Autoimmune encephalitis related to nivolumab followed by tumor regression / Encefalitis autoinmune relacionada con nivolumab se guida de regresión tumoral

Abstract Immune checkpoints inhibitors have shown a re markable improvement in overall survival of stage IV renal cell carcinoma patients. Nevertheless, there is a wide range of immune-related adverse events (IRAE) that arise from these revolutionary treatments. Autoim mune encephalitis is a rare but severe central nervous system IRAE in these cancer patients. The severities of these IRAEs preclude patients from continuing im munotherapy treatment. Few cases of autoimmune encephalitis with immunotherapy have been described in the literature and optimal clinical management of these events as well as patient's immune-mediated response after treatment suspension is still unclear. Here, we report a case of a 67 years-old woman with stage IV renal cell carcinoma under treatment with nivolumab who developed autoimmune encephalitis. After high doses of corticosteroids patient's condition improved significantly with full recovery after 5 days of treatment. Even though nivolumab was not reinstalled, a persistent response of her oncologic disease was evi denced. We expect that this case can contribute to the existing literature of both subjects, the management of autoimmune encephalitis as grade IV immune related adverse event and the responses of immune checkpoint inhibitors after IRAE.

Resumen Los inhibidores de puntos de control inmunológico han mostrado una importante mejoría en la supervi vencia global de los pacientes con carcinoma de riñón estadio IV. Sin embargo, existe una amplia variedad de efectos adversos inmunomediados que surgen a partir de estos tratamientos revolucionarios. La encefalitis au toinmune es un infrecuente pero grave efecto adverso inmunomediado del sistema nervioso central en estos pacientes. La gravedad de este cuadro impide que los pa cientes continúen con el tratamiento de inmunoterapia. Se han descrito pocos casos de encefalitis autoinmune con inmunoterapia en la literatura y aún no está claro el manejo clínico óptimo de estos eventos, ni cómo continua la respuesta inmunomediada después de la suspensión del tratamiento. Presentamos el caso de una mujer de 67 años con carcinoma de células renales estadio IV que desarrolló encefalitis autoinmune durante el tratamiento con nivolumab. La paciente mejoró significativamente luego del inicio del tratamiento con altas dosis de cor ticoides, con una recuperación completa después de 5 días del mismo. Si bien el nivolumab no se reinició, se evidenció una respuesta persistente de su enfermedad oncológica. Esperamos que este caso pueda contribuir a la literatura existente de ambos temas, el manejo de la encefalitis autoinmune como efecto adverso inmunome diado grado IV y las respuestas que se obtienen con la inmunoterapia luego de estos efectos adversos.

Effect of receiving a customizable brochure on breast cancer patients' knowledge about their diagnosis and treatment: A randomized clinical trial.

BACKGROUND: Patients' lack of knowledge about their own disease may function as a barrier to shared decision-making and well-being. This study aimed to evaluate the impact of written educational materials on breast cancer patients. METHODS: This multicenter, parallel, unblinded, randomized trial included Latin American women aged ≥18 years with a recent breast cancer diagnosis yet to start systemic therapy. Participants underwent randomization in a 1:1 ratio to receive a customizable or standard educational brochure. The primary objective was accurate identification of molecular subtype. Secondary objectives included identification of clinical stage, treatment options, participation in decision-making, perceived quality of information received, and illness uncertainty. Follow-up occurred at 7-21 and 30-51 days post-randomization. CLINICALTRIALS: gov identifier: NCT05798312. RESULTS: One hundred sixty-five breast cancer patients with a median age of 53 years and 61 days from diagnosis were included (customizable: 82; standard: 83). At first available assessment, 52%, 48%, and 30% identified their molecular subtype, disease stage, and guideline-endorsed systemic treatment strategy, respectively. Accurate molecular subtype and stage identification were similar between groups. Per multivariate analysis, customizable brochure recipients were more likely to identify their guideline-recommended treatment modalities (OR: 4.20,p = 0.001). There were no differences between groups in the perceived quality of information received or illness uncertainty. Customizable brochure recipients reported increased participation in decision-making (p = 0.042). CONCLUSIONS: Over one third of recently diagnosed breast cancer patients are incognizant of their disease characteristics and treatment options. This study demonstrates a need to improve patient education and shows that customizable educational materials increase patients' understanding of recommended systemic therapies according to individual breast cancer characteristics.

