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Background: Smoking, alcohol use, and obesity appear to increase the risk of developing non-Hodgkin lymphoma (NHL), but to the authors' knowledge, few studies to date have assessed their impact on NHL prognosis.Methods: The association between prediagnosis cigarette smoking, alcohol use, and body mass index (BMI) and overall survival was evaluated in 1286 patients enrolled through population-based registries in the United States from 1998 through 2000. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox regression, adjusting for clinical and demographic factors.Results: Through 2007, 442 patients had died (34%), and the median follow-up for surviving patients was 7.7 years. Compared with never smokers, former (HR, 1.59; 95% CI, 1.12-2.26) and current (HR, 1.50; 95% CI, 0.97-2.29) smokers had poorer survival, and poorer survival was found to be positively associated with smoking duration, number of cigarettes smoked per day, pack-years of smoking, and shorter time since quitting (all P <0.01). Alcohol use was associated with poorer survival (P = 0.03); compared with nonusers. Those drinking >43.1 g/week (median intake among drinkers) had poorer survival (HR, 1.55; 95% CI, 1.06-2.27), whereas those drinkers consuming less than this amount demonstrated no survival disadvantage (HR, 1.13; 95% CI, 0.75-1.71). Greater BMI was associated with poorer survival (P = 0.046), but the survival disadvantage was only noted among obese individuals (HR, 1.32 for BMI > or = 30 vs BMI 20-24.9; 95% CI, 1.02-1.70). These results held for lymphoma-specific survival and were broadly similar for diffuse large B-cell lymphoma and follicular lymphoma.Conclusions: NHL patients who smoked, consumed alcohol, or were obese before diagnosis were found to have a poorer overall and lymphoma-specific survival. [ABSTRACT FROM AUTHOR]

To quantify nonresponse bias and estimate its potential impact, the authors compared census-based socioeconomic and demographic factors and geographic locations among respondents and nonrespondents in a multicenter case-control study of non-Hodgkin lymphoma (1998-2000). Using a geographic information system, the authors mapped current addresses and linked them to the 2000 US Census database to determine group-level demographic and socioeconomic information. They used logistic regression analysis to compute the risk of being a nonrespondent, separately for cases and controls. They used spatial scan methods to evaluate spatial clustering at each study center. Among cases at one or more centers, nonresponse was significantly associated with non-White race, lower household income, a greater proportion of multiple-unit housing, fewer years of education, and living in a more urbanized area. For most factors, the authors observed similar patterns among controls, although findings were mostly nonsignificant. They found two nonrandom elliptical clusters in Los Angeles, California, and Detroit, Michigan, that disappeared after adjustment for the demographic factors. The authors determined the bias in non-Hodgkin lymphoma risk associated with census-tract educational level by comparing risks among respondents and all subjects. The bias was 8%, indicating that the socioeconomic and demographic differences between respondents and nonrespondents did not result in a large bias in the risk estimate for education. [ABSTRACT FROM AUTHOR]

Studies associate alcohol consumption, cigarette smoking, and body size with the risk of overall or subtype lymphoma. Current data come mostly from case-control studies or prospective studies with few cases. In the prospective National Institutes of Health-former American Association of Retired Persons (NIH-AARP) Diet and Health Study, the authors assessed the above lifestyle factors via baseline questionnaire among 285,079 men and 188,905 women aged 50-71 years and ascertained histologically confirmed Hodgkin's lymphoma (n = 58) and non-Hodgkin's lymphoma (n = 1,381) cases through linkage with cancer registries from 1995 to 2000. Compared with nondrinkers, alcohol consumers had a lower risk for non-Hodgkin's lymphoma overall (for >28 drinks/week: adjusted relative risk (RR) = 0.77, 95% confidence interval (CI): 0.59, 1.00; p(trend) among drinkers = 0.02) and for its main subtypes. Compared with never smokers, current smokers and recent quitters (/=35: RR = 1.29, 95% CI: 1.02, 1.64) and taller height (RR = 1.19, 95% CI: 1.03, 1.38) were associated moderately with non-Hodgkin's lymphoma. These findings add to the evidence that lifestyle factors and relevant anthropometric characteristics play a role in lymphoma etiology. