Metagenomic analysis to identify novel infectious agents in systemic anaplastic large cell lymphoma.

Systemic anaplastic large cell lymphoma (ALCL) is a rare CD30-expressing T-cell non-Hodgkin lymphoma. Risk of systemic ALCL is highly increased among immunosuppressed individuals. Because risk of cancers associated with viruses is increased with immunosuppression, we conducted a metagenomic analysis of systemic ALCL to determine whether a known or novel pathogen is associated with this malignancy. Total RNA was extracted and sequenced from formalin-fixed paraffin-embedded tumor specimens from 19 systemic ALCL cases (including one case from an immunosuppressed individual with human immunodeficiency virus infection), 3 Epstein-Barr virus positive diffuse large B-cell lymphomas (DLBCLs) occurring in solid organ transplant recipients (positive controls), and 3 breast cancers (negative controls). We used a pipeline based on the Genome Analysis Toolkit (GATK)-PathSeq algorithm to subtract out human RNA reads and map the remaining RNA reads to microbes. No microbial association with ALCL was identified, but we found Epstein-Barr virus in the DLBCL positive controls and determined the breast cancers to be negative. In conclusion, we did not find a pathogen associated with systemic ALCL, but because we analyzed only one ALCL tumor from an immunosuppressed person, we cannot exclude the possibility that a pathogen is associated with some cases that arise in the setting of immunosuppression.

Tumor Necrosis Factor Inhibitors and the Risk of Cancer among Older Americans with Rheumatoid Arthritis.

BACKGROUND: TNF inhibitors (TNFi) effectively treat rheumatoid arthritis but may increase patient risk of some malignancies, particularly lymphomas or skin cancers. METHODS: We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to conduct a case-control study in patients with rheumatoid arthritis (2007-2015). Cases were individuals with a first cancer diagnosed in SEER registries (ages 66-99, 22 cancer sites, N = 10,263). Skin cancer cases [nonmelanoma skin cancer (NMSC, N = 501), basal cell carcinoma (BCC, N = 161), squamous cell carcinoma (SCC, N = 150)] and cancer-free controls (N = 30,475) were selected from Medicare beneficiaries residing in SEER areas. Cases and controls had prior Medicare claims-based evidence for rheumatoid arthritis, and TNFi exposure was ascertained from part B and part D claims. Logistic regression was used to estimate adjusted odds ratios (aOR). RESULTS: TNFi exposure was present in 16.2% of controls and 12.8% to 33.7% of cancer cases, varying by site. TNFi use was associated with increased risk of NMSC overall (aOR 1.32, 95% confidence interval 1.06-1.63), non-Hodgkin lymphoma (NHL) overall (1.28, 1.06-1.56) and, specifically, follicular lymphoma (2.63, 1.63-4.24). TNFi exposure was not associated with other SEER cancer sites, BCC or SCC specifically, or other common NHL subtypes. CONCLUSIONS: Among older adults with rheumatoid arthritis, TNFi exposure was associated with elevated risk of NMSC and NHL, driven specifically by follicular lymphoma. Exposure was not associated with increased risk for other cancer sites. IMPACT: Our results support a role for TNF in lymphomagenesis. Given the association with NMSC, patients initiating TNFi therapy may benefit from skin cancer screening and sun protection measures.

Anaplastic large cell lymphoma in human immunodeficiency virus-infected people and solid organ transplant recipients.

