Impact of a Moderate CYP3A4 Inducer (Bosentan) on Lurbinectedin Pharmacokinetics and Safety in Patients with Advanced Solid Tumors: An Open-Label, Two-Way, Crossover, Phase Ib Drug-Drug Interaction Study.

This open-label, two-way, crossover, phase Ib drug-drug interaction study investigated whether the pharmacokinetics (PKs) and safety profile of lurbinectedin (LRB) are affected by co-administration of a moderate CYP3A4 inducer (bosentan, BOS) in adult patients with advanced solid tumors. Eleven patients were randomly assigned to Sequence 1 (LRB + BOS in Cycle 1 [C1] and LRB alone in Cycle 2 [C2]) or Sequence 2 (LRB alone in C1 and LRB + BOS in C2), and finally, eight patients (four per sequence) were considered evaluable for PK assessment. LRB (3.2 mg/m2, 1 h [h], intravenous) was administered alone or combined with multiple BOS administration (125 mg/12 h oral; 5.5 days). Co-administration with BOS decreased the systemic total exposure (area under the curve, AUC) of LRB by 21% for AUC0-t and 20% for AUC0-∞ and increased clearance by 25%. Co-administration with BOS did not significantly modify the unbound plasma LRB PK parameters. BOS increased the conversion of LRB to its metabolite M1, with no changes on its metabolite M4. The LRB safety profile was consistent with the toxicities previously described for this drug. No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥30 days and without central nervous metastases.

OBJECTIVES: This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland. MATERIALS AND METHODS: Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients). RESULTS: Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan. CONCLUSION: With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan.

Pooled Safety Analysis of Single-Agent Lurbinectedin in Patients With Advanced Solid Tumours.

BACKGROUND: Lurbinectedin was approved by FDA and other health regulatory agencies for treating adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Safety profile at approved dose (3.2 mg/m2 every 3 weeks) was acceptable and manageable in 105 adult SCLC patients from a phase II basket trial. This study analyses safety data from several solid tumours treated at the lurbinectedin-approved dose. METHODS: Data were pooled from 554 patients: 335 from all nine tumour-specific cohorts of the phase II basket trial and 219 from a randomised phase III trial (CORAIL) in platinum-resistant ovarian cancer. Events and laboratory abnormalities were graded using NCI-CTCAE v.4. RESULTS: Most common tumours were ovarian (n = 219, 40%), SCLC (n = 105, 19%) and endometrial (n = 73, 13%). Transient haematological laboratory abnormalities were the most frequent grade 3 or more events: neutropenia (41%), leukopenia (30%), anaemia (17%) and thrombocytopenia (10%). Most common treatment-emergent non-haematological events (any grade) were transient transaminase increases (alanine aminotransferase [66%], aspartate aminotransferase [53%]), fatigue (63%), nausea (57%), constipation (32%), vomiting (30%) and decreased appetite (25%). Dose reductions were mostly due to haematological toxicities, but most patients (79%) remained on full lurbinectedin dose. Serious events mostly consisted of haematological disorders. Eighteen treatment discontinuations (3%) and seven deaths (1%) were due to treatment-related events. CONCLUSIONS: This analysis confirms a manageable safety profile for lurbinectedin in patients with advanced solid tumours. Findings are consistent with those reported in patients with relapsed SCLC, Ewing sarcoma, germline BRCA1/2 metastatic breast cancer, neuroendocrine tumours and ovarian cancer.

Lurbinectedin in patients with pretreated endometrial cancer: results from a phase 2 basket clinical trial and exploratory translational study.