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous epidemiological studies of the relation between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) have been inconsistent, probably because of small sample sizes of individual studies that result from stratification by NHL subtype and type of alcoholic beverage. We aimed to assess the role of alcohol consumption in NHL with sufficient sample size to analyse by both type of alcoholic beverage and disease subtype. METHODS: We obtained original data from nine case-control studies from the USA, UK, Sweden, and Italy in the International Lymphoma Epidemiology Consortium (InterLymph), yielding a pooled study population of 15 175 individuals (6492 cases and 8683 controls). We derived odds ratios (OR) and 95% CI from unconditional logistic regression models, controlling for study centre and other confounding factors. Heterogeneity between studies was assessed by comparison of results from joint fixed-effects logistic regression and two-stage random-effects logistic regression, and by calculation of Wald chi(2) statistics. FINDINGS: People who drank alcohol had a lower risk of NHL than did non-drinkers (OR 0.83 [95% CI 0.76-0.89]). Compared with non-drinkers, risk estimates were lower for current drinkers than for former drinkers (0.73 [0.64-0.84] vs 0.95 [0.80-1.14]), but risk did not decrease with increasing alcohol consumption. The protective effect of alcohol did not vary by beverage type, but did change with NHL subtype. The lowest risk estimates were recorded for Burkitt's lymphoma (0.51 [0.33-0.77]). INTERPRETATION: People who drink alcoholic beverages might have a lower risk of NHL than those who do not, and this risk might vary by NHL subtype. Further study designs are needed to determine whether confounding lifestyle factors or immunomodulatory effects of alcohol explain this association. [ABSTRACT FROM AUTHOR]

Several recent studies have suggested a potential role of menstrual and reproductive factors in the risk of non-Hodgkin's lymphoma. To further examine the relation, the authors analyzed data from a population-based case-control study of non-Hodgkin's lymphoma in Connecticut women between 1996 and 2000. A total of 601 histologically confirmed cases and 717 randomly selected population-based controls were included in this study. An in-person interview was conducted using a standardized and structured questionnaire to collect information on menstrual and reproductive factors and potential confounding factors. Compared with nulliparous women, women who had four or more pregnancies during their lifetime were found to have a significantly reduced risk of non-Hodgkin's lymphoma (odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.4, 0.9). Risk appeared to decrease with increasing number of pregnancies (p(trend) = 0.03). The authors also observed an increased risk of non-Hodgkin's lymphoma overall (OR = 1.5, 95% CI: 1.0, 2.2) and of diffuse non-Hodgkin's lymphoma (OR = 1.7, 95% CI: 1.1, 2.7) for women who started their first menstrual period at age 15 or more years compared with those who started their first menstrual period before age 12 years. These findings support a reduced risk of non-Hodgkin's lymphoma associated with multiple pregnancies and an increased risk of non-Hodgkin's lymphoma associated with later age at menarche. [ABSTRACT FROM AUTHOR]

The incidence and mortality rates of non-Hodgkin's lymphoma have been increasing worldwide. Allogeneic blood transfusion has been suggested as a risk factor for non-Hodgkin's lymphoma, but the results from epidemiologic studies have been inconsistent. Data from a population-based case-control study of Connecticut women were analyzed to evaluate this relation. A total of 601 histologically confirmed, non-Hodgkin's lymphoma incident cases identified between 1996 and 2000 and 717 randomly selected controls were included in this study. Allogeneic blood transfusion was not associated with the increased risk of non-Hodgkin's lymphoma overall (odds ratio = 1.0, 95% confidence interval: 0.7, 1.3) or by subtype of the disease. The risk also did not vary by number of allogeneic blood transfusions, age at first transfusion, or time since first transfusion. When the reason for blood transfusion was considered, an increased risk of non-Hodgkin's lymphoma was found only for allogeneic blood transfusion for reason of anemia. In summary, the authors' findings do not support the hypothesis that allogeneic blood transfusion increases the risk of non-Hodgkin's lymphoma. [ABSTRACT FROM AUTHOR]

Not available.

