Multidisciplinary approach to COVID-19 and cancer: consensus from scientific societies in Argentina.

INTRODUCTION: The world is living through an outbreak of an acute respiratory syndrome caused by a new betacoronavirus known as coronavirus 2 (SARS CoV-2), which has been declared an international public health emergency by the World Health Organisation. Cancer patients are a very special population in this setting since they are more susceptible to viral infections than the general population. Several recommendations have been made on this issue, most of them based on expert opinion and institutional experience. It is essential to gather the evidence available for decision making. OBJECTIVE: To review the evidence available in order to create a multi-institutional position from the perspective of scientific societies in Argentina involved in the management of cancer patients. METHODOLOGY: The review included two phases: 1) search and systematic revision of the medical literature; 2) consensus and revision of the document drafted by national scientific societies involved in the management and care of cancer patients using the modified Delphi method. The final results were presented at a videoconference with all the participants. Also, additional comment and recommendations were discussed. The final document was revised and approved for publication by the members of the panel. RESULTS: The consensus panel included 18 representatives from scientific societies from Argentina who assessed the evidence and then made recommendations for the management of cancer patients in our country. International guidelines (CDC; ASCO, NCCN and ESMO) were considered as a background for analysis, as well as institutional guidelines and an open ad hoc survey administered to 114 healthcare professionals from the scientific societies involved in this study.The recommendations are grouped as follows: 1) general care interventions-training of the personnel, cleaning and disinfection of the hospital premises and patient scheduling; 2) treatment decisions-patient care, surgeries, immunosuppressive therapy, radiotherapy and screening; 3) ethical considerations-optimisation of resources, end-of-life care for critically-ill patients; 4) management of hospitalised patients; and 5) wellbeing of the healthcare team.The general recommendation arising from the study is that the management of cancer patients must adapt to the exceptional pandemic status quo without disregarding treatment or cure options. Moreover, healthcare professional accompaniment of all patients should not be neglected. All healthcare professionals must make a significant joint effort to create multidisciplinary teams to discuss the most appropriate measures for each particular situation. CONCLUSIONS: The scientific evidence available on this topic worldwide is in progress. This together with the epidemiologically shifting scenario poses unprecedented challenges in the management of cancer amidst this global pandemic. Furthermore, the key role of the healthcare structural organisation appears evident, such as the drafting of clear guidelines for all the stakeholders, adaptability to constant change and an interdisciplinary shared vision through consensus to provide adequate care to our cancer patients in the light of uncertainty and fast-paced change.

Efficacy and Safety of Nivolumab in Previously Treated Patients With Non-Small-cell Lung Cancer: Real World Experience in Argentina.

BACKGROUND: Nivolumab was the first anti-programmed cell death 1 drug approved in Argentina for non-small-cell lung cancer treatment in the second-line setting. MATERIALS AND METHODS: The present study was a multicenter, observational, retrospective study of patients with progression to stage IV NSCLC during platinum-based chemotherapy who had received nivolumab monotherapy in a drug-expanded access program in Argentina. RESULTS: The data from 109 patients were assessed retrospectively for safety and clinical outcomes. The follow-up period was 8.83 months (interquartile range, 3.4-12.67); 57.8% were men, 29.4% were current smokers, and 78.0% had a diagnosis of nonsquamous cell cancer. The median number of chemotherapy lines before nivolumab was 2 (range, 1-4). Also, 59.6% had received radiotherapy and 89% had received platinum-based chemotherapy. The drug-related toxicity rate was 78.9%, the grade 2-3 toxicity rate was 28.4%, and 33.9% of patients had required corticosteroids. The treatment response was evaluated in 104 patients. The best response was a complete response in 2 (2%), partial response in 28 (27%), stable disease in 33 (32%), and progressive disease in 41 (39%). Univariate analysis revealed that the absence of corticosteroid use (P = .034), toxicity grade 1-3 (P = .0025), and performance status of ≤ 1 (P = .049) were associated with longer disease-free survival, performance status of ≤ 1 (P < .001), and toxicity grade 1-3 (P = .001) were associated with longer overall survival. On multivariate Cox regression analysis, toxicity grade 1-3 (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.81; P = .008) and age ≤ 50 years (HR, 0.28; 95% CI, 0.13-0.61; P = .001) were associated with longer progression-free survival and corticosteroid use was associated with shorter progression-free survival (HR, 2.06; 95% CI, 1.22-3.48; P = .007). CONCLUSIONS: The use of nivolumab in the real world setting in patients with heavily pretreated NSCLC was well tolerated and showed promising clinical efficacy. The performance status, use of corticosteroids, and immune-mediated toxicity seem to be the conditions that can affect the clinical outcomes.