Second-line treatment of endometrial cancer is an unmet medical need. Lurbinectedin showed promising antitumor activity in a phase I study in combination with doxorubicin in advanced endometrial cancer. This phase 2 Basket trial evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 73 patients with pretreated endometrial cancer. The primary endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and an exploratory translational study. Confirmed complete (CR) and partial response (PR) was reported in two and six patients, respectively (ORR = 11.3%; 95%CI, 5.0-21.0%). Median DoR was 9.2 months (95%CI, 3.4-18.0 months), median PFS was 2.6 months (95%CI, 1.4-4.0 months) and median OS was 9.3 months (95%CI, 6.1-12.8 months). Molecular subtypes showed differences in PFS rate at 6 months (p53abn 23.7% vs. "No Specific Molecular Profile" [NSMP] 42.9%) and median OS (p53abn 6.6 months vs. NSMP 16.1 months). The most common treatment-related adverse events (mostly grade 1/2) were fatigue (54.8% of patients), nausea (50.7%), vomiting (26.0%) decreased appetite (17.8%). and constipation, (19.2%). The most common grade 3/4 toxicity was neutropenia (43.8%; grade 4, 19.2%; febrile neutropenia, 4.1%). In conclusion, considering the exploratory aim of this trial and the hints of antitumor activity observed together with a predictable and manageable safety profile, further biomarker-based development of lurbinectedin is recommended in this indication in combination with other agents. Clinicaltrials.gov identifier: NCT02454972.

The influence of the Artisan-Verisyse position on the postoperative outcomes: A systematic review and meta-analysis.

Iris-fixated intraocular lens (IOL) is considered a safe and effective option for the correction of aphakia in patients with insufficient capsular support. This systematic review aims to summarize the existing evidence about the Artisan/Verisyse IOLs and to assess the influence of the IOL position on the postoperative outcomes. Three different databases were used for this systematic review and metaanalysis (PubMED, Scopus, and Embase). We searched for case series or clinical trials comparing the prepupillary versus retropupillary Artisan/Verisyse implantation. The statistical analysis was performed with the programming language R (version 3.6.1 2019-07-05). The number of articles included in the meta-analysis was six, with 506 eyes included in total. We found no significant differences in postoperative corrected distance visual acuity (CDVA) (0.309 [0.089-0.528] vs. 0.32 [0.2-0.44]), spherical equivalent (SE) (0.0153 D [-0.362 to 0.393] vs. -0.329 D [-0.62 to - 0.038]), and central corneal cell density (CECD) (1669.85 cells [1605.949-2150.937] vs. 1635.99 cells [1413.64-1858.363]) between the prepupillary and the retropupillary implantation, respectively. There were no significant differences in the rates of cystoid macular edema (CME; 7.70% vs. 9.8%), pupil deformation (4.5% vs. 5.4% retropupillary), or IOL luxation (2.3% and 2.2%). We found little influence of the IOL position in the postoperative analyzed outcomes. Thus, the implant position should be based on the surgeon's technical experience. Double-blind randomized prospective studies would improve the available evidence on the best implant position for the Artisan/Verisyse IOL.

Lurbinectedin in patients with pretreated neuroendocrine tumours: Results from a phase II basket study.

BACKGROUND: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. PATIENTS AND METHODS: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). CONCLUSIONS: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population. TRIAL REGISTRATION NUMBER: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42. CLINICALTRIALS: gov reference: NCT02454972.

Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study.

PURPOSE: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. PATIENTS AND METHODS: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. RESULTS: ORR was 14.3% [95% confidence interval (CI), 4.0%-32.7%], with median duration of response of 4.2 months (95% CI, 2.9-5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5-18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. CONCLUSIONS: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

Experiencias de salud mapuche en Atención Primaria de Salud desde trabajadores sanitarios y usuarios/as en zona urbana de Chile / Mapuche health experiences in Primary Health Care from health workers and users in urban Chile