Studies are lacking on long-term effects among retinoblastoma patients in low- and middle-income countries. Therefore, we examined cause-specific mortality in a retrospective cohort of retinoblastoma patients treated at Antonio Candido de Camargo Cancer Center (ACCCC), São Paulo, Brazil from 1986 to 2003 and followed up through December 31, 2018. Vital status and cause of death were ascertained from medical records and multiple national databases. We estimated overall and cause-specific survival using the Kaplan-Meier survival method, and estimated standardized mortality ratios (SMRs) and absolute excess risk (AER) of death. This cohort study included 465 retinoblastoma patients (42% hereditary, 58% nonhereditary), with most (77%) patients diagnosed at advanced stages (IV or V). Over an 11-year average follow-up, 80 deaths occurred: 70% due to retinoblastoma, 22% due to subsequent malignant neoplasms (SMNs) and 5% to non-cancer causes. The overall 5-year survival rate was 88% consistent across hereditary and nonhereditary patients (p = .67). Hereditary retinoblastoma patients faced an 86-fold higher risk of SMN-related death compared to the general population (N = 16, SMR = 86.1, 95% CI 52.7-140.5), corresponding to 42.4 excess deaths per 10,000 person-years. This risk remained consistent for those treated with radiotherapy and chemotherapy (N = 10, SMR = 90.3, 95% CI 48.6-167.8) and chemotherapy alone (N = 6, SMR = 80.0, 95% CI 35.9-177.9). Nonhereditary patients had only two SMN-related deaths (SMR = 7.2, 95% CI 1.8-28.7). There was no excess risk of non-cancer-related deaths in either retinoblastoma form. Findings from this cohort with a high proportion of advanced-stage patients and extensive chemotherapy use may help guide policy and healthcare planning, emphasizing the need to enhance early diagnosis and treatment access in less developed countries., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Acute myeloid leukemia (AML) often requires allogeneic hematopoietic cell transplantation (alloHCT) for cure, but historically alloHCT has been strikingly underutilized. Reasons for this remain uncertain at the population level. We examined alloHCT utilization over time and explored associations between demographic/healthcare factors and use of alloHCT by age group (AYA 15-39y, adult 40-64y, older adult 65-79y) using a linked dataset merging the Center for International Blood and Marrow Transplant Research, California Cancer Registry, and California Patient Discharge Database. Eligibility included patients newly diagnosed with AML in California between 2001-2016 who received induction therapy and had no prior HCT. Multivariable Fine-Gray regression analyses were fitted separately across age groups. Among 7,925 patients with AML, alloHCT utilization increased over time across all age groups; however, in the most recent time period studied (2011-2016), utilization within 2 years of diagnosis remained lowest in older adults (13%) relative to adults (41%) and AYAs (49%). Factors statistically significantly associated with lower alloHCT utilization: (1) AYAs: female sex, lower neighborhood socioeconomic status (nSES), uninsured or Indian Health Services (IHS) coverage; (2) adults: older age, male sex, non-Hispanic Black or Asian race and ethnicity, unmarried, lower nSES, uninsured or covered by Medicaid, Medicare, or IHS, higher comorbidity, and living 100+ miles from a transplant center; and (3) older adults: older age, Asian race, and unmarried. In conclusion, using a population-based linked dataset, we demonstrate that utilization of alloHCT among older patients newly diagnosed with AML remains low in California, and factors associated with utilization vary by age group.

Abstract: Compared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Background: Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC , ELP1 , GPR161 , PTCH1 , SUFU , and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions., Methods: Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes ( APC , ELP1 , GPR161 , PTCH1 , SUFU , TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls., Results: Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10 -3 ), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10 -8 ). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 ( p=3.0x10 -4 ) and SUFU (p=1.4x10 -3 )., Conclusion: Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rees, Gianferante, Kim, Stavrou, Reaman, Sapkota, Gramatges, Morton, Hudson, Armstrong, Freedman, Huang, Diver, Lori, Luo, Hicks, Liu, Hutchinson, Goldstein and Mirabello.)

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers ( 131 I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately., Purpose: To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients., Methods: The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach., Results: The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8 cm (mean) with 0.5 cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7 Gy (mean) with 1.0 Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2 Gy (mean) with 10.8 Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4 Gy (mean) with 0.4 Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient)., Conclusions: We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Type II diabetes is associated with cancer risk in the general population but has not been well studied as a risk factor for subsequent malignancies among cancer survivors. We investigated the association between diabetes and subsequent cancer risk among older (66-84 years), 1-year breast cancer survivors within the linked Surveillance Epidemiology and End Results (SEER)-Medicare database using Cox regression analyses to quantify hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Among 133 324 women, 29.3% were diagnosed with diabetes before or concurrent with their breast cancer diagnosis, and 10 452 women developed subsequent malignancies over a median follow-up of 4.3 years. Diabetes was statistically significantly associated with liver (HR = 2.35, 95% CI = 1.48 to 3.74), brain (HR = 1.94, 95% CI = 1.26 to 2.96), and thyroid cancer risks (HR = 1.38, 95% CI = 1.01 to 1.89). Future studies are needed to better understand the spectrum of subsequent cancers associated with diabetes and the role of diabetes medications in modifying subsequent cancer risk, alone or in combination with cancer treatments., (Published by Oxford University Press 2024.)

