Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer.

BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.

Core principles of Malakit intervention for transferability in other contexts.

To eliminate malaria, all populations must be included. For those who are not reached by the health care system, specific interventions must be tailor-made. An innovative Malakit strategy, based on the distribution of self-diagnosis and self-treatment kits, has been evaluated in the Suriname-French Guiana- Amapá (Brazil) region. The results showed effectiveness and good acceptability. The Malakit intervention is complex and has many components. Its transferability requires adaptation to other populations and regions, while retaining the main features of the intervention. This article provides the keys to adapting, implementing and evaluating it in other contexts facing residual malaria in hard-to-reach and/or mobile populations. The process of transferring this intervention includes: diagnosis of the situation (malaria epidemiology, characteristics of the population affected) to define the relevance of the strategy; determination of the stakeholders and the framework of the intervention (research project or public health intervention); adaptation modalities (adaptation of the kit, training, distribution strategy); the role of community health workers and their need for training and supervision. Finally, evaluation needs are specified in relation to prospects for geographical or temporal extension. Malaria elimination is likely to increasingly involve marginalized people due to climate change and displacement of populations. Evaluation of the transferability and effectiveness of the Malakit strategy in new contexts will be essential to increase and refine the evidence of its value, and to decide whether it could be an additional tool in the arsenal recommended in future WHO guidelines.

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

[Box: see text].

Single High Dose of Liposomal Amphotericin B in Human Immunodeficiency Virus/AIDS-Related Disseminated Histoplasmosis: A Randomized Trial.

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.

From an interventional study to a national scale-up: lessons learned from the Malakit strategy at the French Guiana-Suriname border.

Scaling-up an experimental intervention is always a challenge. On the border between French Guiana, Brazil and Suriname, an interventional study demonstrated the effectiveness of distributing self-diagnosis and self-treatment kits (Malakits) to control malaria in mobile and hard-to-reach populations. Its integration into the Suriname's National Malaria Elimination Plan after a 2-year experiment faced numerous challenges, including human resources to cope with the additional workload of coordinators and to maintain the motivation of community health workers. The economic recession in Suriname, the Covid pandemic, and logistical issues also hampered the scale-up. Finally, thanks to the commitment of stakeholders in Suriname and French Guiana, the integration of Malakit distribution into the Surinamese national programme was proved possible.

Diabetes in a hospital cohort of persons living with HIV: a descriptive and comparative study in French Guiana.

BACKGROUND: In French Guiana (population 294,000) the prevalence of type 2 diabetes (10%) and of HIV(1.1%) are very high. Our objective was to determine the prevalence of diabetes and its complications in a HIV cohort. MATERIALS AND METHODS: We enrolled HIV-infected persons followed in Cayenne, Kourou, and Saint Laurent du Maroni hospitals between January 1, 1992 and December 31, 2021 in the French Hospital Database for HIV (FHDH) a national database compiling data from all French regions. RESULTS: There was no difference of diabetes prevalence between men (8.2%) and women (8.8%), P = 0.4. Patients with diabetes were older (56 years ± 13.4) than those without diabetes (44.7 years ± 13.6) and prevalence increased with age. The proportion of persons with diabetes was greater among virologically suppressed persons (10%) than those with a detectable viral load under antiretroviral treatment (5.8%). Persons with diabetes had substantially greater CD4 counts at diagnosis than persons without diabetes. The majority of macro and microvascular complications were observed in people with diabetes. Persons with diabetes and HIV were significantly less likely to have had AIDS (1.6 versus 2.2 per 100 person-years, respectively). Overall, 374 persons living with HIV of 4167 had died (9%) the proportion of persons with diabetes among the dead was greater than those who did not die 11.7% versus 8.1%, respectively, p = 0.017. However, persons with diabetes were older and hence died older, 62.3 years (SD = 1.9) for deceased persons with diabetes versus 50.4 years (SD = 0.8), P < 0.0001. However, using Cox regression to adjust for age, initial CD4 count, country of birth there was no significant difference in the Hazard for death between persons with diabetes and persons without diabetes (aHR = 0.99, 95%CI = 0.65-1.5), P = 0.9. CONCLUSIONS: The prevalence of diabetes in our HIV cohort was high. Persons with diabetes had greater CD4 counts, earlier care, and greater virological suppression than persons without diabetes. There were no significant differences between persons with diabetes and without diabetes in terms of survival.