Resumen Este estudio describe experiencias y percepciones sobre interculturalidad en Atención Primaria de Salud (APS) desde la perspectiva de trabajadores/as y usuarios/as de salud mapuche. Se realizó una sistematización cualitativa de experiencias de un Programa de Salud Intercultural en APS en una comuna urbana de Chile. Participaron 19 usuarios/as y 13 trabajadores/as en entrevistas individuales y tres entrevistas grupales, respectivamente. Se realizó un análisis de contenido semántico. Para los participantes, la salud mapuche es percibida positivamente, los/as usuarios/as la asimilan al concepto de interculturalidad, mientras que los/as trabajadores/as señalan que, si bien se respeta, no se promueve un trabajo integrado. Los/las participantes identifican como barreras aspectos administrativos, falta de integración y cuestionamientos científicos. Se requiere reconocimiento de la salud indígena y mayor formación de trabajadores/as sobre salud indígena e interculturalidad.

Abstract This study describes experiences and perceptions on interculturality in Primary Health Care (PHC) from the perspective of health workers and Mapuche health users. For this purpose, a qualitative systematization of these experiences was carried out in a PHC Intercultural Health Program at an urban commune in Chile. Data were collected by means of individual and group interviews, respectively, with 19 users and 13 professionals. The semantic content analysis was performed. While service users perceive Mapuche health positively, assimilating it to the concept of interculturality, health workers reported that Mapuche health is respected but no integrated work is promoted. As barriers, participants cited administrative aspects, lack of integration, and scientific issues. In conclusion, recognition of indigenous health and greater occupational training on indigenous health and interculturality is necessary.

Abordaje quirúrgico y protésico para resolución de defecto Clase IV C de Zucchelli en el maxilar anterior. Reporte de Caso / Surgical and prosthetic approach for resolution of Zucchelli Class IV C defect in the anterior maxilla. Case report

RESUMEN: Se describe el caso clínico de una paciente de 37 años, sexo femenino, sana, con sonrisa gingival, la cual presentaba problemas estéticos en relación, a un implante en la 1.1, instalado hace 7 años, el implante no presentaba una correcta posición tridimensional, correspondiendo a una Clase IVc de Zucchelli. El presente reporte clínico describe los pasos quirúrgicos y protésicos para resolver la estética del maxilar anterior pasando de un PES/WES inicial de 8 a un valor final de 16.

ABSTRACT: We describe the clinical case of a 37-year-old female patient, healthy, with a gingival smile, who had aesthetic problems in relation to an implant in 1.1, installed 7 years ago. The implant did not present a correct three-dimensional position, corresponding to a Class IVc according to Zucchelli. This clinical report describes the surgical and prosthetic steps to resolve the aesthetics of the anterior maxilla, going from an initial PES / WES of 8 to a final value of 16.

Preliminary Evaluation of the Clinical Benefit of a Novel Visual Rehabilitation Program in Patients Implanted with Trifocal Diffractive Intraocular Lenses: A Blinded Randomized Placebo-Controlled Clinical Trial.

The authors of this study evaluated the potential benefit on visual performance of a novel 3 week visual rehabilitation program based on the use of Gabor patches in patients undergoing bilateral cataract surgery with the implantation of two models of trifocal diffractive intraocular lens (IOL). A total of 30 patients were randomly assigned to two groups: a study group (15 patients) that used a videogame based on Gabor patches and a placebo group (15 patients) that used a videogame without specific stimuli for improving visual performance. No statistically significant differences between groups were found in distance, intermediate, and near post-training visual acuity (p ≥ 0.15). Significantly better distance contrast sensitivity (CS) was found for the spatial frequencies of 6 (p = 0.02) and 12 cpd (p = 0.01) in the study group. Likewise, significantly better values of near CS were found in the study group compared to the placebo group for the spatial frequency of 1.5 cpd (p = 0.02). In conclusion, a 3 week visual rehabilitation program based on the use of Gabor patches in the immediate postoperative period after the bilateral implantation of trifocal diffractive IOLs seems to be beneficial for improving both distance and near visual performance achieved with the implant.

Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL).