Purpose: Autologous hematopoietic cell transplantation (autoHCT) is associated with survival benefits in multiple myeloma (MM), but utilization remains low and differs by sociodemographic factors. Prior population-based studies have not fully captured autoHCT utilization or examined relationships between sociodemographic factors and autoHCT trends over time., Patients and Methods: We used a novel data linkage between the California Cancer Registry, Center for International Blood and Marrow Transplant Research, and hospitalizations to capture autoHCT in a population-based MM cohort (n = 29, 109; 1991-2016). Due to interactions by treatment era, stratified multivariable Cox proportional hazards regression models determined factors associated with autoHCT., Results: The frequency of MM patients who received autoHCT increased from 5.7% (1991-1995) to 27.4% (2011-2016). In models by treatment era, patients with public/no (vs. private) health insurance were less likely to receive autoHCT (2011-2016 Medicare hazard ratio (HR) 0.70, 95% confidence interval (CI): 0.63-0.78; Medicaid HR 0.81, CI: 0.72-0.91; no insurance HR 0.56, CI: 0.32-0.99). In each treatment era, Black/African American (vs. non-Hispanic White) patients were less likely to receive autoHCT (2011-2016 HR 0.83, CI: 0.72-0.95). Hispanic patients were less likely to undergo autoHCT, most prominently in the earliest treatment era (1991-1995 HR 0.58, 95% CI: 0.37-0.90; 2011-2016 HR 1.07, CI: 0.96-1.19). Patients in lower socioeconomic status neighborhoods were less likely to utilize autoHCT, but differences decreased over time., Conclusions: Despite increases in autoHCT utilization, sociodemographic disparities remain. Identifying and mitigating barriers to autoHCT is essential to ensuring more equitable access to this highly effective therapy., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Population-based survival studies of adult acute myeloid leukemia (AML) have not simultaneously evaluated age at diagnosis, race and ethnicity, sex, calendar period or AML subtypes/subgroups among chemotherapy-treated patients., Methods: For 28,473 chemotherapy-treated AML patients diagnosed at ages ≥20 years in population-based cancer registry areas of the Surveillance, Epidemiology, and End Results Program (2001-2018, followed through 2019), we evaluated 1-month through 5-year relative survival (RS) and 95% confidence intervals (95% CI) using the actuarial method in the SEER∗Stat Survival Session and overall survival (OS) using multivariable Cox regression to estimate proportional hazard ratios (HR) and 95% CI., Findings: RS decreased with increasing age (20-39, 40-59, 60-74, 75-84, ≥85 years) at AML diagnosis. RS declined substantially within the first month and, except for acute promyelocytic leukemia, decreasing patterns continued thereafter for core binding factor AML, AML with antecedent condition/therapy, and all other AML. For all ages, acute promyelocytic leukemia RS stabilized after the first year. For total AML the hazard of death was significantly increased for non-Hispanic (NH)-Black (HR = 1.18, 95% CI = 1.12-1.24) and NH-Pacific Islander patients (HR = 1.31, 95% CI = 1.11-1.55) compared with NH-White patients. In contrast, NH-Asian and Hispanic patients had similar OS to NH-White patients across all ages and most AML subgroups. Males had significantly inferior survival to females with some exceptions. Compared to 2001-2006, in 2013-2018 OS improved for all age and AML subgroups., Interpretation: Chemotherapy-treated U.S. adults with AML have notable differences in survival by age, race and ethnicity, sex, calendar-year period, and AML subgroup. Despite survival gains over time, our findings highlight the need for improving early outcomes across all AML subgroups, older ages, and Black and Pacific Islander patients and long-term outcomes among most treated groups., Funding: Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology., Competing Interests: The authors have no relationships to disclose.