Pulmonary Histoplasmosis in People Living with Human Immunodeficiency Virus in French Guiana: Clinical Epidemiology, Medical Imaging and Prognostic.

BACKGROUND: Histoplasmosis is mainly described as a disseminated disease in people living with HIV (PLHIV). Compared to historical descriptions in immunocompetent individuals, knowledge is lacking on the detailed clinical and radiological findings and outcomes of pulmonary histoplasmosis (PH). Overlooked or misdiagnosed with other AIDS-defining condition, prognostic of PLHIV may be at risk because of inappropriate care. METHODS: A retrospective multicentric study was conducted in PLHIV from French Guiana between January 1988 and October 2019. Proven PH were documented through mycological direct examination, culture, or histology. Patients with concomitant respiratory infections were excluded. RESULTS: Among 65 patients, sex ratio M:F was 2.4 with a median age of 39 years [IQR 25-75%: 34-44]. Median CD4 count was 24 cells/mm3 [11-71], with histoplasmosis as the AIDS-defining condition in 88% and concomitant AIDS-defining conditions in 29%. Clinical findings were fever (89%), cough (58%), dyspnea (35%), expectoration (14%), and hemoptysis (5%). Sixty-one X-rays and 24 CT-scans were performed. On X-rays, an interstitial lung disease was mainly found (77%). On CT-scans, a nodular pattern was predominant (83%): mostly miliary disease (63%), but also excavated nodules (35%). Consolidations were present in 46%, associated with miliary disease in 21%. Thoracic lymphadenopathies were found in 58%, mainly hilar and symmetric (33%). Despite antifungal treatment, case-fatality rate at one month was 22%. CONCLUSION: When faced with an interstitial lung disease on X-rays or a miliary pattern on CT-scans in advanced PLHIV, physicians in endemic areas, apart from tuberculosis or pneumocystosis, should include histoplasmosis as part of their differential diagnoses.

Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial.

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.

Impact of Malakit intervention on perceptions, knowledge, attitudes, and practices related to malaria among workers in clandestine gold mines in French Guiana: results of multicentric cross-sectional surveys over time.

BACKGROUND: Clandestine gold miners remain key hosts for malaria in French Guiana (FG) and contribute to imported malaria cases in Suriname and Brazil. The Malakit intervention, implemented in FG borders with Suriname and Brazil, provided gold miners with training on malaria and kits for self-diagnosis and self-treatment. Having shown a likely impact on malaria transmission, Suriname has now implemented it in routine care for cross-border moving populations. However, a decrease in malaria transmission is frequently associated with a decrease in risk perception, knowledge, and good practices regarding malaria. This study aims to describe the evolution of the perceptions, knowledge, attitudes, and practices (KAP) related to malaria among clandestine gold miners between 2015 and 2019, and to estimate the impact of Malakit on the FG/Suriname border. METHODS: The primary outcome was the overall KAP score over time and among participants and not participants in the Malakit intervention. A propensity score matching analysis and an inverse probability of treatment weighing analysis were used to estimate the Average Treatment effect on the Treated and the Average Treatment Effect of Malakit, respectively. RESULTS: Perception and knowledge scores were significantly lower in 2019 compared to 2015 (- 0.27 and - 0.23 points, respectively, p < 0.001) while attitude and practice scores were higher (+ 0.16 and + 0.47 points, respectively, p < 0.001). The overall KAP score was significantly higher among participants in Malakit with both propensity score matching (+ 0.72 points, 95%IC [0.29; 1.15]) and inverse probability of treatment weighting analysis (+ 0.70 points, 95%IC [0.34; 1.05]). CONCLUSION: A decrease in perception and knowledge about malaria but an improvement of attitudes and practices as the incidence of malaria decreased are observed. The Malakit intervention seems to have a significant positive impact on the overall KAP related to malaria. The integration of this strategy into malaria control programmes could help to improve the KAP, even in areas where malaria is nearly eliminated, through optimal training and health empowerment. Trial registration ClinicalTrials.gov registration number: NCT03695770.