OBJECTIVE: The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. METHODS: Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1-5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months), and prior chemotherapy lines (1-2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov, NCT02421588. RESULTS: 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1-3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7-3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. CONCLUSIONS: The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

Relationship between Prenatal or Postnatal Exposure to Pesticides and Obesity: A Systematic Review.

In recent years, the worldwide prevalence of overweight and obesity among adults and children has dramatically increased. The conventional model regarding the onset of obesity is based on an imbalance between energy intake and expenditure. However, other possible environmental factors involved, such as the exposure to chemicals like pesticides, cannot be discarded. These compounds could act as endocrine-disrupting chemicals (EDC) that may interfere with hormone activity related to several mechanisms involved in body weight control. The main objective of this study was to systematically review the data provided in the scientific literature for a possible association between prenatal and postnatal exposure to pesticides and obesity in offspring. A total of 25 human and 9 animal studies were analyzed. The prenatal, perinatal, and postnatal exposure to organophosphate, organochlorine, pyrethroid, neonicotinoid, and carbamate, as well as a combined pesticide exposure was reviewed. This systematic review reveals that the effects of pesticide exposure on body weight are mostly inconclusive, finding conflicting results in both humans and experimental animals. The outcomes reviewed are dependent on many factors, including dosage and route of administration, species, sex, and treatment duration. More research is needed to effectively evaluate the impact of the combined effects of different pesticides on human health.

Pesticides and aging: Preweaning exposure to Chlorpyrifos induces a general hypomotricity state in late-adult rats.

The molecular and behavioral effects of the developmental exposure to low doses of Chlorpyrifos (CPF) have been intensively studied in young (neonates and adolescents), and adult animals. However, no study examined influences of developmental CPF exposure in older adult or geriatric rats. This is relevant as such ages are generally linked to cognitive decline and the onset of specific neurodegenerative disorders, some of them previously associated with CPF exposure in both preclinical and human studies. 1 mg/kg/mL of CPF was orally administered to both male and female Wistar rats from Postnatal day 10 to 15. Animals' spatial memory, learning, compulsivity, motricity, and anxiety were analyzed with Morris Water Maze (15-16 months of age) and the Plus-maze (at 18 months of age). Results showed that postnatal CPF exposure did not alter either spatial memory, compulsive-like behaviors, or anxiety levels in late-adult rats. However, CPF exposed rats were hyposensitive to brief disruptions (Probe stage) following the learning phase and showed a general decrease in locomotor activity in both paradigms. These data are relevant as it is the first time that developmental exposure to CPF has been studied at such a late age, observing important effects in locomotor activity that could be linked to specific pathologies previously associated with CPF effects in people. Future studies should extend these findings to other behaviors and molecular outcomes.

Relationship between Autism Spectrum Disorder and Pesticides: A Systematic Review of Human and Preclinical Models.

Autism spectrum disorder (ASD) is a complex set of neurodevelopmental pathologies characterized by impoverished social and communicative abilities and stereotyped behaviors. Although its genetic basis is unquestionable, the involvement of environmental factors such as exposure to pesticides has also been proposed. Despite the systematic analyses of this relationship in humans, there are no specific reviews including both human and preclinical models. The present systematic review summarizes, analyzes, and discusses recent advances in preclinical and epidemiological studies. We included 45 human and 16 preclinical studies. These studies focused on Organophosphates (OP), Organochlorine (OC), Pyrethroid (PT), Neonicotinoid (NN), Carbamate (CM), and mixed exposures. Preclinical studies, where the OP Chlorpyrifos (CPF) compound is the one most studied, pointed to an association between gestational exposure and increased ASD-like behaviors, although the data are inconclusive with regard to other ages or pesticides. Studies in humans focused on prenatal exposure to OP and OC agents, and report cognitive and behavioral alterations related to ASD symptomatology. The results of both suggest that gestational exposure to certain OP agents could be linked to the clinical signs of ASD. Future experimental studies should focus on extending the analysis of ASD-like behaviors in preclinical models and include exposure patterns similar to those observed in human studies.

