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Background: Previous studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients., Methods: We used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and competing risk methods were used for the cumulative incidence of colorectal cancer., Results: We evaluated 10,179 lung recipients (1681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged <50 at transplant and 6.4% aged ≥50., Conclusions: CF recipients have increased risk for colorectal cancer, suggesting a need for enhanced screening., (Copyright © 2016 European Cystic Fibrosis Society. All rights reserved.)

Renal cell carcinoma (RCC) is a common malignancy following kidney transplantation. We describe RCC risk and examine RCC risk factors among US kidney recipients (1987-2010). The Transplant Cancer Match Study links the US transplant registry with 15 cancer registries. Standardized incidence ratios (SIRs) were used to compare RCC risk (overall and for clear cell [ccRCC] and papillary subtypes) to the general population. Associations with risk factors were assessed using Cox models. We identified 683 RCCs among 116 208 kidney recipients. RCC risk was substantially elevated compared with the general population (SIR 5.68, 95% confidence interval 5.27-6.13), especially for papillary RCC (SIR 13.3 versus 3.98 for ccRCC). Among kidney recipients, RCC risk was significantly elevated for blacks compared to whites (hazard ratio [HR] 1.50) and lower in females than males (HR 0.56). RCC risk increased with prolonged dialysis preceding transplantation (p-trend < 0.0001). Risk was variably associated for RCC subtypes with some medical conditions that were indications for transplantation: ccRCC risk was reduced with polycystic kidney disease (HR 0.54), and papillary RCC was increased with hypertensive nephrosclerosis (HR 2.02) and vascular diseases (HR 1.86). In conclusion, kidney recipients experience substantially elevated risk of RCC, especially for papillary RCC, and multiple factors contribute to these cancers., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

US transplant centers are required to report cancers in transplant recipients to the transplant network. The accuracy and completeness of these data, collected in the Scientific Registry of Transplant Recipients (SRTR), are unknown. We compared diagnoses in the SRTR and 15 linked cancer registries for colorectal, liver, lung, breast, prostate and kidney cancers; melanoma; and non-Hodgkin lymphoma (NHL). Among 187 384 transplants, 9323 cancers were documented in the SRTR or cancer registries. Only 36.8% of cancers were in both, with 47.5% and 15.7% of cases additionally documented solely in cancer registries or the SRTR, respectively. Agreement between the SRTR and cancer registries varied (kappa = 0.28 for liver cancer and kappa = 0.52-0.66 for lung, prostate, kidney, colorectum, and breast cancers). Upon evaluation, some NHLs documented only in cancer registries were identified in the SRTR as another type of posttransplant lymphoproliferative disorder. Some SRTR-only cases were explained by miscoding (colorectal cancer instead of anal cancer, metastases as lung or liver cancers) or missed matches with cancer registries, partly due to recipients' outmigration from catchment areas. Estimated sensitivity for identifying cancer was 52.5% for the SRTR and 84.3% for cancer registries. In conclusion, SRTR cancer data are substantially incomplete, limiting their usefulness for surveillance and research., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: The biology of HIV-associated cancers may differ depending on immunologic and virologic context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important., Patients and Methods: KS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category., Results: We identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend = .02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend = .81). An increasing proportion of KS and NHL occurred at higher CD4 counts (P < .05 for KS and NHL) and with undetectable HIV RNA (P < .05 for KS and NHL). In recent years, more person-time was contributed by patients who received ART, had high CD4 counts and had undetectable HIV RNA, whereas incidence rates in these same categories remained stable or declined., Conclusion: Over time, KS and NHL occurred at higher CD4 counts and lower HIV RNA values, and KS occurred more frequently after ART initiation. These changes were driven by an increasing proportion of patients with HIV who received effective ART, had higher CD4 counts, and had suppressed HIV RNA and not by increases in cancer risk within these subgroups. An improved understanding of HIV-associated cancer pathogenesis and outcomes in the context of successful ART is therefore important., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