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Despite the excellent disease-specific survival associated with low-risk differentiated thyroid cancer (DTC), its diagnosis and management have been linked to patient concerns about cancer recurrence, treatment-related health risks, and mortality. Lack of information regarding long-term health outcomes can perpetuate these concerns. Therefore, we assessed all-cause and cause-specific mortality in a large cohort of individuals diagnosed with low-risk DTC. Methods: From the U.S. Surveillance, Epidemiology, and End Results-12 cancer registry database (1992-2019), we identified 51,854 individuals (81.8% female) diagnosed with first primary DTC at low risk of recurrence (≤4 cm, localized). We estimated cause-specific cumulative mortality by time since diagnosis, accounting for competing risks. Standardized mortality ratios (SMRs) and CIs were used to compare observed mortality rates in DTC patients with expected rates in the matched U.S. general population, overall and by time since DTC diagnosis. We used Cox proportional hazards models to examine associations between radioactive iodine (RAI) treatment and cause-specific mortality. Results: During follow-up (median = 8.8, range 0-28 years), 3467 (6.7%) deaths were recorded. Thyroid cancer accounted for only 4.3% of deaths ( n  = 148). The most common causes of death were malignancies (other than thyroid cancer) ( n  = 1031, 29.7%) and cardiovascular disease (CVD; n  = 912, 26.3%). The 20-year cumulative mortality rate from thyroid cancer, malignancies (other than thyroid or nonmelanoma skin cancer), and CVD was 0.6%, 4.6%, and 3.9%, respectively. Lower than expected mortality was observed for all causes excluding thyroid cancer (SMR = 0.69 [CI 0.67-0.71]) and most specific causes, including all malignancies combined (other than thyroid cancer; SMR = 0.80 [CI 0.75-0.85]) and CVD (SMR = 0.64 [CI 0.60-0.69]). However, mortality rates were elevated for specific cancers, including pancreas (SMR = 1.58 [CI 1.18-2.06]), kidney and renal pelvis (SMR = 1.85 [CI 1.10-2.93]), and brain and other nervous system (SMR = 1.62 [CI 0.99-2.51]), and myeloma (SMR = 2.35 [CI 1.46-3.60]) and leukemia (SMR = 1.62 [CI 1.07-2.36]); these associations were stronger ≥10 years after diagnosis. RAI was not associated with risk of cause-specific death, but numbers of events were small and the range of administered activities was likely narrow. Conclusions: Overall, our findings provide reassurance regarding low overall and cause-specific mortality rates in individuals with low-risk DTC. Additional research is necessary to confirm and understand the increased mortality from certain subsequent cancers.

Assessing outcomes following hematopoietic cell transplantation (HCT) poses challenges due to the necessity for systematic and often prolonged patient follow-up. Linking the HCT database of the Center for International Blood and Marrow Transplant Research (CIBMTR) with cancer registry data may improve long-term outcome ascertainment, but the reliability of mortality data in death certificates from cancer registries among HCT recipients remains unknown. We compared the classification of vital status and primary cause of death (COD), as well as the length of follow-up between the CIBMTR and California Cancer Registry (CCR) to assess the possibility of supplementing the CIBMTR with cancer registry data. This retrospective study leveraged a linked CIBMTR-CCR dataset. We included patients who were California residents at the time of HCT and received a first allogeneic (allo) or autologous (auto) HCT for a hematologic malignancy diagnosed during 1991-2016. Follow-up was through 2018. We analyzed 18,450 patients (alloHCT, n = 8232; autoHCT, n = 10,218). The Vital status agreement was 97.7% for alloHCT and 97.2% for autoHCT. Unknown COD was higher in CIBMTR (12.9%) than in CCR (1.6%). After excluding patients with unknown COD information, the overall agreement of primary COD (cancer versus noncancer) was 53.7% for alloHCT and 83.2% for autoHCT. This agreement was lower within the first 100 days post-HCT (alloHCT, 31.0%; autoHCT, 54.6%). Compared with CIBMTR, deaths due to cancer were higher in CCR (alloHCT, 90.0%; autoHCT, 90.1% versus alloHCT, 47.3%; autoHCT, 82.5% in CIBMTR). CIBMTR reports more frequently noncancer-related deaths, including graft-versus-host disease and infections. The cumulative incidence of cancer-specific mortality at 20 years differed, particularly for alloHCT (CCR, 53.7%; CIBMTR, 27.6%). The median follow-up among alive patients was longer in CCR (alloHCT, 6.0 years; autoHCT, 4.7 years) than in CIBMTR (alloHCT, 5.0 years; autoHCT, 3.8 years). Our findings highlight the completeness of vital status data in CIBMTR but reveal substantial disagreement in primary COD. Consequently, caution is required when interpreting HCT studies that use only death certificates to estimate cause-specific mortality outcomes. Improving the accuracy of COD registration and follow-up completeness by developing communication pathways between cancer registries and hospital-based cohorts may enhance our understanding of late effects and long-term outcomes among HCT survivors., (Copyright © 2023. Published by Elsevier Inc.)