Autoimmune encephalitis related to nivolumab followed by tumor regression.

Immune checkpoints inhibitors have shown a remarkable improvement in overall survival of stage IV renal cell carcinoma patients. Nevertheless, there is a wide range of immune-related adverse events (IRAE) that arise from these revolutionary treatments. Autoimmune encephalitis is a rare but severe central nervous system IRAE in these cancer patients. The severities of these IRAEs preclude patients from continuing immunotherapy treatment. Few cases of autoimmune encephalitis with immunotherapy have been described in the literature and optimal clinical management of these events as well as patient's immune-mediated response after treatment suspension is still unclear. Here, we report a case of a 67 years-old woman with stage IV renal cell carcinoma under treatment with nivolumab who developed autoimmune encephalitis. After high doses of corticosteroids patient's condition improved significantly with full recovery after 5 days of treatment. Even though nivolumab was not reinstalled, a persistent response of her oncologic disease was evidenced. We expect that this case can contribute to the existing literature of both subjects, the management of autoimmune encephalitis as grade IV immune related adverse event and the responses of immune checkpoint inhibitors after IRAE.

Los inhibidores de puntos de control inmunológico han mostrado una importante mejoría en la supervivencia global de los pacientes con carcinoma de riñón estadio IV. Sin embargo, existe una amplia variedad de efectos adversos inmunomediados que surgen a partir de estos tratamientos revolucionarios. La encefalitis autoinmune es un infrecuente pero grave efecto adverso inmunomediado del sistema nervioso central en estos pacientes. La gravedad de este cuadro impide que los pacientes continúen con el tratamiento de inmunoterapia. Se han descrito pocos casos de encefalitis autoinmune con inmunoterapia en la literatura y aún no está claro el manejo clínico óptimo de estos eventos, ni cómo continua la respuesta inmunomediada después de la suspensión del tratamiento. Presentamos el caso de una mujer de 67 años con carcinoma de células renales estadio IV que desarrolló encefalitis autoinmune durante el tratamiento con nivolumab. La paciente mejoró significativamente luego del inicio del tratamiento con altas dosis de corticoides, con una recuperación completa después de 5 días del mismo. Si bien el nivolumab no se reinició, se evidenció una respuesta persistente de su enfermedad oncológica. Esperamos que este caso pueda contribuir a la literatura existente de ambos temas, el manejo de la encefalitis autoinmune como efecto adverso inmunomediado grado IV y las respuestas que se obtienen con la inmunoterapia luego de estos efectos adversos.

HER2-Directed Therapy in Advanced Breast Cancer: Benefits and Risks.

Around 20% of breast cancers are associated with amplification or overexpression of human epidermal growth factor receptor 2 (HER2). In this setting, anti-HER2-targeted agents are the cornerstone of cancer therapeutic strategies. This includes monoclonal antibodies, tyrosine kinase inhibitors (TKIs) and, recently, antibody-drug conjugates (ADCs). With the advent of these new alternatives, the decision-making process has become more complex, especially with regard to the treatment sequence possibilities. In spite of the fact that overall survival has significantly improved accordingly, resistance to treatment remains a challenge in HER2-positive breast cancer. The introduction of new agents has created awareness regarding new potential specific adverse events, and consequently, their increasing application pose major challenges in daily patient care. This review describes the therapeutic landscape for HER2-positive advanced breast cancer (ABC) and evaluates its benefits and risks in the clinical setting.

Lack of Prognostic Value of Pretreatment Neutrophil-to-Lymphocyte Ratio in Early Breast Cancer.