It is suspected that primary central nervous system lymphoma (PCNSL) rates are increasing among immunocompetent people. We estimated PCNSL trends in incidence and survival among immunocompetent persons by excluding cases among human immunodeficiency virus (HIV)-infected persons and transplant recipients. PCNSL data were derived from 10 Surveillance, Epidemiology and End Results (SEER) cancer registries (1992-2011). HIV-infected cases had reported HIV infection or death due to HIV. Transplant recipient cases were estimated from the Transplant Cancer Match Study. We estimated PCNSL trends overall and among immunocompetent individuals, and survival by HIV status. A total of 4158 PCNSLs were diagnosed (36% HIV-infected; 0·9% transplant recipients). HIV prevalence in PCNSL cases declined from 64·1% (1992-1996) to 12·7% (2007-2011), while the prevalence of transplant recipients remained low. General population PCNSL rates were strongly influenced by immunosuppressed cases, particularly in 20-39 year-old men. Among immunocompetent people, PCNSL rates in men and women aged 65+ years increased significantly (1·7% and 1·6%/year), but remained stable in other age groups. Five-year survival was poor, particularly among HIV-infected cases (9·0%). Among HIV-uninfected cases, 5-year survival increased from 19·1% (1992-1994) to 30·1% (2004-2006). In summary, PCNSL rates have increased among immunocompetent elderly adults, but not in younger individuals. Survival remains poor for both HIV-infected and HIV-uninfected PCNSL patients., (© 2016 John Wiley & Sons Ltd.)

Background: Recombinant bone morphogenetic proteins (BMPs) are growth factors utilized in lumbar arthrodeses. Limited data from randomized trials suggest that BMP may increase cancer risk. We sought to evaluate cancer risk and mortality following the use of BMP in lumbar arthrodesis., Methods: Within the linked Surveillance, Epidemiology, and End Results (SEER) Program-Medicare cohort, we conducted a case-cohort study of 7,278 individuals who were ≥65 years of age and had undergone a lumbar arthrodesis from 2004 to 2011. Of these patients, 3,627 were individuals in a 5% random subcohort of Medicare enrollees in SEER areas including 191 who developed cancer, and there were 3,651 individuals outside the subcohort who developed cancer. Weighted Cox proportional-hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cancer on the basis of exposure to BMP., Results: In the SEER-Medicare subcohort, 30.7% of individuals who underwent a lumbar arthrodesis received BMP. BMP was not associated with overall cancer risk in univariate analyses (HR, 0.92 [95% CI, 0.82 to 1.02]) or after adjustment for demographic characteristics, comorbidities, hospital size, history of cancer, and calendar year (adjusted HR, 0.94 [95% CI, 0.84 to 1.05]). Individual cancer types were also not significantly elevated (p > 0.05 for all) in BMP users compared with nonusers. In addition, BMP use was not associated with a new cancer in people who had cancer prior to undergoing lumbar arthrodesis (adjusted HR, 1.04 [95% CI, 0.71 to 1.52]) or with mortality after a cancer diagnosis (adjusted HR, 1.05 [95% CI, 0.93 to 1.19])., Conclusions: In a large population of elderly U.S. adults undergoing lumbar arthrodesis, BMP use was not associated with cancer risk or mortality., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Certain medical conditions affect risk of non-Hodgkin lymphoma (NHL), but the full range of associations is unknown. We implemented a novel method ("medical condition-wide association study," MedWAS) to comprehensively evaluate medical risk factors for NHL documented in administrative health claims., Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we conducted a case-control study comparing NHL cases [N = 52,691, age 66+ years, with five subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma (TCL)] to controls (N = 200,000). We systematically screened for associations with 5,926 medical conditions documented in Medicare claims more than 1 year before selection., Results: Fifty-five conditions were variously associated with NHL. Examples include well-established associations of human immunodeficiency virus, solid organ transplantation, and hepatitis C virus with increased DLBCL risk (ORs 3.83, 4.27, and 1.74, respectively), and autoimmune conditions with DLBCL and MZL (e.g., ORs of 2.10 and 4.74, respectively, for Sjögren syndrome). Risks for all NHL subtypes were increased after diagnoses of nonmelanoma skin cancer (ORs 1.19-1.55), actinic keratosis (1.12-1.25), or hemolytic anemia (1.64-4.07). Nine additional skin conditions increased only TCL risk (ORs 2.20-4.12). Diabetes mellitus was associated with increased DLBCL risk (OR 1.09). Associations varied significantly across NHL subtypes for 49 conditions (89%)., Conclusion: Using an exploratory method, we found numerous medical conditions associated with NHL risk, and many associations varied across NHL subtypes., Impact: These results point to etiologic heterogeneity among NHL subtypes. MedWAS is a new method for assessing the etiology of cancer and other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1105-13. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objective: HIV-infected people and elderly people have higher cancer risk, but the combined effects of aging and HIV are not well described. We aimed to evaluate the magnitude of cancer risk in the HIV-infected elderly population., Design: We conducted a case-cohort study including a 5% sample of U.S. Medicare enrollees and all cancer cases aged at least 65 in linked cancer registries., Methods: HIV was identified through Medicare claims. Among the HIV-infected, absolute cancer risk was calculated accounting for the competing risk of death. Associations between HIV and cancer were estimated with weighted Cox regression adjusting for demographic characteristics., Results: Among 469 954 people in the 5% sample, 0.08% had an HIV diagnosis. Overall, 825 776 cancer cases were identified in cancer registries. Over 5 years, 10.1% of the HIV-infected elderly developed cancer, the most common diagnoses comprising lung (5-year cumulative incidence=2.2%), prostate (2.7%, among men), and colorectal cancer (0.9%), and non-Hodgkin lymphoma (0.8%). HIV was strongly associated with incidence of Kaposi sarcoma [adjusted hazard ratio (aHR)=94.4, 95% confidence interval (95%CI)=54.6-163], anal cancer (aHR=34.2, 95%CI=23.9-49.0) and Hodgkin lymphoma (aHR=6.3, 95%CI=2.8-14.3). HIV was also associated with incidence of liver cancer, non-Hodgkin lymphoma and lung cancer (aHR=3.4, 2.6, and 1.6, respectively)., Conclusion: In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention.