Human immunodeficiency virus (HIV)-infected people and solid organ transplant recipients have elevated risk of anaplastic large cell lymphoma (ALCL). Little is known regarding ALCL risk factors in immunosuppressed populations. We used data from US cancer registries linked to HIV registries (1996-2016) and to the national transplant registry (1992-2017). ALCL risk in HIV-infected people and transplant recipients relative to the general population was calculated as a standardized incidence ratio (SIR). ALCL risk factors were evaluated using Poisson regression. We identified 121 incident ALCL cases in the HIV (n = 86) and transplant (n = 35) populations. We reviewed pathology reports for 45 cases and most (86·7%) were confirmed as ALCL. Epstein-Barr virus tested positive in 1/8 (12·5%) cases. Compared to the general population, ALCL risk was strongly elevated among HIV-infected people [SIR 5·43; 95% confidence interval (CI) 4·27-6·81] and transplant recipients (5·96; 4·03-8·49). Among HIV-infected people, ALCL incidence was strongly related to CD4 count [adjusted incidence rate ratio (aIRR) 0·15 for ≥500 vs. <200 cells/µl; P trend < 0·001]. Among transplant recipients, risk was highest within the first year (aIRR 6·82) and 10+ years post-transplant (5·99). In conclusion, ALCL risk is strongly increased in these immunosuppressed populations but may be unrelated to EBV infection based on limited reports.

The Impact of Liver Transplantation on Hepatocellular Carcinoma Mortality in the United States.

BACKGROUND: Hepatocellular carcinoma (HCC) carries a poor prognosis. Liver transplantation (LT) is potentially curative for localized HCC. We evaluated the impact of LT on U.S. general population HCC-specific mortality rates. METHODS: The Transplant Cancer Match Study links the U.S. transplant registry with 17 cancer registries. We calculated age-standardized incidence (1987-2017) and incidence-based mortality (IBM) rates (1991-2017) for adult HCCs. We partitioned population-level IBM rates by cancer stage and calculated counterfactual IBM rates assuming transplanted cases had not received a transplant. RESULTS: Among 129,487 HCC cases, 45.9% had localized cancer. HCC incidence increased on average 4.0% annually [95% confidence interval (CI) = 3.6-4.5]. IBM also increased for HCC overall (2.9% annually; 95% CI = 1.7-4.2) and specifically for localized stage HCC (4.8% annually; 95% CI = 4.0-5.5). The proportion of HCC-related transplants jumped sharply from 6.7% (2001) to 18.0% (2002), and further increased to 40.0% (2017). HCC-specific mortality declined among both nontransplanted and transplanted cases over time. In the absence of transplants, IBM for localized HCC would have increased at 5.3% instead of 4.8% annually. CONCLUSIONS: LT has provided survival benefit to patients with localized HCC. However, diagnosis of many cases at advanced stages, limited availability of donor livers, and improved mortality for patients without transplants have limited the impact of transplantation on general population HCC-specific mortality rates. IMPACT: Although LT rates continue to rise, better screening and treatment modalities are needed to halt the rising HCC mortality rates in the United States.See related commentary by Zhang and Thrift, p. 435.

Chronic hepatitis C virus infection and genitourinary cancers: A case-control study.

BACKGROUND: Chronic Hepatitis C virus (HCV) infection has been associated with extrahepatic cancers. Few studies have reported associations between HCV and genitourinary cancers such as kidney and prostate cancers with inconsistent findings. We sought to study associations between HCV and the most common genitourinary cancers including kidney, prostate and urinary bladder. MATERIAL AND METHODS: This case-control study included adult (≥18 years at diagnosis) cancer patients who were screened for HCV antibody (anti-HCV) at MD Anderson Cancer Center from June 2004 through January 2018. Cases had incident primary genitourinary cancers (cancers of the kidney, prostate, renal pelvis and ureter, or urinary bladder). Controls had smoking-associated cancers (esophagus, lung and pancreas). Multivariate logistic regression models were used. RESULTS: Among 42,244 patients screened for anti-HCV, 1,493 cases (527 kidney, 691 prostate, 58 renal pelvis and ureter, and 217 urinary bladder cancer) and 1,187 controls (242 esophagus, 709 lung, and 236 pancreas cancer) were studied. In the univariate analysis, the prevalence of anti-HCV positivity did not differ significantly between the controls and the cases with cancers of the renal pelvis and ureter (8% v9%, P = .81), prostate (10% v8%, P = .34), or urinary bladder (8% v 6%, P = .18). In contrast, the prevalence of anti-HCV positivity was lower among the cases with kidney cancer than among the controls (4% v 8%, P< .001). However, in the multivariate analyses after adjustment for cofounders, no significant association between anti-HCV positivity and any genitourinary cancer we evaluated. CONCLUSION: Our results do not support an association between chronic HCV and common genitourinary cancers.