Exposición al asbesto en casos de mesotelioma pleural en la República Argentina / Asbestos Exposure in Cases of Pleural Mesothelioma in the Argentine Republic

Introducción: El mesotelioma pleural es un tumor poco frecuente de alto grado de malignidad. Es considerada una enfermedad profesional cuyo desarrollo fue paralelo al uso industrial del asbesto. En Argentina, el asbesto fue prohibido en el año 2003. El objetivo de este estudio fue conocer las características clínicas, de diagnóstico y tratamiento del mesotelioma pleural y determinar las características de exposición al asbesto en 40 casos de mesotelioma en distintas regiones de la República Argentina. Materiales y métodos: Se trata de un estudio descriptivo y multicéntrico. Participaron hospitales de Buenos Aires, Tucumán, Córdoba y Rosario desde enero del 2013 a enero del 2015. Se recogieron los datos clínicos en un Formulario Médico y los antecedentes de exposición ambiental, doméstica y laboral en un Formulario de Exposición. Se clasificó a cada participante como expuesto, no expuesto o desconocido. Se consideró expuesto cuando tenían identificado al menos uno de los tres tipos de exposición laboral, ambiental o doméstica. Resultados: Se analizaron 40 casos de mesotelioma pleural, 55% masculinos; encontrando referencia de al menos una exposición al asbesto en el 75% de los casos, el 7,5% negó todas las posibles exposiciones y en el 17,5% la exposición resultó desconocida. La probabilidad de exposición ambiental fue del 57,5%, doméstica del 60% y laboral del 37%. Se encontró mayor proporción de varones con exposición laboral en forma estadísticamente significativa. Conclusión: El aporte del presente trabajo radica en la información sobre los distintos tipos de exposición al asbesto en casos de mesotelioma pleural en la República Argentina.

Asbestos Exposure in Cases of Pleural Mesothelioma in the Argentine Republic / Exposición al asbesto en casos de mesotelioma pleural en la República Argentina

Introduction: Pleural mesothelioma is a rare tumor with a high degree of malignancy. It is considered an occupational disease that has developed in parallel with the industrial use of asbestos. In Argentina, the asbestos was prohibited in 2003. The objective of this study is to know the clinical and diagnostic characteristics and treatment of pleural mesothelioma and to determine the characteristics of asbestos exposure in 40 cases of mesothelioma in different regions of the Argentine Republic. Materials and Methods: It is a descriptive, multicenter study. Hospitals from Buenos Aires, Tucumán, Córdoba and Rosario participated in this study from January 2013 until January 2015. Clinical data were recorded in a Medical Form, and history of environmental, domestic and occupational exposure was recorded in an Exposure Form. Each participant was classified as: exposed, not exposed or unknown. The patient was considered as "exposed" if he/she identified at least one of the three types of exposure: occupational, environmental or domestic. Results: 40 cases of pleural mesothelioma were analyzed, 55% of which were male. We found reference of at least one exposure to asbestos in 75% of the cases; 7.5% denied every possible type of exposure and in 17.5% exposure was unknown. The probability of exposure was: 57.5% environmental, 60% domestic and 37% occupational. There was a greater statistically significant proportion of men with occupational exposure. Conclusion: The contribution of this work relies on the information about the different types of asbestos exposure in cases of pleural mesothelioma in the Argentine Republic.

Analysis of EML4-ALK rearrangement in non-small cell lung cancer in Argentina.