For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-specific mortality, and all-cause mortality, adjusting for recipient ethnicity, calendar year of transplant, total tumor volume, alpha-fetoprotein, transplant center size, use of interleukin 2 induction therapy, and allocated and calculated Model for End-Stage Liver Disease score. We performed stratified analyses among recipients who met Milan criteria, among those without renal failure, among those with deceased liver donors, by age at transplantation, and by tumor size. Among the 3936 included HCC LTs, 234 (6%) were SRL users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in SRL users and nonusers (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.73-1.39). HCC recurrence and cancer-specific mortality rates appeared lower in SRL users, but associations were not statistically significant (recurrence aHR, 0.86; 95% CI, 0.45-1.65; cancer-specific mortality aHR, 0.80; 95% CI, 0.43-1.50). Among recipients >55 years old, associations were suggestive of better outcomes for SRL users (all-cause mortality aHR, 0.62; 95% CI, 0.38-1.01; recurrence aHR, 0.52; 95% CI, 0.19-1.44; cancer-specific mortality aHR, 0.34; 95% CI, 0.11-1.09), whereas among recipients ≤55 years old, SRL users had worse outcomes (all-cause mortality aHR, 1.76; 95% CI, 1.12-2.75; recurrence aHR, 1.49; 95% CI, 0.62-3.61; cancer-specific mortality aHR, 1.54; 95% CI, 0.71-3.32). In conclusion, among HCC liver recipients overall, SRL did not appear beneficial in reducing all-cause mortality. However, there were suggestions of reductions in recurrence and cancer-specific mortality, and effects appeared to be modified by age at transplantation. Liver Transplantation 22 627-634 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)

Among patients with ESRD, cancer risk is affected by kidney dysfunction and by immunosuppression after transplant. Assessing patterns across periods of dialysis and kidney transplantation may inform cancer etiology. We evaluated 202,195 kidney transplant candidates and recipients from a linkage between the Scientific Registry of Transplant Recipients and cancer registries, and compared incidence in kidney function intervals (time with a transplant) with incidence in nonfunction intervals (waitlist or time after transplant failure), adjusting for demographic factors. Incidence of infection-related and immune-related cancer was higher during kidney function intervals than during nonfunction intervals. Incidence was most elevated for Kaposi sarcoma (hazard ratio [HR], 9.1; 95% confidence interval (95% CI), 4.7 to 18), non-Hodgkin's lymphoma (HR, 3.2; 95% CI, 2.8 to 3.7), Hodgkin's lymphoma (HR, 3.0; 95% CI, 1.7 to 5.3), lip cancer (HR, 3.4; 95% CI, 2.0 to 6.0), and nonepithelial skin cancers (HR, 3.8; 95% CI, 2.5 to 5.8). Conversely, ESRD-related cancer incidence was lower during kidney function intervals (kidney cancer: HR, 0.8; 95% CI, 0.7 to 0.8 and thyroid cancer: HR, 0.7; 95% CI, 0.6 to 0.8). With each successive interval, incidence changed in alternating directions for non-Hodgkin's lymphoma, melanoma, and lung, pancreatic, and nonepithelial skin cancers (higher during function intervals), and kidney and thyroid cancers (higher during nonfunction intervals). For many cancers, incidence remained higher than in the general population across all intervals. These data indicate strong short-term effects of kidney dysfunction and immunosuppression on cancer incidence in patients with ESRD, suggesting a need for persistent cancer screening and prevention., (Copyright © 2016 by the American Society of Nephrology.)

