Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. METHODS: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB node positive vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49-1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

A community-specific framework of risk factors for youth violence: A qualitative comparison of community stakeholder perspectives in a low-income, urban community.

This study offers a qualitative comparison of risk factors for youth violence from the perspectives of community stakeholders in a low-income, urban community experiencing elevated rates of violence. One-on-one interviews were conducted with 36 community stakeholders across three key categories: 10 community residents who cared for youth living in the community, 15 program or service providers, and 11 leaders in community agencies and organizations. A grounded theory approach was used for data collection and analysis to extract themes that emerged from the question, "What are the things in the community that lead to youth violence?" While there was significant overlap in stakeholders' beliefs about precursors to youth violence, important differences also emerged. In order for youth violence prevention strategies to be successful, they must consider and address risk factors identified by community stakeholders involved in the implementation and sustainability.

Validation of the T86I mutation in the gyrA gene as a highly reliable real time PCR target to detect Fluoroquinolone-resistant Campylobacter jejuni.

BACKGROUND: Campylobacter jejuni is a leading cause of bacterial diarrhea worldwide, and increasing rates of fluoroquinolone (FQ) resistance in C. jejuni are a major public health concern. The rapid detection and tracking of FQ resistance are critical needs in developing countries, as these antimicrobials are widely used against C. jejuni infections. Detection of point mutations at T86I in the gyrA gene by real-time polymerase chain reaction (RT-PCR) is a rapid detection tool that may improve FQ resistance tracking. METHODS: C. jejuni isolates obtained from children with diarrhea in Peru were tested by RT-PCR to detect point mutations at T86I in gyrA. Further confirmation was performed by sequencing of the gyrA gene. RESULTS: We detected point mutations at T86I in the gyrA gene in 100% (141/141) of C. jejuni clinical isolates that were previously confirmed as ciprofloxacin-resistant by E-test. No mutations were detected at T86I in gyrA in any ciprofloxacin-sensitive isolates. CONCLUSIONS: Detection of T86I mutations in C. jejuni is a rapid, sensitive, and specific method to identify fluoroquinolone resistance in Peru. This detection approach could be broadly employed in epidemiologic surveillance, therefore reducing time and cost in regions with limited resources.

Clinicopathological features, response patterns, outcomes and BRAF status in patients with advanced acral melanoma: a preliminary Peruvian study.

Background: Globally, acral melanoma (AM) is underrepresented in most clinical trials, being predominant in Caucasian populations. Latin America is a niche that needs to be explored. Therefore, this study aimed to determine the clinical features, response patterns, outcomes and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) status in Peruvian patients with advanced AM. Methods: We retrospectively reviewed the medical records of 19 patients with advanced AM who received immunotherapy (IO) in first- or subsequent-line therapy. The samples were analysed, and their mutational state was performed by deoxyribonucleic acid sequencing, focusing primarily on the most frequently mutated gene, BRAF. Descriptive statistics were used to assess the baseline characteristics. Overall survival was estimated using the Kaplan-Meier method. Results: The median age was 64 years and 63.2% were men. Plantar was the site most frequently affected (84.2%). The most frequent stage was stage III (68.4%), with 26.4% receiving adjuvant therapy. The majority of cases exhibited a Breslow thickness of >4 mm (52%), a Clark level of IV/V (89.4%), and all patients presented ulceration and a high range of mitosis. During follow-up, all patients experienced recurrent advanced disease, with 52.6% developing visceral metastasis. Patients who received IO as first or subsequent line had an overall response rate (ORR) of 33.3%, and those who received it as first-line therapy had an ORR of 40%. Twenty-one percent of the patients harbored BRAF V6000E mutation and, showing an ORR of 50% compared to wild-type individuals (44.4%) after the first line of treatment. Conclusion: Our preliminary study reported that AM has poor clinico-pathological features and response rates to IO in Peruvian patients. However, those who received IO as a first-line treatment or harbored the BRAF mutation appeared to have a slightly better response than wild-type patients.

Environmental assessment of mercury pollution in urban tailings from gold mining.

It is well-known that small-scale artisanal mining is a source of mercury emissions into the environment, mainly from the use of rudimentary technologies that use mercury amalgamation in the extraction process. Mines near Andacollo, which is located in the Coquimbo region of Chile, use primitive methods to mine gold and copper. In this study, we determined the mercury content of gold mining wastes from Andacollo. At each site, we randomly sampled the soil at the surface and at a depth of 2 m following the ISO 10381 guidelines. Mercury analysis was performed with a direct mercury analyzer. At least one site was contaminated at a mercury concentration of 13.6±1.4 mg kg(-1), which was above the international recommendations that were set by the Canadian Council of Ministers of the Environment's soil quality guidelines (CA-SQG) and the Dutch guidelines (NL-RIVM). At least four of the fourteen sites in this study were within the control and tolerance levels of these recommendations. Better characterization of these sites is required to establish whether they represent a risk to the local community. Based on the US-EPA recommendations, which have a higher tolerance limit, none of the fourteen sites should pose a risk to humans.

