Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Disease ecology, health and the environment: a framework to account for ecological and socio-economic drivers in the control of neglected tropical diseases.

Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases may fail to do so in the case of human pathogens with an environmental reservoir. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. We present mechanisms through which the environment can influence the dynamics of poverty via disease feedbacks. For illustration, we present the case studies of Buruli ulcer and schistosomiasis, two devastating waterborne NTDs for which control is particularly challenging.This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

Effect of isoniazid chemoprophylaxis on HIV-related mycobacterial disease.

OBJECTIVES: The aims of this study were to (1) identify trends and risk factors for mycobacterial disease and (2) determine the effect of expanded access to isoniazid chemoprophylaxis on tuberculosis incidence. METHODS: A prospective observational cohort study was conducted among community-based injecting drug users (IDUs); 2960 IDUs (942 human immunodeficiency virus [HIV] seropositive) were followed up from January 1988 to June 1994. Directly observed chemoprophylaxis with twice-weekly isoniazid (10 to 15 mg/kg) was offered to purified protein derivative (PPD) tuberculin-positive (> or = 5-mm induration diameter in HIV-seropositive subjects and > or = 10-mm diameter in HIV-seronegative subjects) individuals but not to those with cutaneous anergy. Overall and annual incidence rates of disease due Mycobacterium tuberculosis, Mycobacterium avium complex, and other atypical mycobacteria were estimated using Poisson regression. RESULTS: HIV seropositivity was the strongest risk factor for tuberculosis, M avium complex, and other mycobacterial disease (relative risk [RR], 3.8, 17.2, and 6.9, respectively). Median CD4 lymphocyte cell counts for the three groups of mycobacterial disease were 0.17, 0.03, and 0.02 x 10(9)/L (167/microL, 30/microL, 18/microL) within 6 months of diagnosis (before or after). Overall incidence rates of tuberculosis, M avium complex disease, and other mycobacterial disease were 1.9, 8.8, and 2.7 per 1000 person-years, respectively. Tuberculosis incidence peaked in 1991 at six per 1000 person-years. However, after access to directly observed preventive therapy was expanded for tuberculin-positive subjects, incidence fell to only one case in 1992 and zero cases for 24 months from mid-1992 to mid-1994. During this period the number of PPD-positive patients who completed at least 26 weeks of therapy (or were still receiving isoniazid) more than tripled (from 21 to 70). None of the 12 patients with tuberculosis diagnosed during follow-up had received any preventive therapy. In addition, no tuberculosis developed among participants with cutaneous anergy. Calendar trends in risk for M avium complex and tuberculosis diverged after expanded access to isoniazid prophylaxis. Compared with 1988-1989, risk of M avium complex increased sevenfold. Tuberculosis risk fell 83% from the peak risk in 1990-1991. CONCLUSIONS: Expanded access to directly observed isonazid therapy for tuberculin-positive IDUs with and without HIV infection was associated with an 83% drop in tuberculosis incidence, while in the same period M avium complex incidence significantly increased. These population-based data are consistent with those obtained from clinical trials of isoniazid prophylaxis and were obtained without offering chemoprophylaxis to HIV-infected patients with cutaneous energy.

Prevalence of tuberculin positivity and skin test anergy in HIV-1-seropositive and -seronegative intravenous drug users.

OBJECTIVES: --To identify differences in purified protein derivative (PPD) tuberculin positivity and skin test anergy rates by human immunodeficiency virus (HIV) serostatus, CD4+ lymphocyte count, and other risk factors in intravenous drug users (IVDUs); and to evaluate the appropriateness of the Centers for Disease Control (CDC)--recommended definition for a positive PPD tuberculin skin test result in HIV-1-seropositive patients. DESIGN: --Nested case-control and cross-sectional analyses. SETTING: --Community-based cohort of IVDUs. PATIENTS: --Two hundred sixty HIV-1-seropositive and -seronegative IVDUs, drawn from an unselected cohort, were skin-tested for sensitivity to PPD tuberculin, mumps, and Candida antigens using the Mantoux method. OUTCOME MEASURES: --Positivity to PPD tuberculin, skin test anergy. RESULTS: --Even using the CDC definition of an induration 5 mm or greater in diameter in HIV-1 seropositives, this group was substantially less likely to be PPD tuberculin positive than HIV-1 seronegatives (13.8% vs 25.2%; P = .02). In the HIV-1 seropositives the relative odds of being PPD positive varied depending on whether 10 mm or greater (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.2 to 0.7), 5 mm or greater (OR, 0.5; 95% CI, 0.2 to 0.9), or 2 mm or greater (OR, 0.7; 95% CI, 0.4 to 1.3) was used to define a positive test result. The mean diameter induration in the HIV-1-seropositive group was 2.6 mm vs 5.4 mm in the seronegative group (P = .005). Skin test anergy (to mumps and Candida) appeared to explain the differential. Anergy was substantially higher in the HIV-1 seropositive group and increased as the CD4+ lymphocyte count fell (chi 2 for linear trend, 24.5; P less than .0001). An inverse linear trend for PPD positivity and CD4+ lymphocyte count was also observed (chi 2 for trend, 6.1; P = .01). In multivariate analyses, being 35 years of age or older and being HIV-1 seronegative were significantly associated with PPD positivity, while history of previous police arrest was of borderline significance. Only HIV-1 seropositivity was significantly associated with anergy. CONCLUSIONS: --These findings show that CDC-recommended definition of an induration 5 mm or greater in diameter for PPD tuberculin positivity in HIV-1 seropositives significantly underestimates the "true" infection rate (using the PPD positivity rate in HIV-1 seronegatives as the criterion standard). A definition of 2 mm or greater would appear to be a better cutoff for reducing misclassification in HIV-1 seropositives. This study also confirms that delayed-type hypersensitivity is seriously depressed in HIV-1 seropositive IVDUs and that anergy testing is mandatory to properly assess a negative PPD test result.

Isoniazid preventive therapy, hepatitis C virus infection, and hepatotoxicity among injection drug users infected with Mycobacterium tuberculosis.

Treatment of latent Mycobacterium tuberculosis infection with isoniazid can cause hepatotoxicity, but the risk of isoniazid-associated hepatotoxicity among persons coinfected with hepatitis C virus (HCV) is unknown. We conducted a prospective study among 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminase values who were treated with isoniazid. Of 146 participants, 138 (95%) were HCV-seropositive. Thirty-seven participants (25%) were human immunodeficiency virus (HIV)-seropositive. Thirty-two (22%; 95% confidence interval [CI], 16%-30%) of 146 participants developed transaminase value elevations to >3 times the upper limit of normal. Transaminase value elevation was associated with concurrent alcohol use but not with race, age, presence of hepatitis B surface antigen, HIV-1 infection, or current injection drug use. Isoniazid was withdrawn from 11 participants (8%; 95% CI, 4%-13%). Of 8 deaths during follow-up, none were attributed to isoniazid-associated hepatotoxicity. The risk of transaminase value elevation and drug discontinuation for HCV-infected persons receiving isoniazid was within the range reported for populations with lower HCV prevalence.