Tratamiento protésico y quirúrgico del maxilar atrófico / Prosthetic and surgical treatment of the atrophic maxilla

RESUMEN: Proponer un plan de tratamiento con técnicas quirúrgicas y protocolos protésicos predecibles representa un gran desafío profesional, especialmente en pacientes con un maxilar atrófico. Entre las alternativas terapéuticas, la prótesis híbrida sobre cuatro implantes dentales correctamente distribuidos permite formar un área de distribución de carga, la cual guarda relación con las necesidades biomecánicas del elemento protésico.

ABSTRACT: Proposing a treatment plan with surgical techniques and predictable prosthetic protocols means a great professional challenge, especially in patients with an atrophic maxilla. Among the therapeutic alternatives, the hybrid prosthesis on four correctly distributed dental implants, allows to form a load distribution area, which is related to the biomechanical needs of the prosthetic element.

Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment.

INTRODUCTION: The National Comprehensive Cancer Network guidelines recommend re-challenge with the first-line treatment for relapsed small cell lung cancer (SCLC) with chemotherapy-free interval (CTFI)≥180 days. A phase II study (NCT02454972) showed remarkable antitumor activity in SCLC patients treated with lurbinectedin 3.2 mg/m2 1 -h intravenous infusion every 3 weeks as second-line therapy. We report results for the pre-planned subset of patients with CTFI ≥ 180 days. MATERIAL AND METHODS: Twenty patients aged ≥18 years with pathologically proven SCLC diagnosis, pretreated with only one prior platinum-containing line, no CNS metastases, and with CTFI ≥ 180 days were evaluated. The primary efficacy endpoint was the overall response rate (ORR) assessed by the Investigators according to RECIST v1.1. RESULTS: ORR was 60.0 % (95 %CI, 36.1-86.9), with a median duration of response of 5.5 months (95 %CI, 2.9-11.2) and disease control rate of 95.0 % (95 %CI, 75.1-99.9). Median progression-free survival was 4.6 months (95 %CI, 2.6-7.3). With a censoring of 55.0 %, the median overall survival was 16.2 months (95 %CI, 9.6-upper level not reached). Of note, 60.9 % and 27.1 % of patients were alive at 1 and 2 years, respectively. The most common grade 3/4 adverse events and laboratory abnormalities were hematological disorders (neutropenia, 55.0 %; anemia; 10.0 % thrombocytopenia, 10.0 %), fatigue (10.0 %) and increased liver function tests (GGT, 10 %; ALT and AP, 5.0 % each). No febrile neutropenia was reported. CONCLUSION: Lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with CTFI ≥ 180 days, with acceptable safety and tolerability. These encouraging results suggest that lurbinectedin can be another valuable therapeutic option rather than platinum re-challenge.

Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial.

BACKGROUND: Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. METHODS: In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972. FINDINGS: Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. INTERPRETATION: Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. FUNDING: Pharma Mar.

Salud intercultural en Chile: desarrollo histórico y desafíos actuales / Intercultural health in Chile: historical development and current challenges

RESUMEN En 1992, Chile implementó por primera vez un programa de salud para los pueblos indígenas, el Programa de Salud para Población Mapuche (Promap), cuyo objetivo fue entregar una atención de salud con pertinencia cultural, favoreciendo la complementariedad entre los sistemas médico indígena y el sistema oficial. La versión actual de esa iniciativa - el Programa especial de Salud para Pueblos Indígenas (PESPI) - ha logrado llegar con este enfoque a casi la totalidad de los Servicios de Salud del país. La revisión que el mundo académico ha hecho de estas experiencias, basados en la salud pública o en la antropología médica, se ha centrado en el análisis de las iniciativas llevadas en contextos indígenas rurales, desde el punto de vista de las dificultades que han debido enfrentar y las nociones de interculturalidad en salud que han logrado consolidar. Sin embargo, poco se ha abordado este programa en los contextos urbanos (espacio en que mayoritariamente están ocupando hoy nuestros pueblos indígenas) o desde el punto de vista de las nociones de interculturalidad en salud que implican. Considerando lo anterior, el artículo ofrece una revisión temática de publicaciones científicas nacionales e internacionales acerca del tema, un análisis crítico de los programas de salud intercultural desarrollados en Chile y una reflexión acerca de sus desafíos en el marco de la dinámica indígena urbana.(AU)