Background: There are limited data on outcomes in transplant recipients with a history of pretransplant melanoma., Objective: To determine whether pretransplant melanoma is associated with differences in survival or posttransplant melanoma risk., Materials and Methods: We evaluated the outcomes of 185,039 US transplant recipients from the Transplant Cancer Match Study. We also evaluated the impact of transplantation on 141,441 patients with melanoma identified in cancer registries., Results: There were 336 transplant recipients (0.18%) with pretransplant melanoma; they had increased risk of melanoma-specific mortality (hazard ratio [HR], 27; 95% confidence interval [CI], 11-64, p < .0001), overall mortality (HR, 1.3; 95% CI, 1.0-1.5, p = .02), and incident melanoma (HR, 5.4; 95% CI, 2.9-9.8, p < .0001) after transplant, compared with recipients without pretransplant melanoma. The 10-year absolute risk difference was 2.97% for melanoma-specific mortality, 3.68% for incident melanoma, and 14.32% for overall mortality. Among the 141,441 patients with melanoma in the general population, 68 (0.05%) subsequently received a transplant. Transplantation increased melanoma-specific mortality, but not significantly (HR, 1.7; 95% CI, 0.61-4.5, p = .32)., Conclusion: Pretransplant melanoma is associated with increased melanoma-specific mortality, overall mortality, and incident melanoma after transplant. Nonetheless, the rarity of melanoma-related events supports the current practice for listing transplant candidates with a history of melanoma.

Background: Herpes zoster (HZ) arises in older people due to age-related decline in immunity. We assessed whether HZ, as a marker of immune suppression, is associated with increased cancer risk., Methods: We conducted a case-control study in U.S. adults with ages ≥ 65 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Cases (n = 1,108,986) were people with first cancers identified in cancer registries (1992-2005). Controls (n = 100,000) were cancer-free individuals frequency matched to cases on age, sex, and year of selection. We identified HZ diagnosis using Medicare claims. Logistic regression models were constructed to determine adjusted associations between cancer and HZ., Results: HZ prevalence was modestly higher in cases than controls (1.4% vs. 1.2%). We identified significant associations between HZ and oral cavity/pharyngeal [adjusted OR (aOR) = 1.21], colon (aOR = 1.10), lung (aOR = 1.11), and non-melanoma skin (aOR = 1.46) cancers; myeloma (aOR = 1.38); diffuse large B-cell lymphoma (aOR = 1.30); lymphoplasmacytic lymphoma (aOR = 1.99); and chronic lymphocytic leukemia/small lymphocytic lymphoma (aOR = 1.55). Among solid cancers, HZ was mostly associated with regional and/or distant stage tumors. Associations were strongest when HZ was diagnosed 13 to 35 months before cancer diagnosis/selection; they were significant for some cancers in the 36 to 59 months period, and 60+ months for lymphoplasmacytic lymphoma (OR = 1.99)., Conclusion: HZ is associated with modestly increased risk of a few cancers, particularly hematologic malignancies. Associations were strongest at short latency intervals for many cancers, and for regional/distant stages among solid cancers, perhaps reflecting reverse causality., Impact: Age-related immune decline does not play a major role in cancer development in older people, but it may be important for some lymphomas., (©2015 American Association for Cancer Research.)

Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked US transplant-cancer registry data (1987-2010). We used standardized incidence ratios (SIRs) to compare incidence with the general population and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (n=182) and non-recipients (n=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (n=519) was elevated (SIR=2.20, 95% CI 2.01-2.39), especially for regional stage tumors (SIR=4.11, 95% CI 3.27-5.09). Risk of localized tumors was stable over time after transplantation but higher with azathioprine maintenance therapy (IRR=1.35, 95% CI 1.03-1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95% CI 1.02-2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (hazard ratio 2.98, 95% CI 2.26-3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with UV radiation, whereas T-cell-depleting induction therapies may promote late-stage tumors. Our findings support sun safety practices and skin screening for transplant recipients.