Lymphoid cancers are among the most frequent cancers diagnosed in adolescents and young adults (AYA), ranging from approximately 30%-35% of cancer diagnoses in adolescent patients (age 10-19) to approximately 10% in patients aged 30-39 years. Moreover, the specific distribution of lymphoid cancer types varies by age with substantial shifts in the subtype distributions between pediatric, AYA, adult, and older adult patients. Currently, biology studies specific to AYA lymphomas are rare and therefore insight into age-related pathogenesis is incomplete. This review focuses on the paradigmatic epidemiology and pathogenesis of select lymphomas, occurring in the AYA patient population. With the example of posttransplant lymphoproliferative disorders, nodular lymphocyte-predominant Hodgkin lymphoma, follicular lymphoma (incl. pediatric-type follicular lymphoma), and mediastinal lymphomas (incl. classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma and mediastinal gray zone lymphoma), we here illustrate the current state-of-the-art in lymphoma classification, recent molecular insights including genomics, and translational opportunities. To improve outcome and quality of life, international collaboration in consortia dedicated to AYA lymphoma is needed to overcome challenges related to siloed biospecimens and data collections as well as to develop studies designed specifically for this unique population., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Adolescents and young adults (AYA) with lymphoma experience treatment-related effects in the short and long term that impact their quality of life and survivorship experience. The effort to improve outcomes for AYA lymphoma survivors requires understanding the available literature, identifying current knowledge deficits, designing better clinical trials incorporating the patient perspective, using novel tools to bridge data gaps and building survivorship guidelines that translate research to clinical practice. This review article summarizes the current state of lymphoma treatment-related outcomes in AYAs and provides future direction., Competing Interests: P.A.P. Scientific Advisory Board: SeaGen. G.T. Advisory board: SeaGen (August 2022, all funds to research at Mayo Clinic, no personal remuneration). T.H. Data Monitoring Committee: Seagen, Tess Therapeutics, Eli Lilly & Co.; Scientific Advisory Board: Morpohsys, Incyte, Biegene, Loxo Oncology; Research Support to the LEO grant: Genentech, Sorrento, BMS., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Importance: Compared with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) can spare nearby tissue but may result in increased scatter radiation to distant normal tissue, including red bone marrow. It is unclear whether second primary cancer risk varies by radiotherapy type., Objective: To evaluate whether radiotherapy type (IMRT vs 3DCRT) is associated with second primary cancer risk among older men treated for prostate cancer., Design, Setting, and Participants: In this retrospective cohort study of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries (2002-2015), male patients aged 66 to 84 diagnosed with a first primary nonmetastatic prostate cancer from 2002 to 2013, as reported to SEER, and who received radiotherapy (IMRT and/or 3DCRT without proton therapy) within the first year following prostate cancer were identified. The data were analyzed from January 2022 through June 2022., Exposure: Receipt of IMRT and 3DCRT, based on Medicare claims., Main Outcomes and Measures: The association between radiotherapy type and development of a subsequent hematologic cancer at least 2 years after prostate cancer diagnosis or a subsequent solid cancer at least 5 years after prostate cancer diagnosis. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional regression., Results: The study included 65 235 2-year first primary prostate cancer survivors (median [range] age, 72 [66-82] years; 82.2% White patients) and 45 811 5-year survivors with similar demographic characteristics (median [range] age, 72 [66-79] years; 82.4% White patients). Among 2-year prostate cancer survivors (median [range] follow-up, 4.6 [0.003-12.0] years), 1107 second hematologic cancers were diagnosed (IMRT, 603; 3DCRT, 504). Radiotherapy type was not associated with second hematologic cancers overall or any specific types evaluated. Among 5-year survivors (median [range] follow-up, 3.1 [0.003-9.0] years), 2688 men were diagnosed with a second primary solid cancer (IMRT, 1306; 3DCRT, 1382). The overall HR for IMRT vs 3DCRT was 0.91 (95% CI, 0.83-0.99). This inverse association was restricted to the earlier calendar year period of prostate cancer diagnosis (HR2002-2005 = 0.85; 95% CI, 0.76-0.94; HR2006-2010 = 1.14; 95% CI, 0.96-1.36), with a similar pattern observed for colon cancer (HR2002-2005 = 0.66; 95% CI, 0.46-0.94; HR2006-2010 = 1.06; 95% CI, 0.59-1.88)., Conclusions and Relevance: The results of this large, population-based cohort study suggest that IMRT for prostate cancer is not associated with an increased risk of second primary cancers, either solid or hematologic, and any inverse associations may be associated with calendar year of treatment.