ABSTRACT In 1992, Chile implemented for the first time a health program for indigenous peoples, the Health Program for the Mapuche Population (PROMAP), whose objective was to provide health care with cultural relevance, favoring the complementarity between the indigenous medical systems and the official system The current version of this initiative - named PESPI - has managed to reach almost all the Health Services in the country with this approach. The review that the academic world has made of these experiences, based on public health or medical anthropology, has focused on the analysis of the initiatives taken in rural indigenous contexts, from the point of view of the difficulties they have had to face and the meaning of the interculturality in health that they have managed to consolidate. However, little has been said about this program in urban contexts (currently, a space which our indigenous peoples are occupying progresively) or from the point of view of the notions of interculturality in health that they imply. Considering the above, the article offers a thematic review of national and international scientific publications on the subject, a critical analysis of intercultural health programs developed in Chile and a reflection on their challenges in the framework of urban indigenous dynamics.(AU)

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy.

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Ultra-Violet Light Emission from HPV-G Cells Irradiated with Low Let Radiation From (90)Y; Consequences for Radiation Induced Bystander Effects.

In this study, we aimed to establish the emission of UV photons when HPV-G cells and associated materials (such as the cell substrate and cell growth media) are exposed to low LET radiation. The potential role of UV photons in the secondary triggering of biological processes led us to hypothesize that the emission and absorption of photons at this wavelength explain some radiation induced "bystander effects" that have previously been thought to be chemically mediated. Cells were plated in Petri-dishes of two different sizes, having different thicknesses of polystyrene (PS) substrate, and were exposed to ß-radiation from (90)Y produced by the McMaster Nuclear Reactor. UV measurements were performed using a single photon counting system employing an interference-type filter for selection of a narrow wavelength range, 340±5 nm, of photons. Exposure of the cell substrates (which were made of polystyrene) determined that UV photons were being emitted as a consequence of ß particle irradiation of the Petri-dishes. For a tightly collimated ß-particle beam exposure, we observed 167 photons in the detector per unit µCi in the shielded source for a 1.76 mm thick substrate and 158 photons/µCi for a 0.878 mm thick substrate. A unit µCi source activity was equivalent to an exposure to the substrate of 18 ß-particles/cm(2) in this case. The presence of cells and medium in a Petri-dish was found to significantly increase (up to a maximum of 250%) the measured number of photons in a narrow band of wavelengths of 340±5 nm (i.e. UVA) as compared to the signal from an empty control Petri-dish. When coloured growth medium was added to the cells, it reduced the measured count rate, while the addition of transparent medium in equal volume increased the count rate, compared to cells alone. We attribute this to the fact that emission, scattering and absorption of light by cells and media are all variables in the experiment. Under collimated irradiation conditions, it was observed that increasing cell density in medium of fixed volume resulted in a decrease in the observed light output. This followed a roughly exponential decline. We suggest that this may be due to increased scattering at the cell boundary and absorption of the UV in the cells. We conclude that we have measured UVA emitted by cells, cell medium and cell substrates as a consequence of their irradiation by low LET ß-particle radiation. We suggest that these secondary UV photons could lead to effects in non-targetted cells. Some effects that had previously been attributed to a chemically mediated "bystander effect" may in fact be due to secondary UV emission. Some radiation bystander effect studies may require re-interpretation as this phenomenon of UV emission is further investigated.