Cancer risk following lymphoid malignancies among HIV-infected people.

OBJECTIVE(S): HIV-infected people have increased cancer risk. Lymphoma survivors have an increased risk of certain second primary cancers in the general population, but second cancer risk among HIV-infected people is poorly understood. Herein, we characterized the risk of cancers following lymphoid malignancies among HIV-infected people. DESIGN: Population-based linkage of HIV and cancer registries. METHODS: We used data from the US HIV/AIDS Cancer Match Study (1996-2015) and evaluated the risk of first nonlymphoid malignancy in Cox regression models, with first lymphoid malignancy diagnosis as a time-dependent variable. RESULTS: Among 531 460 HIV-infected people included in our study, 6513 first lymphoid and 18 944 first nonlymphoid malignancies were diagnosed. Risk of nonlymphoid cancer following a lymphoid malignancy was increased overall [adjusted hazard ratio (aHR) = 2.7; 95% confidence interval (CI) = 2.3--3.2], and specifically for cancers of the oral cavity (aHR = 2.6; 95% CI = 1.2-5.5), colon (2.4; 1.1-5.0), rectum (3.6; 1.9-6.7), anus (3.6; 2.5-5.1), liver (2.0; 1.2-3.5), lung (1.6; 1.1-2.4), vagina/vulva (6.1; 2.3-16.3), and central nervous system (5.0; 1.6-15.6), Kaposi sarcoma (4.6; 3.4-6.2), and myeloid malignancies (9.7; 6.1-15.4). After additional adjustment for prior AIDS diagnosis and time since HIV diagnosis, aHRs were attenuated overall (aHR = 1.7; 95% CI = 1.5-2.0) and remained significant for cancers of the rectum, anus, and vagina/vulva, Kaposi sarcoma, and myeloid malignancies. CONCLUSION: HIV-infected people with lymphoid malignancies have an increased risk of subsequent non-lymphoid cancers. As risks remained significant after adjustment for time since HIV diagnosis and prior AIDS diagnosis, it suggests that immunosuppression may explain some, but not all, of these risks.

Autoimmune conditions and primary central nervous system lymphoma risk among older adults.

Primary central nervous system lymphoma (PCNSL) risk is highly increased in immunosuppressed individuals, such as those with human immunodeficiency virus infection and solid organ transplant recipients, but rates are increasing among immunocompetent older adults (age ≥65 years). We utilized data from a large, nationally-representative cohort of older adults in the United States and found that PCNSL is significantly associated with systemic lupus erythematosus, polyarteritis nodusa, autoimmune hepatitis, myasthenia gravis and uveitis. Immunosuppressive drugs given to treat these conditions may increase PCNSL risk, but these associations cannot explain the observed temporal increase in PCNSL rates, given the low prevalence of these conditions.

Hepatitis D virus infection, cirrhosis and hepatocellular carcinoma in The Gambia.

Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q-MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case-control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha-foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q-MAC, western blot and RNA assays. We evaluated separate cut-offs of the Q-MAC assay for predicting anti-HDV and RNA positivity. Q-MAC correctly identified 29/29 subjects who were western blot-positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA-positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA-; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV-HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti-HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74-11.98) and HBV-HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97-134.95). In this Gambian population, HDV Q-MAC had high sensitivity and specificity for both anti-HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia.

Sepsis and Risk of Cancer Among Elderly Adults in the United States.

