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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. What's new?: Mortality rate is a key public health measure of progress against cancer and is sometimes markedly impacted by the approval of novel anticancer interventions. Here, the authors evaluated mortality and incidence rates of multiple myeloma (MM) in Japan and the United States, searching for trends associated with new therapeutic interventions. Their analyses show that mortality rates of MM decreased significantly after the introduction of novel therapies in the early 2000s, despite increasing trends in MM incidence rates in both countries. Mortality rates improved considerably among older patients, ages 70 to 79, who are unable to undergo autologous stem‐cell transplantation. [ABSTRACT FROM AUTHOR]

Immunoglobulin (Ig) heavy/light chain ( HLC) assays enable the separate quantification of the different light chain types of each Ig class. We retrospectively analyzed the correlation of heavy/light chain ratio ( HLCR) with clinical status and its impact on outcome in 120 patients with multiple myeloma ( MM). Abnormal HLCR was seen more frequently in patients with poorer myeloma response, and it appeared to be more sensitive for detecting clonality in IgA myeloma compared to IgG myeloma after treatment. Among the 85 patients who achieved ≥ VGPR, the patients remained HLCR abnormal were showed significantly shorter overall survival ( OS) compared to those achieving a normal HLCR (not reached vs 55.5 months, P = 0.032). This correlation was seen in IgA myeloma patients (not reached vs 30.1 months, P = 0.014), but not in IgG myeloma patients when patients were analyzed separately. Univariate and multivariate analysis of factors that may affect survival identified abnormal HLCR at the best response as the only independent risk factor (hazard ratio, 4.7; 95% confidence interval, 1.4 - 15.26; P = 0.012) for shorter OS in this subset of patients. This study highlighted the HLC assay as a prognostic predictor in patients with IgA myeloma. [ABSTRACT FROM AUTHOR]

To investigate the impact of immunophenotypic complete response [iCR, ≤10−4multiple myeloma (MM) cells defined by multicolor flow cytometry (MFC)] on survival in patients with MM, we retrospectively analyzed 78 patients that obtained conventional CR at our hospital. Survivals were landmarked at achievement of CR. The rate of stringent CR (sCR) among patients with CR was 88%, and iCR for CR and sCR patients were 44% and 49%, respectively. Achievement of iCR was associated with significantly longer disease-free survival (DFS) not only in CR patients (p = 0.009) but also in sCR patients (p = 0.002), while sCR attainmentper sedid not have statistically significant impact on DFS (p = 0.06) or overall survival (OS) (p = 0.587). Univariate and multivariate analyses indicated that attainment of iCR was independently associated with longer 2-year DFS in addition to creatinine (≤2.0 mg/dL) and maintenance therapy. This study highlights the importance of pursuing iCR even in patients with sCR. [ABSTRACT FROM AUTHOR]

Numerical analysis of MHD flow in rectangular channel is performed to evaluate the performance of remountable first wall with liquid blanket like Li or Flibe, where fabrication and maintenance of the system become extremely simplified. Four-channel model is used to calculate the MHD pressure drop in variously coated channels. The effect of crack existence in the coated layer of flow channel on the MHD pressure drop is also evaluated for real usage. The numerical results indicate that some amount of crack existence is allowable, which shows possibility to apply the first wall concept to future fusion reactor design. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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.

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., (©2020 American Association for Cancer Research.)

Second allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for patients who relapse after first allo-SCT. Human leukocyte antigen (HLA)-haploidentical related donors provide the broad opportunity to conduct second SCT at the appropriate time, but the efficacy of second SCT from haploidentical donors after relapse has not been established. We retrospectively analyzed the records of 33 patients who underwent second SCT. Twenty patients underwent haplo-SCT with low-dose antithymocyte globulin (ATG), and the other 13 patients underwent conventional- SCTs, including HLA-matched related peripheral blood, unrelated bone marrow or cord blood. Three years after the second SCT, the overall survival (OS) and progression-free survival (PFS) of all patients were 32.5% and 23.9%. Multivariate analyses indicated that non-complete response at second SCT, less than 1-year interval to relapse after first- SCT, and total score ≥ 3 on the hematopoietic cell transplantation-specific comorbidity index were significantly associated with a lower PFS rate. The haplo- and conventional- SCT groups showed equivalent results regarding OS, PFS, cumulative incidences of relapse, non-relapse mortality and graft-versus-host disease. The neutropenic period after transplantation was significantly shorter in haplo- SCT than conventional- SCT (10.5 days vs. 16 days, p=0.001). Our analysis revealed that haplo-SCT could be an alternative therapeutic option for relapsed patients after first SCT., Competing Interests: No potential conflict of interest relevant to this article was reported.

We retrospectively explored the prognostic relevance of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the association of NT-proBNP with cardiac and renal functions in 153 patients with newly diagnosed symptomatic multiple myeloma and no concomitant light chain amyloidosis who received novel agents. We also examined the usefulness of the new frailty system recently introduced by Mayo Clinic (combining age, performance status, and NT-proBNP). Patients with higher NT-proBNP levels (≥300 ng/L) had a significantly higher incidence of left ventricular diastolic dysfunction (LVDD) and myeloma-related renal insufficiency and significantly shorter overall survival (OS) than did those with lower NT-proBNP levels (<300 ng/L). NT-proBNP remained predictive of OS on multivariate analysis. Mayo Clinic's new frailty system showed excellent discrimination of OS. Furthermore, the Instrumental Activity of Daily Living (IADL) score (not evaluated in Mayo Clinic's study) predicted OS independently of this system, and a sharper discrimination of OS curves was obtained by the incorporation of IADL into this system. Our findings demonstrated that NT-proBNP levels were associated with both LVDD (as a host risk factor) and myeloma-related renal insufficiency (resulting from the disease aggressiveness) and provided predictive information regarding OS in patients with symptomatic myeloma. Furthermore, we, for the first time, validated Mayo Clinic's new frailty system. Our modification further improved Mayo Clinic's system by newly incorporating the IADL score., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest.

Accurate quantification of plasma cells (PCs) in bone marrow (BM) is critical for diagnosis and assessment of treatment response in patients with multiple myeloma (MM). We compared the % of BM PC quantified by 250 cell differential count on May-Giemsa-stained BM smears, by counting 500 - 2500 cells in 2 - 5 representative microscopy fields in CD138-immunostained BM clot and biopsy sections, and CD38/CD45/CD138 gated BM PCs on flow cytometry (FCM) in 150 sets of BM samples from 120 patients. Percentages of PC were significantly correlated between BM biopsy and clot, and between smear and FCM (r = 0.96, 0.93, respectively). However, quantification by smear and FCM significantly underestimated the PC compared to biopsy or clot, and the degree of underestimation increased with blood dilution. FCM consistently showed lower % of PC compared to aspirate smears. Fifty-nine of 103 patients with M-protein level < 3000 mg/dL in serum or 500 mg/24 h in urine and diagnosed with monoclonal gammopathy of undetermined significance (MGUS) based on smear alone were reclassified as smoldering MM when reassessed using CD138-stained biopsy/clot sections. Among the 72 patients with sMM diagnosed by BM biopsy and/clot, three patients (4.2%) had extensive BM infiltration of PC (≥ 60%) and required treatment. Our data clearly showed the necessity of CD138 immunostaining of BM biopsy/clot specimens for correct diagnosis of MM and related disorders. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)