Current situation of endemic mycosis in the Americas and the Caribbean: Proceedings of the first international meeting on endemic mycoses of the Americas (IMEMA).

BACKGROUND: The Americas are home to biologically and clinically diverse endemic fungi, including Blastomyces, Coccidioides, Emergomyces, Histoplasma, Paracoccidioides and Sporothrix. In endemic areas with high risk of infection, these fungal pathogens represent an important public health problem. OBJECTIVES: This report aims to summarise the main findings of the regional analysis carried out on the status of the endemic mycoses of the Americas, done at the first International Meeting on Endemic Mycoses of the Americas (IMEMA). METHODS: A regional analysis for the Americas was done, the 27 territories were grouped into nine regions. A SWOT analysis was done. RESULTS: All territories reported availability of microscopy. Seventy percent of territories reported antibody testing, 67% of territories reported availability of Histoplasma antigen testing. None of the territories reported the use of (1-3)-ß-d-glucan. Fifty two percent of territories reported the availability of PCR testing in reference centres (mostly for histoplasmosis). Most of the territories reported access to medications such as trimethoprim-sulfamethoxazole, itraconazole, voriconazole and amphotericin B (AMB) deoxycholate. Many countries had limited access to liposomal formulation of AMB and newer azoles, such as posaconazole and isavuconazole. Surveillance of these fungal diseases was minimal. CONCLUSIONS: A consensus emerged among meeting participants, this group concluded that endemic mycoses are neglected diseases, and due to their severity and lack of resources, the improvement of diagnosis, treatment and surveillance is needed.

Implementation of a novel malaria management strategy based on self-testing and self-treatment in remote areas in the Amazon (Malakit): confronting a-priori assumptions with reality.

BACKGROUND: A novel strategy to combat malaria was tested using a methodology adapted to a complex setting in the Amazon region and a hard-to-reach, mobile community. The intervention strategy tested was the distribution, after training, of malaria self-management kits to gold miners who cross the Surinamese and Brazilian borders with French Guiana to work illegally in the remote mining sites in the forest of this French overseas entity. MAIN TEXT: This article aims at presenting all process and implementation outcomes following the Conceptual Framework of Implementation Fidelity i.e. adherence, including content and exposure, and moderators, comprising participant responsiveness, quality of delivery, facilitation strategies, and context. The information sources are the post-intervention survey, data collected longitudinally during the intervention, a qualitative study, data collected during an outreach mission to a remote gold mining site, supervisory visit reports, in-depth feedback from the project implementers, and videos self-recorded by facilitators based on opened ended questions. As expected, being part of or close to the study community was an essential condition to enable deliverers, referred to as "facilitators", to overcome the usual wariness of this gold mining population. Overall, the content of the intervention was in line with what was planned. With an estimated one third of the population reached, exposure was satisfactory considering the challenging context, but improvable by increasing ad hoc off-site distribution according to needs. Participant responsiveness was the main strength of the intervention, but could be enhanced by reducing the duration of the process to get a kit, which could be disincentive in some places. Regarding the quality of delivery, the main issue was the excess of information provided to participants rather than a lack of information, but this was corrected over time. The expected decrease in malaria incidence became a source of reduced interest in the kit. Expanding the scope of facilitators' responsibilities could be a suitable response. Better articulation with existing malaria management services is recommended to ensure sustainability. CONCLUSIONS: These findings supplement the evaluation outcomes for assessing the relevance of the strategy and provide useful information to perpetuate and transfer it in comparable contexts. TRIAL REGISTRATION: ClinicalTrials.gov.  NCT03695770 . 10/02/2018 "Retrospectively registered".

FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer.

BACKGROUND: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. METHODS: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, ß = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. DISCUSSION: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. TRIAL REGISTRATION: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .

Review of diagnostic methods and results for HIV-associated disseminated histoplasmosis: Pathologists are not sufficiently involved.

OBJECTIVES: Disseminated histoplasmosis is a major killer of HIV-infected persons in Latin America. Antigen detection, fungal culture and Polymerase Chain Reaction are often not available, but cytology and histology are present in most hospitals and may offer a diagnostic alternative. In this study, we review 34 years of clinical experience to describe the roles of cytology and histology in diagnosing disseminated histoplasmosis. METHODS: Retrospective multicentric study of 349 patients between 1 January 1981 and 1 October 2014 with confirmed disseminated histoplasmosis. RESULTS: Around 32/214 (14.9%) of samples were screened using cytopathology, as were 10/101 (9.9%) bronchoalveolar lavage samples and 5/61 (8.2%) of spinal fluid samples. The samples most commonly sent to pathology were liver biopsies, lower digestive tract and lymphnode biopsies; the greatest proportion of positive results were found in lower digestive tract (43/59 (72.9%) positives), lymph node (39/63 (66.1%)), and liver (38/75 (50.7%)) samples. Overall, 97.2% of bone marrow and 97% of bronchoalveolar lavage samples were directly examined by a mycologist. Positive direct examination was independently associated with death (aHR = 1.5 (95%CI = 1-2.2)). CONCLUSIONS: Opportunities for a rapid diagnosis were regularly missed, notably for bone marrow samples, which could have been examined using staining methods complementary to those of the mycologist.

Cost-Utility Analysis of Continuation Versus Discontinuation of First-Line Chemotherapy in Patients With Metastatic Squamous-Cell Esophageal Cancer: Economic Evaluation Alongside the E-DIS Trial.

OBJECTIVES: Continuous chemotherapy has been used to treat patients with metastatic esophageal squamous cell carcinoma (mESCC), despite weak evidence supporting a clinical benefit, associated side effects for the patients, and unjustified medical costs. In the French setting, we conducted a cost-utility analysis alongside the randomized E-DIS trial (NCT01248299), which compared first-line fluorouracil/platinum-based chemotherapy continuation (CT-CONT) to CT discontinuation (CT-DISC) in progressive-free patients after an initial 6-week treatment phase. METHODS: A partitioned survival analysis was performed using patient-level data collected during the trial for survival outcomes, quality of life (EQ-5D-3L), and medical costs. The mean quality-adjusted life-years (QALYs) and medical costs were estimated over an 18-month period to assess the incremental net monetary benefit and incremental cost-effectiveness ratio. Uncertainty was handled using the nonparametric bootstrap and univariate analysis. Sixty-seven patients with mESCC were randomized and included in the cost-utility analysis. RESULTS: On average, CT-CONT slightly decreased the number of QALYs (-0.038) and increased the cost per patient (+ €1177). At a willingness-to-pay threshold of €50 000/QALY, the incremental net monetary benefit was negative (-€3077 [95% confidence interval: -6564; 4359]), and the incremental cost-effectiveness ratio was -30 958€/QALY (CT-CONT dominated). The probability of the CT-CONT treatment option being cost-effective at a willingness-to-pay threshold of €50 000/QALY, compared to CT-DISC, was 29%. CONCLUSIONS: CT-DISC may be considered as an alternative therapeutic option to CT-CONT in patients with mESCC who have stable disease after an initial chemotherapy treatment phase. A continuous chemotherapy could indeed reduce the number of QALYs because of the disutility associated with the continuous treatment.