BACKGROUND: Sepsis is an important cause of mortality among older adults in the United States. The association between sepsis and subsequent risk of cancer is poorly understood. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we conducted a case-control study in US adults. We included 1801156 cases with a first cancer diagnosis in SEER during 1992-2013 (ages 66-115 years) and 200000 cancer-free controls from a 5% random sample of Medicare beneficiaries. Sepsis was identified using inpatient Medicare claims. Associations with sepsis were estimated using logistic regression. RESULTS: After correction for multiple comparisons, sepsis was significantly associated with increased risk for cancers of the colon (adjusted odds ratio [aOR] = 1.12), rectum (1.13), liver (1.47), lung (1.17), and cervix (1.52), as well as acute myeloid leukemia (AML, 1.19), chronic myeloid leukemia (1.54), and myelodysplastic syndrome (1.30). Inverse associations were observed for cancers of the breast (aOR = 0.86), prostate (0.75), kidney (0.90), and thyroid (0.68) and for melanoma (0.83), diffuse large B-cell lymphoma (0.89), and follicular lymphoma (0.65). Sepsis was significantly associated with the following 9 types of cancer in the period >5 years following sepsis diagnosis: thyroid, prostate, colon, rectum, lung, and liver and follicular lymphoma, melanoma, and AML. CONCLUSIONS: Sepsis is associated with increased or decreased risks for a small group of cancers. Factors that may explain these associations include etiologic effects. Other associations may reflect the presence of precursor conditions or patterns in ascertainment of cancer and screening.

Sofosbuvir-Based Therapy in Hepatitis C Virus-Infected Cancer Patients: A Prospective Observational Study.

BACKGROUND: Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients. METHODS: Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed. RESULTS: We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%). CONCLUSIONS: SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Hepatitis B virus infection and the risk of cancer in the elderly US population.

Hepatitis B virus (HBV) infection causes hepatocellular carcinoma (HCC). Associations with other cancers are not established. We systematically assessed associations between HBV infection and cancers in the US elderly population. We conducted a case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database in US adults aged ≥66 years. Cases (N = 1,825,316) were people with first cancers diagnosed in SEER registries (1993-2013). Controls (N = 200,000) were randomly selected, cancer-free individuals who were frequency-matched to cases on age, sex, race and calendar year. Associations with HBV infection (ascertained by Medicare claims) were assessed by logistic regression. HBV prevalence was higher in cases than controls (0.6% vs. 0.5%). HBV was positively associated with cancers of the stomach (adjusted odds ratio [aOR] = 1.19; 95% confidence intervals [CI] = 1.03-1.37), anus (1.66; 1.17-2.33), liver (10.6; 9.66-11.6), intrahepatic bile ducts (1.67; 1.18-2.37), nasopharynx (2.08; 1.33-3.25), as well as myelodysplastic syndrome (1.26; 1.07-1.49) and diffuse large B-cell lymphoma (DLBCL) (1.24; 1.06-1.46). Inverse associations were observed with female breast (aOR = 0.86; 95%CI = 0.76-0.98) and prostate (0.81; 0.73-0.91) cancers and chronic lymphocytic leukemia (0.77; 0.62-0.96). Associations were maintained in sensitivity analyses conducted in people without claims for cirrhosis or hepatitis C or human immunodeficiency virus infections. HBV infection is associated with increased risk of cancers other than HCC, such as bile duct cancers and DLBCL. The biological mechanisms by which HBV may lead to these cancers need to be explored.

Risk of lung cancer in lung transplant recipients in the United States.

Lung transplant recipients have an increased risk of lung cancer that is poorly understood. Prior studies are largely descriptive and single-center, and have not examined risk factors or outcomes in this population. This registry-linkage study utilized matched transplant and cancer registry data from 17 US states/regions during 1987-2012. We used standardized incidence ratios (SIRs) to compare incidence with the general population, Poisson models to identify lung cancer risk factors, and Cox models to compare survival after diagnosis. Lung cancer risk was increased among lung recipients (SIR 4.8, 95% confidence interval [CI] 4.1-5.5). Those with single lung transplant had 13-fold (95% CI 11-15) increased risk in the native lung. Native lung cancer risk factors included age, prior smoking, time since transplant, and idiopathic pulmonary fibrosis. Compared with cases in the general population, lung cancers in recipients were more frequently localized stage (P = .02) and treated surgically (P = .05). However, recipients had higher all-cause (adjusted hazard ratio 1.90, 95% CI 1.52-2.37) and cancer-specific mortality (adjusted hazard ratio 1.67, 95% CI 1.28-2.18). In conclusion, lung cancer risk is increased after lung transplant, especially in the native lung of single lung recipients. Traditional risk factors are associated with lung cancer in these patients. Lung cancer survival is worse among lung recipients despite earlier diagnosis.