Background: Historically, survivors of common lymphoid neoplasms (LNs) had increased risks for therapy-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Despite major treatment advances in the treatment of LNs over the last two decades, a comprehensive evaluation of tMDS/AML trends following both common and rare LNs treated in this contemporary period is lacking., Methods: In US cancer registries during 2000-2018, we identified 1496 tMDS/AML cases among 186,503 adults who were treated with initial chemo/immunotherapy for first primary LN and survived ≥1 year. We quantified tMDS/AML standardized incidence ratios (SIRs), excess absolute risks (EARs, per 10,000 person-years), and cumulative incidence., Findings: The highest tMDS/AML risks occurred after precursor leukemia/lymphoma (SIR = 39, EAR = 30), Burkitt leukemia/lymphoma (SIR = 20, EAR = 24), peripheral T-cell lymphoma (SIR = 12, EAR = 23), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; SIR = 9.0, EAR = 27), and mantle cell lymphoma (SIR = 8.5, EAR = 25). Elevated risks (SIRs = 4.2-6.9, EARs = 4.9-15) also were observed after all other LN subtypes except hairy cell leukemia and mycosis fungoides/Sézary syndrome. Among patients treated more recently, tMDS/AML risks were significantly higher after CLL/SLL (SIR 2000-2005  = 4.8, SIR 2012-2017  = 10, P trend  = 0.0043), significantly lower after Hodgkin (SIR 2000-2005  = 15, SIR 2012-2017  = 6.3, P trend  = 0.024) and marginal zone (SIR 2000-2005  = 7.5, SIR 2012-2017  = 2.3, P trend  = 0.015) lymphomas, and non-significantly lower after mantle cell lymphoma (SIR 2000-2005  = 10, SIR 2012-2017  = 3.2, P trend  = 0.054), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR 2000-2005  = 6.9, SIR 2012-2017  = 1.0, P trend  = 0.067), and plasma cell neoplasms (SIR 2000-2005  = 5.4, SIR 2012-2017  = 3.1, P trend  = 0.051). EAR and cumulative incidence trends generally were similar to SIR trends. Median survival after tMDS/AML was 8.0 months (interquartile range, 3.0-22.0)., Interpretation: Although tMDS/AML risks are significantly elevated after initial chemo/immunotherapy for most LNs, patients treated more recently have lower tMDS/AML risks, except after CLL/SLL. Though rare, the poor prognosis following tMDS/AML emphasizes the importance of continued efforts to reduce treatment-associated toxicity., Funding: This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. LMM, GMD, REC, and CBS verified the data, and all authors had access to the data and made the decision to submit for publication., Competing Interests: The authors have no relationships to disclose.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

The use of publicly available sequencing datasets as controls (hereafter, "public controls") in studies of rare variant disease associations has great promise but can increase the risk of false-positive discovery. The specific factors that could contribute to inflated distribution of test statistics have not been systematically examined. Here, we leveraged both public controls, gnomAD v2.1 and several datasets sequenced in our laboratory to systematically investigate factors that could contribute to the false-positive discovery, as measured by λΔ95, a measure to quantify the degree of inflation in statistical significance. Analyses of datasets in this investigation found that 1) the significantly inflated distribution of test statistics decreased substantially when the same variant caller and filtering pipelines were employed, 2) differences in library prep kits and sequencers did not affect the false-positive discovery rate and, 3) joint vs. separate variant-calling of cases and controls did not contribute to the inflation of test statistics. Currently available methods do not adequately adjust for the high false-positive discovery. These results, especially if replicated, emphasize the risks of using public controls for rare-variant association tests in which individual-level data and the computational pipeline are not readily accessible, which prevents the use of the same variant-calling and filtering pipelines on both cases and controls. A plausible solution exists with the emergence of cloud-based computing, which can make it possible to bring containerized analytical pipelines to the data (rather than the data to the pipeline) and could avert or minimize these issues. It is suggested that future reports account for this issue and provide this as a limitation in reporting new findings based on studies that cannot practically analyze all data on a single pipeline., Competing Interests: All authors have declared no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Advances in hematopoietic cell transplantation (HCT) have substantially improved patient survival, increasing the importance of studying outcomes and long-term adverse effects in the rapidly growing population of HCT survivors. Large-scale registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR) are a valuable resource for studying mortality and late effects after HCT, providing detailed data reported by HCT centers on transplantation-related factors and key outcomes. This study was conducted to evaluate the robustness of CIBMTR outcome data and assess health-related outcomes and healthcare utilization among HCT recipients. We linked data from the CIBMTR for California residents with data from the population-based California