levels and clinical outcomes in the PTCY-haplo group, and compared them with those in the conventional graft-versus-host disease prophylaxis group (conventional group). METHODS: We retrospectively analyzed 130 patients who received their first allo-HSCT between April 2017 and December 2020, including 26 who received PTCY-haplo. RESULTS: The WT1 mRNA expression level at day + 30 after allo-HSCT associated with increased risk of 1-year cumulative incidence of relapse (CIR) was ≥ 78 copies/µg RNA in the conventional group (p < 0.01) and ≥ 50 copies/µg RNA in the PTCY-haplo group (p = 0.03). CONCLUSIONS: The appropriate cutoff level of WT1 mRNA at day + 30 after allo-HSCT for predicting prognosis in patients treated with PTCY-haplo may be < 50 copies/µg RNA.

Low-intensity cigarette smoking and mortality risks: a pooled analysis of prospective cohort studies in Japan.

BACKGROUND: Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood. METHODS: We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model. RESULTS: The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk. CONCLUSIONS: Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD.

Impact of the combination of donor age and HLA disparity on the outcomes of unrelated bone marrow transplantation.

Impact of donor age considering HLA disparity on hematopoietic cell transplantation (HCT) outcomes has not been fully evaluated. We evaluated 8486 patients who received unrelated bone marrow transplantation (UR-BMT) from 8/8 or 7/8 HLA-matched donors. Compared to 8/8 HLA-matched younger donors (<40 years), 8/8 HLA-matched older donors (subdistribution hazard ratio [SHR], 1.16; 95% CI, 0.97-1.38) and 7/8 HLA-matched younger donors (SHR, 1.33; 95% CI, 1.11-1.58) were associated with increased risk of grade III-IV acute graft-versus-host disease (aGVHD). 7/8 HLA-matched older donors had further increased risk (SHR, 2.00; 95% CI, 1.68-2.38) due to interaction between donor age and HLA disparity (p for interaction = 0.038). Progression-free survival (PFS) after UR-BMT with 8/8 HLA-matched younger donors was comparable to that after UR-BMT with 8/8 HLA-matched older donors, whereas UR-BMT with 7/8 HLA-matched younger or older donors was significantly associated with lower PFS than UR-BMT with 8/8 HLA-matched younger donors (younger donor; HR, 1.12; 95% CI, 1.04-1.21, older donor; HR, 1.28; 95% CI, 1.17-1.40; p for interaction = 0.079). In conclusion, adverse effect of increased donor age requires attention, especially in HLA-mismatched UR-BMT due to interaction between donor age and HLA disparity. Intensive aGVHD prophylaxis may be required to improve outcomes after HCT with mismatched older donors.

Impact of PSCA Polymorphisms on the Risk of Duodenal Ulcer.

BACKGROUND: While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population. METHODS: Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU. RESULTS: PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18-1.51; P = 2.28 × 10-6) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs. CONCLUSIONS: Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.

Metabolites Produced by Kaistia sp. 32K Promote Biofilm Formation in Coculture with Methylobacterium sp. ME121.

Previously, we reported that the coculture of motile Methylobacterium sp. ME121 and non-motile Kaistia sp. 32K, isolated from the same soil sample, displayed accelerated motility of strain ME121 due to an extracellular polysaccharide (EPS) produced by strain 32K. Since EPS is a major component of biofilms, we aimed to investigate the biofilm formation in cocultures of the two strains. The extent of biofilm formation was measured by a microtiter dish assay with the dye crystal violet. A significant increase in the amount of biofilm was observed in the coculture of the two strains, as compared to that of the monocultures, which could be due to a metabolite produced by strain 32K. However, in the coculture with strain 32K, using Escherichia coli or Pseudomonas aeruginosa, there was no difference in the amount of biofilm formation as compared with the monoculture. Elevated biofilm formation was also observed in the coculture of strain ME121 with Kaistia adipata, which was isolated from a different soil sample. Methylobacterium radiotolerans, isolated from another soil sample, showed a significant increase in biofilm formation when cocultured with K. adipata, but not with strain 32K. We also found that the culture supernatants of strains 32K and K. adipata accelerated the motility of strains ME121 and M. radiotolerans, wherein culture supernatant of K. adipata significantly increased the motility of M. radiotolerans, as compared to that by the culture supernatant of strain 32K. These results indicated that there was a positive relationship between accelerated motility and increased biofilm formation in Methylobacterium spp. This is the first study to report that the metabolites from Kaistia spp. could specifically modulate the biofilm-forming ability of Methylobacterium spp. Methylobacterium spp. biofilms are capable of inhibiting the biofilm formation of mycobacteria, which are opportunistic pathogens that cause problems in infectious diseases. Thus, the metabolites from the culture supernatant of Kaistia spp. have the potential to contribute to the environment in which increased biofilm production of Methylobacterium is desired.

Changing trend in mortality rate of multiple myeloma after introduction of novel agents: A population-based study.

Previously, the main treatment for multiple myeloma (MM) was cytotoxic chemotherapies, including autologous stem-cell transplantation (ASCT), but survival benefit in the elderly was limited. More recently, clinical trials and practical experience with novel agents with superior efficacy have shown improved survival, including in the elderly. However, this improvement cannot be simply interpreted as a decline in mortality rate that is an important public health measure of progress against cancer. Here, we assessed the trends in mortality rates of MM in parallel with incidence rates in Japan and the U.S. We used national mortality data and population-based cancer registry data in both countries from 1995 to 2015, during which 74 972 patients in Japan and 229 290 patients in the U.S. died of MM. Trends in mortality and incidence rates were characterized using joinpoint regression analysis. Despite upward trends in incidence, mortality rates showed a significant decrement after 2005 in Japan, with an annual percent change [APC (95% confidence interval)] of -2.5% (-2.9% to -2.1%), and after 2002 in the U.S., with an APC of -2.0% (-2.6% to -1.5%). In both countries, the change in mortality trend coincided with the introduction of the novel agents. Moreover, improvements in mortality were particularly large in patients aged 70 to 79 years, who cannot receive ASCT. Our results indicate that the benefits of novel agents for MM are appreciable at the population level and may encourage further development of novel agents for malignancies that can be widely applied to the patients.

A Factor Produced by Kaistia sp. 32K Accelerated the Motility of Methylobacterium sp. ME121.

Motile Methylobacterium sp. ME121 and non-motile Kaistia sp. 32K were isolated from the same soil sample. Interestingly, ME121 was significantly more motile in the coculture of ME121 and 32K than in the monoculture of ME121. This advanced motility of ME121 was also observed in the 32K culture supernatant. A swimming acceleration factor, which we named the K factor, was identified in the 32K culture supernatant, purified, characterized as an extracellular polysaccharide (5-10 kDa), and precipitated with 70% ethanol. These results suggest the possibility that the K factor was directly or indirectly sensed by the flagellar stator, accelerating the flagellar rotation of ME121. To the best of our knowledge, no reports describing an acceleration in motility due to coculture with two or more types of bacteria have been published. We propose a mechanism by which the increase in rotational force of the ME121 flagellar motor is caused by the introduction of the additional stator into the motor by the K factor.

Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis.

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43-2.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers. SIGNIFICANCE: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.