Risk of Breast, Prostate, and Colorectal Cancer Diagnoses Among HIV-Infected Individuals in the United States.

Background: Although people living with HIV or AIDS (PLWHA) are at higher risk for many cancers, breast, prostate, and colorectal cancer rates are lower in this patient population. Because these tumors are often screen-detected, these inverse associations could be driven by HIV-related differences in utilization of cancer screening. Methods: We ascertained incident breast, prostate, and colorectal cancer in PLWHA using data from the HIV/AIDS Cancer Match Study (1996-2012). Comparisons with general population cancer rates were made using standardized incidence ratios (SIRs), overall and stratified by tumor stage/size, breast cancer estrogen receptor status, and colorectal site. We also examined the potential effect of study design and unmeasured confounding on inverse standardized incidence ratios. Results: Compared with the general population, PLWHA had lower rates of invasive breast (SIR = 0.63, 95% confidence interval [CI] = 0.58 to 0.68), prostate (SIR = 0.48, 95% CI = 0.46 to 0.51), proximal colon (SIR = 0.67, 95% CI = 0.59 to 0.75), distal colon (SIR = 0.51, 95% CI = 0.43 to 0.59), and rectal cancers (SIR = 0.69, 95% CI = 0.61 to 0.77). Reduced risk persisted across tumor stage/size for prostate and colorectal cancers. Although distant-stage breast cancer rates were not reduced (SIR = 0.94, 95% CI = 0.73 to 1.20), HIV-infected women had lower rates of large (>5 cm) breast tumors (SIR = 0.65, 95% CI = 0.50 to 0.83). The magnitude of these inverse standardized incidence ratios could not plausibly be attributed to case underascertainment, out-migration, or unmeasured confounding. Conclusions: Breast, prostate, and colorectal cancer rates are markedly lower among PLWHA, including rates of distant-stage/large tumors that are not generally screen-detected. This set of inverse HIV-cancer associations is therefore unlikely to be due primarily to differential screening and may instead represent biological relationships requiring future investigation.

Cancer Risk in Older Persons Living With Human Immunodeficiency Virus Infection in the United States.

Background: Cancer risk is increased in persons living with human immunodeficiency virus (HIV) (PLWH). Improved survival has led to an aging of PLWH. We evaluated the cancer risk in older PLWH (age ≥50 years). Methods: We included data from the HIV/AIDS Cancer Match Study (1996-2012) and evaluated risks of Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and cervical, anal, lung, liver, oral cavity/pharyngeal, breast, prostate, and colon cancers in older PLWH with risk in the general population by calculating standardized incidence ratios (SIRs) and excess absolute risks (EARs). Cancer risk by time since HIV diagnosis was estimated using Poisson regression. Results: We identified 10371 cancers among 183542 older PLWH. Risk was significantly increased for KS (SIR, 103.34), NHL (3.05), Hodgkin lymphoma (7.61), and cervical (2.02), anal (14.00), lung (1.71), liver (2.91), and oral cavity/pharyngeal (1.66) cancers, and reduced for breast (0.61), prostate (0.47), and colon (0.63) cancers. SIRs declined with age for all cancers; however, EARs increased with age for anal, lung, liver, and oral cavity/pharyngeal cancers. Cancer risk was highest for most cancers within 5 years after HIV diagnosis; risk decreased with increasing time since HIV diagnosis for KS, NHL, lung cancer, and Hodgkin lymphoma. Conclusions: Cancer risk is elevated among older PLWH. Although SIRs decrease with age, EARs are higher for some cancers, reflecting a greater absolute excess in cancer incidence among older PLWH. High risk in the first 5 years after HIV diagnosis for some cancers highlights the need for early HIV diagnosis and rapid treatment initiation.