INTRODUCTION: Identification of EML4-ALK rearrangement by FISH test has become standard in advanced NSCLC patients. There is limited information about the prevalence and clinical characteristics of ALK translocation in Latin America. The aim of our study was to evaluate this lung cancer subtype features in Argentinian patients and the factibility of FISH test with different methods used for obtaining tissue samples. METHODS: Between August 2014 and February 2017, 183 non-squamous NSCLC patients were prospectively enrolled from five Argentinian institutions. Different techniques and procedures were used to obtained tissue samples material. ALK determination was performed by FISH and immunohistochemistry (IHC). Correlation with clinico-pathological information and different biopsy procedures was assessed. RESULTS: From 183 non-squamous NSCLC samples, 131 could perform FISH test, finding 123 (93.9%) negative and 8 (6.1%) positive patients. Fifty-one samples were not evaluable by FISH, 35 because of technical problems and 16 due to not/weak signal. The difficulties in obtaining adequate FISH tests were observed significantly more frequently for fine-needle aspiration (FNA) and core-needle biopsy than for excisional and incisional biopsy (p = 0.009). Regarding the procedures, surgery was the most efficient, obtaining only 12.7% (10/79) of not evaluable samples for FISH, while CT guided biopsy and transbronchial biopsy (TBB) failed in 43.8% (21/48) and 41.3% (19/46) of patients respectively (p < 0.001). We observed a significant association between ALK translocation and never smoking habit (p = 0.004). CONCLUSION: Our ALK rearrangements frequency (6.1%) was similar to the reports worldwide. One of the major determinants for the ALK FISH test success is the quality of the tissue sample obtained.

Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice.

OBJECTIVE: The actual prevalence of drug induced QTc prolongation in clinical practice is unknown. Our objective was to determine the occurrence and characteristics of drug-induced QT prolongation in several common clinical practices. Additionally, a subgroup of patients treated with dextropropoxyphene of particular interest for the regulatory authority was analysed. RESEARCH DESIGN AND METHODS: Medical history and comorbidities predisposing to QT interval prolongation were registered for 1270 patient requiring medical assistance that involved drug administration. Three ionograms and ECGs were performed: baseline, intra- and after treatment; QT interval was corrected with Bazzet formula. RESULTS: Among patients, 9.9% presented QTc >450/470 ms, 3% QTc > 500 ms, 12.7% ΔQTc >30 ms and 5.2% ΔQTc >60 ms. QTc prolongation associated with congestive heart failure, ischemic cardiopathy, diabetes, renal failure, arrhythmias, hypothyroidism, and bradycardia. At univariate analysis, clarithromycin, haloperidol, tramadol, amiodarone, glyceryl trinitrate, amoxicillin + clavulanic acid, amoxicillin + sulbactam, ampicillin + sulbactam, fentanyl, piperacillin + tazobactam, and diazepam prolonged QTc. Prolongation remained significantly associated with furosemide, clarithromycin, glyceryl trinitrate and betalactamase inhibitors after multivariate analysis. CONCLUSION: QT interval prolongation in everyday practice is frequent, in association to clinical factors and drugs that can be easily identified for monitoring and prevention strategies.

Afatinib: El primer bloqueador irreversible de la familia ErbB aprobado para pacientes con cáncer de pulmón de células no pequeñas portadores de la mutación del EGFR / Afatinib: The first ErbB family irreversible blocker aproved for non-small cells lung cáncer patients with EGFR mutation

La desregulación del receptor ErbB (por sus siglas en inglés “proto-oncogen B of the avian erythroblastosis virus AEV-H strain”, en español proto-oncogén del virus de la eritroblastosis aviaria) es bien reconocido como un driver oncogénico en diferentes casos de cáncer epitelial. La vía de señalización del ErbB juega un rol importante en el desarrollo del tejido epitelial y la homeostasis. Al menos 10 ligandos distintos regulan la actividad de los receptores. La familia ErbB consta de 4 miembros: EGFR/HER1/ErbB1, HER2/ErbB-2neu, HER3/ ErbB-3 y HER4/ErbB-4. Varias moléculas que interactúan con estos receptores han sido desarrolladas. Entre ellas, anticuerpos monoclonales y moléculas pequeñas.