Background: Breast cancer is a highly heterogeneous disease with large differences in the risk of recurrence. An elevated neutrophil-to-lymphocyte ratio (NLR) is correlated with a poor prognosis in a variety of tumors, and although it is still controversial in breast cancer, there are multiple studies, including meta-analysis, suggesting this. The purpose of this study was to analyze the prognostic value of preoperative NLR in an Argentine population of patients with nonmetastatic breast cancer, not exposed to neoadjuvant treatment. Methods: Retrospective multicenter cohort study that includes patients over 18 years of age from three centers in the city and province of Buenos Aires who have had surgery for early breast cancer between January 1, 1999, and December 31, 2014. Based on the previous literature, a cutoff value of 2.0 was defined. Results: A total of 791 patients were eligible for the analysis. Median age was 55 years (IQR 45-65). Median NLR was 1.92 (IQR 1.50-2.56). The distribution of groups according to the 8th edition of the AJCC was 54.1% for stage I, 35.6% stage II, and 10.4% stage III. Among the different tumor phenotypes, 79.0% were HR+/HER2-, 11.4% were HR+ or-/HER2+, and 9.2% were HR-/HER2-. With a median follow-up of 5.3 years, 112 patients (14.2%) had disease recurrence. Stage III patients had a higher NLR than stage I and stage II patients (p = 0.002). The rest of the clinical and pathological characteristics did not show differences in the groups according to NLR. There were no differences in relapse-free survival according to the NLR (p = 0.37), and it did not change after adjusting for other prognostic variables. Conclusion: We consider it is important to determine the efficacy of prognostic markers that are easily accessible and of simple, systematic application. However, NLR does not appear to be an independent prognostic factor for recurrence in our population. In this sense, we consider it is important to publish negative results in order to avoid publication bias.

Registro OBELISCO-SAC. OBsErvaciones de cLinicas, Instituciones y Servicios de Cardio-Oncología SAC / OBELISCO-SAC Registry. OBsErvations from cLinics, InstitutionS and Cardio-Oncology services SAC

RESUMEN Introducción: La cardio-oncología (CO) es una nueva disciplina, que genera nuevas áreas de trabajo en las instituciones. Desconocemos cuántos equipos de CO existen en nuestro país, su estructura y el manejo de los pacientes. Objetivos: Nuestro objetivo primario es reportar cuántos centros de CO existen en nuestro país, y de ellos cuántos trabajan de acuerdo con las recomendaciones de guías y consensos. Secundariamente, definir la especialidad y formación de los médicos integrantes, si se realiza evaluación de riesgo previo al inicio del tratamiento oncológico, cómo se evalúa la función ventricular y cómo se utilizan los biomarcadores. Material y métodos: Registro nacional, multicéntrico, transversal, descriptivo, y prospectivo que incluyó 51 instituciones generales, de oncología y/o de cardiología que referían poseer grupos de trabajo o servicios de CO. Resultados: De los 51 centros, pertenecen al ámbito público el 47,1% y al privado el 52,9%. El 49% se halla en la Ciudad Autónoma de Buenos Aires, el 17,6% en la Provincia de Buenos Aires y el resto en otros lugares del país. Sobre 47 centros, el 48,9% considera funcionar de acuerdo con las recomendaciones de Guías Internacionales y el Consenso de la Sociedad Argentina de Cardiología. El 27,7% de los centros realiza siempre estratificación de riesgo cardio-oncológico o cardiovascular antes de iniciar el tratamiento. Un 35,3% de los centros deriva siempre a cardiología a los pacientes que iniciarán un tratamiento potencialmente cardiotóxico, un 47,1% ocasionalmente. El 43,1% de los centros realiza ecocardiografía basal en todos los pacientes, el 56,9% solo en algunos. Durante el seguimiento el ecocardiograma se indica de acuerdo con el esquema utilizado en el 64,7% y en el resto según su evolución. Todos los centros evalúan la fracción de eyección ventricular izquierda mediante ecocardiografía, en el 68,1% bidimensional. El 63,8% utiliza el análisis de la deformación longitudinal sistólica global. El 47,1% deriva algunos pacientes a resonancia cardíaca y el 35,3% a tomografía cardíaca. Solo el 7,8% utiliza biomarcadores. El 5,9% indica siempre prevención primaria con antagonistas neurohormonales. El dexrazoxano es utilizado en el 5,9%, la antraciclina liposomal en el 74,5%. Frente a la aparición de cardiotoxicidad, el 76,5% inicia tratamiento cardioprotector. El 41% suspende la quimioterapia, el 47% la modifica. Conclusiones: este es el primer registro nacional de CO. Brinda información y un panorama actual del estado de esta subespecialidad en nuestro país. Casi la mitad de los centros consideró funcionar de acuerdo con Guías y Consensos. Solo un tercio de los pacientes que van a iniciar tratamiento oncológico potencialmente cardiotóxico son derivados a CO. El método más utilizado en nuestro país para evaluar la función ventricular es el ecocardiograma bidimensional, los biomarcadores son poco utilizados.