Trends in Risks for Second Primary Cancers Associated With Index Human Papillomavirus-Associated Cancers.

Importance: In the last 4 decades, survival among patients with human papillomavirus (HPV)-associated cancers has improved, while the incidence of these cancers has increased among younger cohorts. Among survivors of HPV-associated cancers, persistent HPV infection may remain a risk factor for preventable HPV-associated second primary cancers (HPV-SPCs). Objectives: To investigate the risk of HPV-SPCs among survivors of HPV-associated index cancers and to test the hypothesis that the HPV-SPC risk among these persons has increased over the last 4 decades. Design, Setting, and Participants: A retrospective cohort study of 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to identify patients with HPV-associated (cervical, vaginal, vulvar, oropharyngeal, anal, and penile) cancers diagnosed from January 1, 1973, through December 31, 2014. The dates of analysis were July 1, 2017, to January 31, 2018. Main Outcomes and Measures: The HPV-SPC risk was quantified by calculating standard incidence ratios (SIRs) and excess absolute risks (EARs) per 10 000 person-years at risk (PYR). The HPV-SPC risk by time was estimated using Poisson regression. Results: From 113 272 (73 085 female and 40 187 male) survivors of HPV-associated cancers, 1397 women and 1098 men developed HPV-SPCs. The SIRs for HPV-SPCs were 6.2 (95% CI, 5.9-6.6) among women and 15.8 (95% CI, 14.9-16.8) among men. The EARs were 18.2 per 10 000 PYR for women and 53.5 per 10 000 PYR for men. Among both women and men, those who had index oropharyngeal cancers had the highest HPV-SPC risk (SIR, 19.8 [95% CI, 18.4-21.4] and EAR, 80.6 per 10 000 PYR among women; SIR, 18.0 [95% CI, 16.9-19.1] and EAR, 61.5 per 10 000 PYR among men). Women who had index cervical cancers and men who had index anal cancers had the lowest HPV-SPC risk (SIR, 2.4 [95% CI, 2.2-2.7] and EAR, 4.5 per 10 000 PYR among women; SIR, 6.5 [95% CI, 4.7-8.8] and EAR, 18.5 per 10 000 PYR among men). Both women and men who had index HPV-associated cancers of any kind had a significantly higher risk of oropharyngeal HPV-SPCs. Over the last 4 decades, the risk of developing most types of HPV-SPCs after index cervical, vaginal, and vulvar cancers increased. Conclusions and Relevance: According to this study, the HPV-SPC risk among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs. These findings have the potential to inform surveillance recommendations for survivors of HPV-associated cancers.

The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection.

BACKGROUND AND AIM: Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited. METHODS: We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models. RESULTS: Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin's lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke. CONCLUSIONS: Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke.

Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study.

Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV-infected patients receiving cancer treatment at our institution between November 2012 and July 2016 were studied. Reactivation was defined as an increase in HCV-RNA ≥1 log10 IU/mL over baseline and hepatitis flare as an increase in alanine aminotransferase to ≥3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 (23%) patients, including 18 (36%) patients with hematologic malignancies and 5 (10%) patients with solid tumors. In univariate analysis, patients with reactivation were more likely than those without reactivation to have prolonged lymphopenia (median, 95 versus 22 days; P = 0.01) and to have received rituximab (44% versus 9%; P < 0.0001), bendamustine (22% versus 0%; P < 0.001), high-dose steroids (57% versus 21%; P = 0.001), or purine analogs (22% versus 5%; P = 0.02). Rituximab (odds ratio = 9.52; P = 0.001), and high-dose steroids (odds ratio = 5.05; P = 0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver-related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare, six of whom had reactivation, required discontinuation or dose reduction of cancer treatment. CONCLUSION: HCV reactivation occurred in 23% of HCV-infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. (Hepatology 2018;67:36-47).