Davis, S. Scott

Background Biliopancreatic diversion with duodenal switch (BPD-DS) is the most effective and durable metabolic and bariatric surgery to achieve a target weight loss. However, many surgeons are hesitant to adopt BPD-DS due to a lack of training, technical complexity, and long-term nutrition deficiencies. This meta-analysis aimed to investigate long-term nutrition outcomes after primary BPD-DS in the management of obesity. Methods Cochrane, Embase, PubMed, Scopus, and Web of Science were searched for articles from their inception to February 2023 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) system. The review was registered prospectively with PROSPERO (CRD42023391316). Results From 834 studies screened, 8 studies met the eligibility criteria, with a total of 3443 patients with obesity undergoing primary BPD-DS. At long-term follow-up (≥5 years), 25.4% of patients had vitamin A deficiency (95% CI: -.012, .520, I 2 = 94%), and 57.3% had vitamin D deficiency (95% CI: .059, 1.086, I 2 = 86%). Calcium deficiency was observed in 125 patients (22.2%, 95% CI: .061, .383, I 2 = 97%), and 69.7% had an abnormal parathyroid hormone level (95% CI: .548, .847, I 2 = 78%). Ferritin level was abnormal in 30 patients (29.0%, 95% CI: .099, .481, I 2 = 79%). Conclusions Despite displaying comparable nutrition-related outcomes to mid-term follow-up, our study demonstrated that BPD-DS could result in a high level of long-term nutrition deficiency after BPD-DS for selected patients. However, further randomized controlled studies with standardized supplementation regimens and improvement in compliance are necessary to evaluate and prevent long-term nutritional deficiencies after BPD-DS.

Abstract Subtle differences in immune response may play a role in non-Hodgkin lymphoma (NHL) etiology. Because adult immune response may be influenced by early childhood exposures, we examined the role of childhood crowding, history of atopic disease, and other childhood immune-related exposures on the risk of non-Hodgkin lymphoma in a multi-center case-control study. Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Health Care Financing Administration (HCFA) database. The association between NHL risk in relation to atopy and other exposures was assessed using multivariable logistic regression methods. Most types of allergy were associated with protection from NHL, with hay fever especially protective against all NHL combined (Odds Ratio [OR] = 0.71, 95% confidence interval [CI]= 0.54–0.94), diffuse large B-cell lymphoma [DLBCL] (OR=0.61, 95% CI=0.41–0.91), and follicular lymphoma (OR=0.70, 95% CI=0.45–1.09). A history of eczema increased risk of follicular lymphoma (OR=1.92, 95% CI= 1.08–3.41) but not DLBCL (OR=1.06, 95% CI= 0.55.2.04). Asthma in childhood was not associated with risk of NHL. Risk of DLBCL (OR =1.72, 95% CI=1.17–2.52), but not follicular lymphoma (OR=1.15, 95% CI=0.75–1.76) was elevated for the youngest compared to the oldest of siblings. Neither number of siblings nor years between births of siblings were significantly associated with risk. These results suggest that some immune-related exposures may affect NHL risk.

Abstract Background. The incidence of non-Hodgkin lymphoma (NHL) has increased dramatically since at least the 1950s, and only a fraction of this increase can be explained by established risk factors. During this timeframe, there has been a major increase in the use of blood transfusions, anesthesia, and invasive surgical procedures, all of which can impact immune function. Methods. We conducted a population-based case-control study from 1998–2000 using SEER cancer registries in Detroit, Iowa, Los Angeles and Seattle. NHL cases (N=759) were newly diagnosed, HIV-negative, and aged 20–74 years. Controls (N=589) were identified through random digit dialing (<65 years old) and Medicare files (age 65 years and older), and were frequency matched to cases on sex, age, race, and study site. Data on history of blood transfusions, anesthetics (general and regional), and surgeries (type, frequency, and age for 21 anatomic regions) >1 year before diagnosis (or date of enrollment for controls) were collected during in-person interviews. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusted for the matching factors. NHL subtypes (follicular and diffuse) were designated according to SEER cancer registry pathology reports, and risk of each subtype was estimated using polychotomous logistic regression. Results. History of blood transfusion was weakly associated with increased risk of NHL (OR=1.26; 95% CI 0.91–1.73), and the elevated risk was specific to transfusions first given 5 to 29 years before diagnosis (OR=1.69; 95% CI 1.08–2.62). Risk was also specific to blood transfusions given for a medical indication (OR=2.09; 95% CI 1.03–4.26), while transfusions given for trauma, obstetric or surgical indications were not associated with risk. Exposure to general or regional anesthesia (OR=1.35 for 24+ times compared to 0–6; 95% CI 0.91–2.02) and total number of surgeries (OR=1.22 for 7+ surgeries compared to 0; 95% CI 0.77–1.93) were weakly and positively associated with risk of NHL, although neither association achieved statistical significance. Results were similar for general versus regional anesthesia. In analysis of surgeries at specific anatomic sites, there were no associations with NHL risk, except for a suggestive positive association for surgery involving the appendix, stomach or bowel (OR=1.24; 95% CI 0.98–1.58). When blood transfusion, anesthesia, and total number of surgeries were included in the same model, ORs for time since first transfusion and total number of surgeries remained unchanged, while the association for anesthesia weakened. These results were generally similar for both diffuse and follicular subtypes, with the exception that total number of surgeries showed a suggestive positive association with follicular (OR=1.61 for 7+ surgeries compared to 0; 95% CI 0.74–3.51) but not diffuse NHL. Conclusion: History of blood transfusion was associated with an increased risk of NHL. Total number of surgeries, type of surgery, and use of anesthesia were only weakly associated with risk, although the suggestive positive association for number of surgeries with follicular lymphoma warrants further investigation.