Afatinib: El primer bloqueador irreversible de la familia ErbB aprobado para pacientes con cáncer de pulmón de células no pequeñas portadores de la mutación del EGFR / Afatinib: The first ErbB family irreversible blocker aproved for non-small cells lung cáncer patients with EGFR mutation

La desregulación del receptor ErbB (por sus siglas en inglés ôproto-oncogen B of the avian erythroblastosis virus AEV-H strainö, en español proto-oncogén del virus de la eritroblastosis aviaria) es bien reconocido como un driver oncogénico en diferentes casos de cáncer epitelial. La vía de señalización del ErbB juega un rol importante en el desarrollo del tejido epitelial y la homeostasis. Al menos 10 ligandos distintos regulan la actividad de los receptores. La familia ErbB consta de 4 miembros: EGFR/HER1/ErbB1, HER2/ErbB-2neu, HER3/ ErbB-3 y HER4/ErbB-4. Varias moléculas que interactúan con estos receptores han sido desarrolladas. Entre ellas, anticuerpos monoclonales y moléculas pequeñas.(AU)

Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells.

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2-3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.

Antineoplastic chemotherapy induced QTc prolongation.

Anticancer drugs are sometimes associated with QT prolongation. Classical, new and candidate agents to treat cancer may affect ventricular repolarization through a set of different mechanisms. Interference on human ether-a-go-go-related gene potassium ion channels (HERG K+) seems to be a common mechanism for many of these drugs. Anthracycline chemotherapy is associated with electrocardiographic alterations including prolongation of QT interval, development of ventricular late potentials and various arrhythmias. The effects of the interaction of anthracyclines with the monoclonal antibody against HER2/neu (Erb-2) trastuzumab could potentiate the cardiotoxic effects. Electrocardiographic changes have been also reported with the use of 5-fluorouracil. QTc alterations have also been reported with some platinum compounds. Taxanes (paclitaxel and docetaxel) have also been associated with cardiotoxicity, promoting both bradi- and tachyarrhythmias and other cardiac disturbances. Among the newest compounds, symptomatic or asymptomatic QTc aberrations were reported with multitargeted tyrosine-kinase inhibitors, anti HERG2, anti-VEGF, vascular disruption agents and histone deacetylase inhibitors. Patients with cancer are at increased risk of sudden death due to severe cardiac arrhythmias because of the high prevalence of predisposing risk factors such as electrolytic abnormalities, starvation and concomitant medications. The use of specific anticancer drug that may prolong the QT interval need to be properly evaluated in each case to reduce this risk.

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer.

PURPOSE: We studied cisplatin plus gemcitabine as induction (neoadjuvant) therapy in patients with stage III non-small cell lung cancer (NSCLC) to assess its objective remission rate, resectability, survival, and toxicity. PATIENTS AND METHODS: Patients with stage III NSCLC received 2 cycles of gemcitabine 1250 mg/m2 on days 1, 8, and 15, plus cisplatin 100 mg/m2 on day 2. Subsequently, patients were assigned to local therapy--surgery or radiotherapy. RESULTS: Twenty-nine eligible patients (male/female: 21/8) with a median age of 59 years (range, 43-71 years) were enrolled between October 1996 and February 1999. A total of 80 cycles were given, with a median of 3 per patient (range, 1-4 cycles). Overall, toxicities were mild; only one patient had febrile neutropenia, and there were no grade 4 non-hematological toxicities. There was one toxic death following afebrile grade 4 neutropenia. Overall clinical response rate (2 complete responses [CRs] + 16 partial responses [PRs]) was 62% (95% CI, 45%-79%); 10 patients had stable disease and none progressed; one patient was not evaluable. Eight of the 18 operated patients had pathological response: 1 CR and 7 downstagings to N(-); 14 patients were resected. Median survival was 17 months (95% CI, 13-21 months), with 1-year and 2-year actuarial survival rates of 61% and 29%, respectively. CONCLUSIONS: Gemcitabine plus cisplatin is a very active and well-tolerated induction regimen in stage III NSCLC. Comparative studies with other standard regimens are warranted.