Screening for oral leukoplakia, an oral cavity cancer (OCC) precursor, could lead to earlier detection of OCC. However, the progression rate from leukoplakia to OCC and the benefits of leukoplakia screening for improving OCC outcomes are currently unclear. We conducted a case-cohort study of U.S. adults ages ≥65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage. We identified leukoplakia diagnoses through Medicare claims, and OCC diagnoses through SEER cancer registries. Weighted Cox regression was used to estimate leukoplakia associations with OCC incidence, and the absolute OCC risk following leukoplakia diagnosis was calculated. Among OCC cases, we compared OCC stage and OCC survival between cases with a prior leukoplakia diagnosis versus those without prior leukoplakia. Among 470,266 individuals in the SEER-Medicare subcohort, 1,526 (0.3%) had a leukoplakia diagnosis. Among people with leukoplakia, the cumulative OCC incidence was 0.7% at 3 months and 2.5% at 5 years. OCC risk was most increased <3 months after leukoplakia diagnosis (HR, 115), likely representing the diagnosis of prevalent cancers. Nonetheless, risk remained substantially increased in subsequent follow-up [HR ≥ 3 months, 24; 95% confidence interval (CI), 22-27; HR ≥ 12 months, 22, 95% CI, 20-25]. Among OCC cases (N = 8,927), those with prior leukoplakia were less likely to be diagnosed at regional/distant stage (OR, 0.36; 95% CI, 0.30-0.43), and had lower mortality (HR, 0.74; 95% CI, 0.65-0.84) when compared with OCC cases without a prior leukoplakia. Individuals with leukoplakia have substantially elevated risk of OCC. Lower stage and better survival after OCC diagnosis suggest that leukoplakia identification can lead to earlier OCC detection and reduced mortality., (©2015 American Association for Cancer Research.)

Sirolimus, an immunosuppressant option for kidney transplant recipients, may reduce cancer risk by interrupting the mammalian target of rapamycin pathway. However, studies of sirolimus and cancer incidence in kidney recipients have not been definitive, and have had limited ability to examine specific cancer types. The literature was systematically reviewed to identify randomized controlled trials (RCTs) and observational studies of kidney recipients that compared sirolimus users to sirolimus nonusers. Meta-analytic methods were used to obtain pooled estimates of the association between sirolimus use and incidence of total cancer and specific cancer types. Estimates were stratified by study type (RCT vs. observational) and use of cyclosporine (an immunosuppressant that affects DNA repair). Twenty RCTs and two observational studies were eligible for meta-analysis, including 39,039 kidney recipients overall. Sirolimus use was associated with lower overall cancer incidence (incidence rate ratio [IRR] = 0.71, 95% CI = 0.56-0.90), driven by a reduction in incidence of nonmelanoma skin cancer (NMSC, IRR = 0.49, 95% CI = 0.32-0.76). The protective effect of sirolimus on NMSC risk was most notable in studies comparing sirolimus against cyclosporine (IRR = 0.19, 95% CI = 0.04-0.84). After excluding NMSCs, there was no overall association between sirolimus and incidence of other cancers (IRR = 1.06, 95% CI = 0.69-1.63). However, sirolimus use had associations with lower kidney cancer incidence (IRR = 0.40, 95% CI = 0.20-0.81), and higher prostate cancer incidence (IRR = 1.85, 95% CI = 1.17-2.91). Among kidney recipients, sirolimus users have lower NMSC risk, which may be partly due to removal of cyclosporine. Sirolimus may also reduce kidney cancer risk but did not appear protective for other cancers, and it may actually increase prostate cancer risk., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investigated sirolimus effects on cancer incidence among kidney recipients. The US transplant registry was linked with 15 population-based cancer registries and national pharmacy claims. Recipients contributed sirolimus-exposed time when sirolimus claims were filled, and unexposed time when other immunosuppressant claims were filled without sirolimus. Cox regression was used to estimate associations with overall and specific cancer incidence, excluding nonmelanoma skin cancers (not captured in cancer registries). We included 32,604 kidney transplants (5687 sirolimus-exposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.70-1.11). Prostate cancer incidence was higher during sirolimus use (HR = 1.86, 95% CI = 1.15-3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR = 0.74, 95% CI = 0.57-0.96, excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. This modest association does not provide strong evidence that sirolimus prevents posttransplant cancer, but it may be advantageous among kidney recipients with high cancer risk. Increased prostate cancer diagnoses may result from sirolimus effects on screen detection., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Lymphoma incidence is increased among human immunodeficiency virus (HIV)-infected individuals soon after antiretroviral therapy (ART), perhaps due to unmasking immune reconstitution inflammatory syndrome (IRIS). Clinical characteristics and survival for unmasking lymphoma IRIS have not been described., Methods: We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) from 1996 until 2011. Unmasking lymphoma IRIS was defined as lymphoma within 6 months after ART accompanied by a ≥ 0.5 log10 copies/mL HIV RNA reduction. Differences in presentation and survival were examined between IRIS and non-IRIS cases., Results: Of 482 lymphoma patients, 56 (12%) met criteria for unmasking lymphoma IRIS. Of these, 12 (21%) had Hodgkin lymphoma, 22 (39%) diffuse large B-cell lymphoma, 5 (9%) Burkitt lymphoma, 10 (18%) primary central nervous system lymphoma, and 7 (13%) other non-Hodgkin lymphoma. Median CD4 cell count at lymphoma diagnosis among IRIS cases was 173 cells/µL (interquartile range, 73-302), and 48% had suppressed HIV RNA <400 copies/mL. IRIS cases were similar overall to non-IRIS cases in histologic distribution and clinical characteristics, excepting more frequent hepatitis B and C (30% vs 19%, P = .05), and lower HIV RNA at lymphoma diagnosis resulting from the IRIS case definition. Overall survival at 5 years was similar between IRIS (49%; 95% confidence interval [CI], 37%-64%) and non-IRIS (44%; 95% CI, 39%-50%), although increased early mortality was suggested among IRIS cases., Conclusions: In a large HIV-associated lymphoma cohort, 12% of patients met a uniformly applied unmasking lymphoma IRIS case definition. Detailed studies of lymphoma IRIS might identify immunologic mechanisms of lymphoma control., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To estimate the association between immunologic response to antiretroviral therapy (ART) and non-AIDS defining cancer (NADC) incidence in HIV-infected patients., Design: A prospective cohort including patients with at least 1 cell/μl CD4 cell count and HIV-1 RNA measure after ART initiation between 1996 and 2011 in the Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of eight HIV clinics at major academic medical centres in the United States., Methods: Measures of immunologic response were 6-month CD4 post-ART, latest CD4 and CD4 count-years, a cumulative measure of CD4 lymphopenia. Cox regression with inverse probability-of-exposure weights was used to calculate adjusted hazard ratios of virus-related and virus-unrelated NADC incidence., Results: Among 9389 patients at ART initiation, median CD4 cell count was 200 cells/μl [interquartile range (IQR) 60-332)], and median HIV-1 RNA was 4.8 log10 copies/ml (IQR 4.3-5.4). Median follow-up was 3.3 years (IQR 1.5-6.5). After 6 months of ART, median CD4 cell count was 304 cells/μl (IQR 163-469). One hundred and sixty-four NADCs were diagnosed during study follow-up, 65 (40%) considered virus-related. Virus-related NADCs were inversely associated with 6-month CD4 cell count (hazard ratio per 100 cells/μl increase=0.71), latest CD4 cell count (hazard ratio per 100 cells/μl increase=0.70) and CD4 cell count-years (hazard ratio per 200 cell-years/μl increase=0.91) independent of CD4 cell count at ART initiation, age and HIV-1 RNA response. No associations were found with virus-unrelated NADCs., Conclusion: Poor CD4 cell count response was strongly associated with virus-related NADC incidence, suggesting an important role for T-cell mediated immunity in pathogenesis. Lower CD4 cell count proximal to cancer diagnosis may be a result of subclinical cancer. Intensified cancer screening should be considered for patients on ART with low CD4 cell counts.