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma.

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. Clinical trial registration: NCT04210115 (ClinicalTrials.gov).

Incidence and Trends in Immune Reconstitution Inflammatory Syndrome Associated With Histoplasma capsulatum Among People Living With Human Immunodeficiency Virus: A 20-Year Case Series and Literature Review.

BACKGROUND: Histoplasmosis is among the main acquired immunodeficiency syndrome (AIDS)-defining conditions in endemic areas. Although histoplasmosis has a worldwide distribution, histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with human immunodeficiency virus (PLHIV) is rarely reported.This study aimed to describe the incidence and features of histoplasmosis-associated IRIS in a cohort of PLHIV. METHODS: A retrospective multicenter study was conducted in French Guiana from 1 January 1997 to 30 September 2017. The target population was represented by PLHIV who presented an episode of histoplasmosis within 6 months after antiretroviral therapy initiation. We used a consensual IRIS case definition, submitted to the agreement of 2 experts. Each case was described using a standardized questionnaire, and all patients gave informed consent. RESULTS: Twenty-two cases of histoplasmosis-associated IRIS were included (14 infectious/unmasking and 8 paradoxical), with an overall incidence rate of 0.74 cases per 1000 HIV-infected person-years (95% confidence interval, 0.43-1.05). Mean age was 40.5 years. The ratio of males to females was 1:4. Median time to IRIS was 11 days (interquartile range 7-40 days) after antiretroviral therapy initiation. The main clinical presentation was fever, without any specific pattern, and disseminated disease. We reported 2 severe cases and partial or complete recovery at 1 month was the rule. Twenty-two cases were identified in the literature with similar characteristics. CONCLUSIONS: Histoplasmosis-associated IRIS incidence was low but generated significant morbidity in PLHIV. In endemic areas, screening for latent or subclinical histoplasmosis should be implemented before antiretroviral therapy initiation.

Re-drawing the Maps for Endemic Mycoses.

Endemic mycoses such as histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, and talaromycosis are well-known causes of focal and systemic disease within specific geographic areas of known endemicity. However, over the past few decades, there have been increasingly frequent reports of infections due to endemic fungi in areas previously thought to be "non-endemic." There are numerous potential reasons for this shift such as increased use of immune suppressive medications, improved diagnostic tests, increased disease recognition, and global factors such as migration, increased travel, and climate change. Regardless of the causes, it has become evident that our previous understanding of endemic regions for these fungal diseases needs to evolve. The epidemiology of the newly described Emergomyces is incomplete; our understanding of it continues to evolve. This review will focus on the evidence underlying the established areas of endemicity for these mycoses as well as new data and reports from medical literature that support the re-thinking these geographic boundaries. Updating the endemic fungi maps would inform clinical practice and global surveillance of these diseases.

Spatial dynamics and epidemiology for AIDS in remote areas in French Guiana.

Although AIDS care is generally improving in French Guiana, disparities among regions and certain key populations remain significant. The purpose of this study was to describe the spatial and clinical characteristics of people living with HIV (PLHIV) in remote areas in comparison to those followed in hospitals on the urban coast of French Guiana. The data presented were obtained from outpatient on primary care centers located in rural regions away from the urban coast. Data were compared with that from medical records of PLHIV treated in French Guiana's urban care. The evolution of the annual rate of discovery of HIV seropositivity indicates a lag in remote areas as compared to urban and coastal areas. In recent years, the epidemic appeared as particularly active in rural areas among Brazilian patients. The median age of PLHIV in remote areas was 43.8 years, the sex ratio (M/F) was 0.93. Nearly 37% of PLHIV were discovered with advanced disease (<200 CD4/mm3). The percentage of virological success after six months of HAART was 80% and 88% in remote areas and urban area, respectively. Efforts must be made to control and halt the spread of the HIV epidemic, as these remote sites represent strategic points.