Recomendaciones clínicas para el manejo de pacientes oncológicos en el marco de la pandemia COVID-19 / Clinical Recommendations For The Management Of Cancer Patients In The Context Of The COVID-19 Pandemic

La enfermedad por la nueva cepa de Coronavirus (COVID-19) ha sido catalogada como una pandemia por la OMS. En el Perú, se decretó estado de emergencia nacional y aislamiento social obligatorio desde el 15 de marzo. Los sistemas de salud a nivel mundial han sufrido un gran impacto debido la infección por COVID-19, lo cual obligó a los sistemas de salud, sociedades y asociaciones médicas a diseñar estrategias de intervención priorizada para dar continuidad a la atención de los pacientes en áreas COVID-19 y áreas libres de COVID-19. El paciente con cáncer es catalogado como vulnerable y representa un factor de riesgo para complicaciones, como ingreso a unidad de cuidados intensivos, intubación y muerte temprana por infección por COVID-19. Es así como la Asociación de Médicos Ex-Residentes de Oncología Médica (AMEROM), ha realizado esfuerzos para poder realizar recomendaciones adaptables a nuestro sistema de salud, con la finalidad de dar continuidad a la atención priorizada de los pacientes con cáncer. Mediante la metodología modificada de consenso de expertos, bajo el sustento bibliográfico, se han generado recomendaciones en diferentes etapas de la pandemia, llegando a un consenso final con recomendaciones clínicas para el manejo de pacientes oncológicos en el marco de la pandemia COVID-19 en Perú, con el fin de brindar información útil para los profesionales de la salud. El presente artículo indica los procesos con los que se llegaron a los acuerdos para dictar las recomendaciones y generar el orden de prioridad adoptado por AMEROM.

The disease by the new coronavirus strain (COVID-19) has been classified as apandemic by the WHO. In Peru, a state of national emergency and compulsory socialisolation had been declared since 15 March. Global health systems have been greatlyimpacted by COVID-19, which forced health systems, societies and medicalassociations to design prioritized intervention strategies to provide continuity of patientcare in infected areas and COVID-19-free areas. A cancer patient is classified asvulnerable and represents a risk factor for complications due to COVID-19, such asadmission to the intensive care unit, intubation, and early death due to infection due toCOVID-19. This is how the Asociación de Médicos Ex Residentes de OncologíaMédica (AMEROM), has endeavored to give recommendations adaptable to our healthsystem, to continue with the prioritized care of cancer patients. Through the modifiedmethodology of expert consensus, based on the literature, recommendations have beengenerated at different stages of the pandemic, reaching a final consensus of clinicalrecommendations for the management of cancer patients in the framework of theCOVID-19 pandemic in Peru, to provide useful information to health professionals.This article indicates the processes by which agreements were reached to makerecommendations and generate the order of priority adopted by AMEROM.

Uncertainty of ozone measurements with the primary standard reference photometer (SRP45).

A comparison of the ozone primary reference standard photometer serial number 45 (SRP45) against the National Institute of Standards and Technology (NIST) instruments, serial number 0 (SRP0) and 2 (SRP2), has been performed in order to establish the traceability and comparability of ozone measurements made by the Chilean atmospheric science community. A complete uncertainty budget was developed for SRP45, using a GUM approach. The results of the comparisons allow us to conclude that SRP45, SRP0 and SRP2 are comparable according to international criteria over an ozone mole fraction range of 0 nmol mol(-1) to at least 500 nmol mol(-1). The official result for the validation of SRP45 is x(ozone)(SRP45)=[0.013+0.99806x(ozone)(SRP2)] nmol mol(-1) with an expanded uncertainty of [Formula in text] from 0 to 500 nmol mol(-1).

Inmunizaciones: lo viejo, lo nuevo y lo por venir / Immunizations: the old, the new and the for coming

Sobre un tema tan apasionante y donde el avance del conocimiento se está efectuando a pasos tan agigantados, sin duda podría escribirse mucho. Esta breve síntesis sólo pretende dar una idea global acerca del problema y las principales líneas de investigación que intentan lograr mayor eficiencia, menores riesgos y solucionar el problema de controlar enfermedades que aún permanecen sin un medio eficiente para conseguirlo