Objective: To examine the association between early HIV viremia and mortality after HIV-associated lymphoma., Design: Multicenter observational cohort study., Setting: Center for AIDS Research Network of Integrated Clinical Systems cohort., Participants: HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with at least two HIV RNA values during the 6 months after lymphoma diagnosis., Exposure: Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months., Main Outcome Measure: All-cause mortality between 6 months and 5 years after lymphoma diagnosis., Results: Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma. At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4⁺ cell count was 148 cells/μl (interquartile range 54-322), and 33% had suppressed HIV RNA (<400 copies/ml). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03-1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02-2.63), lower CD4⁺ cell count (AHR 0.75 per 100 cells/μl increase, 95% CI 0.64-0.89), and higher early cumulative viremia (AHR 1.35 per log₁₀ copies × 6-months/ml, 95% CI 1.11-1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4⁺ cell count, and histology., Conclusion: Exposure to each additional 1-unit log₁₀ in HIV RNA throughout the 6 months after lymphoma diagnosis was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Background: Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized., Methods: We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation., Results: At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000-2007) and median CD4 count was 202 cells/mm(3) (IQR, 61-338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%-13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus-related cancer. Calendar year of ART initiation was not associated with cancer incidence., Conclusions: KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care.

Background: Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era., Methods: We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan-Meier curves and Cox proportional hazards., Results: Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year., Conclusions: HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.