Cancer Registry (CCR) and hospitalization information from the California Patient Discharge Database (PDD). In this retrospective cohort study, probabilistic and deterministic record linkage used key patient identifiers, such as Social Security number, ZIP code, sex, birth date, hematologic malignancy type and diagnosis date, and HCT type and date. Among 22,733 patients registered with the CIBMTR who underwent autologous or allogeneic HCT for hematologic malignancy between 1991 and 2016, 89.0% were matched to the CCR and/or PDD (n = 17,707 [77.9%] for both, n = 1179 [5.2%] for the CCR only, and n = 1342 [5.9%] for the PDD only). Unmatched patients were slightly more likely to have undergone a first autologous HCT than an allogeneic HCT (12.6% versus 9.0%), to have a larger number of missing linkage identifiers, and to have undergone HCT prior to 2010. Among the patients reported to the CIBMTR who matched to the CCR, 85.7% demonstrated concordance of both hematologic malignancy type and diagnosis date across data sources. This linkage presents unparalleled opportunities to advance our understanding of HCT practices and patient outcomes., Competing Interests: Conflict of interest statement There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Purpose: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer., Methods: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS., Results: There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10 -8 ), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10 -7 ) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation., Conclusion: There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted., Competing Interests: Danielle N. FriedmanConsulting or Advisory Role: Fennec Pharma M. Monica GramatgesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1175834/summary Rebecca M. HowellResearch Funding: MD Anderson Cancer Center Charles A. SklarHonoraria: Novo NordiskPatents, Royalties, Other Intellectual Property: UpToDate Gregory T. ArmstrongHonoraria: GrailNo other potential conflicts of interest were reported.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10 -8 ) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10 -9 ). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10 -8 ), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Adult survivors of childhood cancer are at increased risk of cardiac late effects., Methods: Using whole-genome sequencing data from 1870 survivors of European ancestry in the St. Jude Lifetime Cohort (SJLIFE) study, genetic variants were examined for association with ejection fraction (EF) and clinically assessed cancer therapy-induced cardiac dysfunction (CCD). Statistically significant findings were validated in 301 SJLIFE survivors of African ancestry and 4020 survivors of European ancestry from the Childhood Cancer Survivor Study. All statistical tests were 2-sided., Results: A variant near KCNK17 showed genome-wide significant association with EF (rs2815063-A: EF reduction = 1.6%; P = 2.1 × 10-8) in SJLIFE survivors of European ancestry, which replicated in SJLIFE survivors of African ancestry (EF reduction = 1.5%; P = .004). The rs2815063-A also showed a 1.80-fold (P = .008) risk of severe or disabling or life-threatening CCD and replicated in 4020 Childhood Cancer Survivor Study survivors of European ancestry (odds ratio = 1.40; P = .04). Notably, rs2815063-A was specifically associated among survivors exposed to doxorubicin only, with a stronger effect on EF (3.3% EF reduction) and CCD (2.97-fold). Whole blood DNA methylation data in 1651 SJLIFE survivors of European ancestry showed statistically significant correlation of rs2815063-A with dysregulation of KCNK17 enhancers (false discovery rate <5%), which replicated in 263 survivors of African ancestry. Consistently, the rs2815063-A was associated with KCNK17 downregulation based on RNA sequencing of 75 survivors., Conclusions: Leveraging the 2 largest cohorts of childhood cancer survivors in North America and survivor-specific polygenomic functional data, we identified a novel risk locus for CCD, which showed specificity with doxorubicin-induced cardiac dysfunction and highlighted dysregulation of KCNK17 as the likely molecular mechanism underlying this genetic association., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Data on incidence rates of myeloid malignancies for subtypes based on the World Health Organization (WHO) classification are lacking in Asian populations. We compared age-adjusted incidence rates for 27 myeloid malignancy WHO-defined subtypes in Hong Kong (HK) (2014-2016) with those for Asian and white individuals living in the United States (U.S.) (2010-2016). Except for overall acute myeloid leukemia (AML) (2.23 cases per 100,000) and myeloproliferative neoplasms (MPNs) (2.10 cases per 100,000), rates of all subtypes were <1 case per 100,000 person-years in HK. Overall rates of AML, myelodysplastic syndrome (MDS), and MDS/MPN were lower in HK compared to white and Asian individuals in the U.S., but the patterns by specific subtype varied. For these three broad groupings of myeloid malignancies, rates in U.S. Asians were intermediate to those in HK and white individuals in the U.S. These results suggest the possibility of a multifactorial etiology for specific myeloid malignancy subtypes that should be evaluated in future epidemiological studies.