Abstract DLBCL is a curable subtype of non-Hodgkin lymphoma, although a significant number of patients do not achieve a remission or they relapse with conventional chemotherapy. While clinical variables (e.g., IPI), tumor (somatic) genetic alterations, and gene expression profiling have all been shown to predict outcome, there remains a need for additional prognostic biomarkers. One understudied class of biomarkers is host genetic background. We evaluated the hypothesis that germline variability in 73 SNPs from 44 candidate immune genes was associated with overall survival in DLBCL. We addressed this hypothesis in 365 DLBCL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 (prior to the use of R-CHOP) through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. Germline DNA was extracted from a venous blood sample or mouthwash buccal cell sample, which was collected a median of 4.8 months after diagnosis in this population-based study. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform, and was successful in over 95% of the DNA samples for the SNPs evaluated. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to evaluate the association between individual SNPs, adjusted for age, demographic and clinical factors. Parallel modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At a median follow-up of 56 months (range, 27-78 months) for surviving patients, there were 96 deaths in 365 patients (26%). In multivariate modeling, SNPs in IL1A (rs1800587; HRCT/TT=1.90, 1.26–2.87), IL6 (rs1800795; HRGG=1.48, 0.99–2.23), IL-10 (rs1800896; HRAG/GG=1.48, 0.91–2.38), and IFNGR2 (rs2070385; HRAG/GG=1.35, 0.86–2.11) were the strongest and most robust predictors of overall survival. A summary score of the number of deleterious genotypes from these four genes in combination with clinical and demographic variables was strongly associated with survival (p=9.3 x 10−12); Kaplan-Meier 5-year survival estimates for low, intermediate, and high risk patients were 89%, 68%, and 47% respectively. In conclusion, host genetic background as measured by germline polymorphisms in immune genes including IL1A, IL6, IL10, and IFNGR2 were associated with overall survival in DLBCL after accounting for clinical and demographic factors. These promising results require confirmation and need further evaluation in patients treated with R-CHOP in conjunction with tumor and other prognostic biomarkers.

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend &lt; 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Abstract Profound disruption of immune function is an established risk factor for non-Hodgkin lymphoma. We report here a large-scale evaluation of common genetic variants in immune genes and their role in lymphoma. We genotyped 57 single nucleotide polymorphisms (SNP) from 36 candidate immune genes in 1,172 non-Hodgkin lymphoma cases and 982 population-based controls from a US multicenter study. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the association between individual SNP and haplotypes with non-Hodgkin lymphoma overall and five well-defined subtypes. A haplotype comprising SNPs in two proinflammatory cytokines, tumor necrosis factor-α and lymphotoxin-α (rs1800629, rs361525, rs1799724, rs909253, and rs2239704), increased non-Hodgkin lymphoma risk overall (OR, 1.31; 95% CI, 1.06-1.63; P = 0.01) and notably for diffuse large B cell (OR, 1.64; 95% CI, 1.23-2.19; P = 0.0007). A functional nonsynonymous SNP in the innate immune gene Fcγ receptor 2A (FCGR2A; rs1801274) was also associated with non-Hodgkin lymphoma; AG and AA genotypes were associated with a 1.26-fold (95% CI, 1.01-1.56) and 1.41-fold (95% CI, 1.10-1.81) increased risk, respectively (Ptrend = 0.006). Among non-Hodgkin lymphoma subtypes, the association with FCGR2A was pronounced for follicular and small lymphocytic lymphomas. In conclusion, common variants in genes influencing proinflammatory and innate immune responses were associated with non-Hodgkin lymphoma risk overall and their effects could vary by subtype. Our results require replication but potentially provide important clues for investigating common genetic variants as susceptibility factors and in disease outcomes, treatment responses, and immunotherapy targets. (Cancer Res 2006; 66(19): 9771-80)

Abstract A possible role for SV40, a macaque polyomavirus, in non-Hodgkin lymphoma (NHL) in humans was raised recently by the reported detection of SV40 DNA in tumor tissue. Animals with SV40-induced tumors frequently produce high-level antibodies against T antigen, the SV40 oncoprotein. In this study, we assessed whether SV40 T antibody measured in humans supported a relationship between SV40 and NHL. Subjects were sampled from a U.S. population-based case-control study of NHL, according to presence of antibodies against capsids of SV40 and BK, a related human polyomavirus (n = 85 cases, n = 95 controls). T antibody was measured by enzyme immunoassay. We also evaluated serum specimens from SV40-infected and SV40-uninfected macaques (n = 19 and n = 8, respectively), SV40-uninfected hamsters (n = 5), and hamsters with SV40-induced tumors (n = 10). Hamsters with SV40-induced tumors all produced robust SV40 T antibody [median absorbance, 0.99), whereas SV40-uninfected hamsters and macaques had much lower levels (median absorbance, 0.05 and 0.04, respectively). NHL cases, controls, and SV40-infected macaques resembled these latter two groups, generally showing only low-level T antibody (median absorbance, 0.03, 0.04, and 0.04, respectively). Overall, only five cases (6%) and five controls (5%) had T antibody responses classified as seropositive (odds ratio, 1.2; 95% confidence interval, 0.3-4.6). Interestingly, all 10 humans with T antibody responses also showed antibody responses to BK capsid. We found no association between the presence of T antibody and NHL, arguing against SV40 as a cause of NHL. Infrequent and low-level T antibody responses among humans could represent cross-reactivity to BK virus T antigen.