Objective: Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States., Design: Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort., Methods: Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation., Results: A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/μl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid=49 [95% confidence interval (CI) 41-58]; hematologic=44 (40-49); hepatic=24 (20-27); and renal=9 (7-11), dropping substantially during weeks 17-104 of cART to lipid=23 (18-29); hematologic=5 (4-6); hepatic=6 (5-8); and renal=2 (1-3) (all P<0.05). Among patients receiving initial cART with no prior abnormality (N=1889), strongest associations for hepatic abnormalities after 16 weeks were hepatitis B and C [hazard ratio=2.3 (95% CI 1.2-4.5) and hazard ratio=3.0 (1.9-4.5), respectively]. The strongest association for renal abnormalities was hypertension [hazard ratio=2.8 (1.4-5.6)]., Conclusion: New abnormalities decreased after week 16 of cART. For abnormalities not present by week 16, subsequent monitoring should be guided by comorbidities., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins)

We assessed laboratory monitoring after combination antiretroviral therapy initiation among 3678 patients in a large US multisite clinical cohort, censoring participants at last clinic visit, combination antiretroviral therapy change, or 3 years. Median days (interquartile range) to first hematologic, hepatic, renal, and lipid tests were 30 (18-53), 31 (19-56), 33 (20-59), and 350 (96-1106), respectively. At 1 year, approximately 80% received more than 2 hematologic, hepatic, and renal tests consistent with guidelines. However, only 40% received 1 or more lipid tests. Monitoring was more frequent in specific subgroups, likely reflecting better clinic attendance or clinician perception of higher susceptibility to toxicities.

Background: In HIV-infected populations in developed countries, the most recent published cancer incidence trend analyses are only updated through 2008. We assessed changes in the distribution of cancer types and incidence trends among HIV-infected patients in North Carolina up until 2011., Methods: We linked the University of North Carolina Center for AIDS Research HIV Clinical Cohort, an observational clinical cohort of 3141 HIV-infected patients, with the North Carolina Cancer registry. Cancer incidence rates were estimated across calendar years from 2000 to 2011. The distribution of cancer types was described. Incidence trends were assessed with linear regression., Results: Across 15,022 person-years of follow-up, 202 cancers were identified (incidence rate per 100,000 person-years [IR]: 1345; 95% confidence interval [CI]: 1166, 1544). The majority of cancers were virus-related (61%), including Kaposi sarcoma (N = 32) (IR: 213; 95%CI: 146, 301), non-Hodgkin lymphoma (N = 34) (IR: 226; 95%CI: 157, 316), and anal cancer (N = 16) (IR: 107; 95%CI: 61, 173). Non-Hodgkin lymphoma was observed to decrease from 2000 to 2011 (decline of 15 cases per 100,000 person-years per calendar year, 95%CI: -27, -3). No other changes in incidence or changes in incidence trends were observed for other cancers (all P > 0.20)., Conclusions: We observed a substantial burden of a variety of cancers in this population in the last decade. Kaposi sarcoma and non-Hodgkin lymphoma were consistently two of the greatest contributors to cancer burden across calendar time. Cancer rates appeared stable across calendar years, except for non-Hodgkin lymphoma, which appeared to decrease throughout the study period.

The associations of acute HIV infection (AHI) and other predictors with transmitted drug resistance (TDR) prevalence were assessed in a cohort of HIV-infected, antiretroviral-naïve patients. AHI was defined as being seronegative with detectable HIV RNA. Binomial regression was used to estimate prevalence ratios and 95% confidence intervals for associations with TDR. Among 43 AHI patients, TDR prevalence was 20.9%, whereas prevalence was 8.6% among 677 chronically infected patients. AHI was associated with 1.9 times the prevalence of TDR (95% confidence intervals: 1.0 to 3.6) in multivariable analysis. AHI patients may represent a vanguard group that portends increasing TDR in the future.

Background and Objectives: Proteinuria is a major determinant of chronic kidney disease. We aimed to characterize the prevalence and correlates of proteinuria in a cohort of HIV-infected and uninfected injection drug users., Design, Setting, Participants, & Measurements: A cross-sectional analysis was performed among 902 injection drug users (273 HIV-infected) in the AIDS Linked to the Intravenous Experience cohort. The primary outcome was proteinuria defined as having a urine protein/creatinine concentration ratio >200 mg/g. Poisson regression with robust variance was used to determine prevalence ratios., Results: Overall, 24.8% of participants had proteinuria; the prevalence was 2.9 times higher among HIV-infected participants (45%) compared with HIV-uninfected participants (16%). In addition, age, health insurance, employment status, hepatitis B and C serostatus, diabetes, and high BP were associated with proteinuria. Neither antiretroviral therapy nor features of illicit drug use history were associated with proteinuria. In multivariate analysis, HIV infection, unemployment, increased age, diabetes, hepatitis C infection, and high BP were significantly associated with a higher prevalence of proteinuria., Conclusions: In an aging, predominantly African-American cohort of injection drug users, we found a striking burden of proteinuria that was strongly associated with HIV status. In addition to being a pathway to ESRD, proteinuria is a potent risk factor for cardiovascular morbidity and mortality. Evaluation of aggressive screening and disease-modification strategies in this high-risk population is warranted.

A community-based, cluster-randomized, placebo-controlled trial of daily zinc and/or iron+folic acid supplementation was conducted in rural southern Nepal to examine motor milestone attainment among 3264 children 1-36 mo of age between 2001 and 2006. Treatment groups included placebo, zinc (10 mg), iron+folic acid (12.5 mg iron + 50 microg folic acid), and zinc+iron+folic acid (10 mg zinc + 12.5 mg iron + 50 microg folic acid). Infants received half of these doses. The iron arms were stopped November 2003 by recommendation of the Data Safety and Monitoring Board; zinc and placebo continued until January 2006. A total of 2457 children had not walked at the time of entry into the trial and 1775 were followed through 36 mo. Mean age at first walking unassisted did not differ among groups and was 444 +/- 81 d (mean +/- SD) in the placebo group, 444 +/- 81 d in the zinc group, 464 +/- 85 d in the iron+folic acid group, and 446 +/- 87 d in the iron+folic acid+zinc group. Results were similar after adjustment for age at enrollment, asset ownership, maternal literacy, and prior child deaths in the household and in children who consumed at least 60 tablets. Compared with placebo, iron+folic acid was associated with an adjusted mean delay of 28.0 d (95% CI: 11.3, 44.7) in time to walking among infants and the delay was more pronounced with mid-upper arm circumference (MUAC) < 9.5 cm [60.6 d, (95% CI: 28.5, 92.6)]. Risks and benefits of universal iron+folic acid supplementation of infants beyond improved hematologic status deserve further consideration.

Background: Exposure to indoor air pollution due to open burning of biomass fuel is common in low- and middle-income countries. Previous studies linked this exposure to an increased risk of respiratory illness, low birth weight (LBW) and other disorders. We assessed the association between exposure to biomass fuel sources and second-hand tobacco smoke (SHTS) in the home and adverse health outcomes in early infancy in a population in rural south India., Methods: A population-based cohort of newborns was followed from birth through 6 months. Household characteristics were assessed during an enrolment interview including the primary type of cooking fuel and smoking behaviour of household residents. Follow-up visits for morbidity were carried out every 2 weeks after delivery. Infants were discharged at 6 months when anthropometric measurements were collected., Results: 11 728 live-born infants were enrolled and followed, of whom 92.3% resided in households that used wood and/or dung as a primary source of fuel. Exposure to biomass fuel was associated with an adjusted 49% increased risk of LBW, a 34% increased incidence of respiratory illness and a 21% increased risk of 6-month infant mortality. Exposed infants also had 45 and 30% increased risks of underweight and stunting at 6 months. SHTS exposure was also associated with these adverse health outcomes except for attained growth., Conclusions: Open burning of biomass fuel in the home is associated with significant health risks to the newborn child and young infant. Community-based trials are needed to clarify causal connections and identify effective approaches to reduce this burden of illnesses.

Purpose: This study aimed to identify risk factors associated with maternal night blindness in rural South India., Methods: At delivery, women enrolled in a population-based trial of newborn vitamin A supplementation were asked whether they were night blind at any time during the pregnancy. Multivariate logistic regression was used to identify socioeconomic, demographic, and pregnancy-related factors associated with maternal night blindness., Results: Women reported night blindness in 687 (5.2%) of 13,171 pregnancies. In a multivariate model, having a concrete roof (Odds Ratio (OR): 0.60, 95% Confidence Interval (CI): 0.47, 0.78), religion other than Hindu (OR: 0.46, 95% CI: 0.27, 0.76), maternal literacy (OR: 0.58, 95% CI: 0.49, 0.69), and maternal age from 25 to 29 years (OR: 0.68, 95% CI: 0.50, 0.93) were associated with a lower risk of night blindness in pregnancy. The odds of night blindness were higher for those leasing rather than owning land (OR: 1.78, 95%CI: 1.08, 2.93), parity 6 or more compared to 0 (OR: 2.11, 95% CI: 1.09, 4.08), and with twin pregnancies (OR: 3.23, 95% CI: 1.93, 5.41). Factors not associated with night blindness in the multivariate model were other markers of socioeconomic status such as electricity in the house, radio and television ownership, type of cooking fuel and household transportation, and number of children under 5 years of age in the household., Conclusions: Maternal night blindness was prevalent in this population. Being pregnant with twins and of higher parity put women at higher risk. Maternal literacy and higher socioeconomic status lowered the risk.