ABSTRACT Background: Cardio-oncology (CO) is a new discipline that generates new work areas within the institutions. We ignore how many CO teams exist in our country, their structure and how patients are managed. Objectives: Our primary objective is to report how many CO centers exist in our country, and how many of them work according to the recommendations of guidelines and consensus statements. We also want to define the specialty and specific training of the physicians involved, determine if they perform risk assessment before cancer treatment, establish the method used to assess ventricular function and how biomarkers are used. Methods: The OBELISCO registry is a national, multicenter, cross-sectional, descriptive and prospective registry including 51 general hospitals, cancer centers and institutions specialized in cardiology with CO work groups or services. Results: Of the 51 centers, 47.1% were public hospitals and 52.9% were private centers. Most centers were in the Autonomous City of Buenos Aires (49%) and in the Province of Buenos Aires and the rest were distributed throughout the country. Of 47 centers, 48.9% considered that their institution had CO services complying with the recommendations of international guidelines and of the consensus statement of the Argentine Society of Cardiology. Global cardio-oncological or cardiovascular risk assessment is always performed in 27.7% of the centers before starting treatment. Patients who will start potentially cardiotoxic treatment are always referred to cardiology in 35.3% of the centers and are sometimes referred to cardiology in 47.1%. Baseline echocardiography is performed in all the patients before starting treatment in 43.1% of the centers and only in some patients in 56.9%. During follow-up, echocardiography is indicated according to the treatment schedule used in 64.7% and according to the patients' outcome in the rest of the centers. All the centers evaluate left ventricular ejection fraction with echocardiography, and 68.1% use twodimensional echocardiography. Global longitudinal systolic strain is used in 63.8% of the centers. Only 47.1% order cardiac magnetic resonance imaging in some patients, and 35.3% indicate cardiac computed tomography scan. Biomarkers are used in only 7.8% of the centers. Primary prevention with neurohormonal antagonist drugs is always indicated in 5.9% of the centers. Dexrazoxane is used in only 5.9% and liposomal anthracycline in 74.5% If cardiotoxicity develops, 76.5% indicate cardioprotection, 41% discontinue chemotheraphy and 47% modify cancer treatment. Conclusions: This is the first national CO registry. It provides information and a current outlook of the status of this subspecialty in our country. Almost 50% of the centers considered to be functioning in line with guidelines and consensus statements. Only one third of the patients who will initiate cancer treatment with potentially cardiotoxic drugs are referred to CO. Two-dimensional echocardiography is the method most used in our country to evaluate ventricular function; biomarkers are scarcely used.

Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer - Proceedings from breast cancer expert group meeting.

PURPOSE: The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 - mBC. DESIGN: A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 - mBC. RESULTS: Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 - mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 - mBC. CONCLUSION: The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 - mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 - mBC.

Optimizing the management of HER2-negative metastatic breast cancer in the era of PARP inhibitors-proceedings from breast cancer expert group meeting.

The therapeutic landscape of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents such as poly-ADP ribose polymerase inhibitors (PARPi), novel chemotherapeutic agents, immunotherapy, and endocrine therapies. In this scenario, optimizing the appropriate treatment sequence is a daunting task for clinicians. To develop evidence-based answers to key clinical questions on treatment selection and appropriate treatment sequence for the management of patients with HER2- mBC in the era of PARPi, a breast cancer expert group meeting was convened. The expert panel comprised of eight key opinion leaders from Argentina, Brazil, Colombia, Egypt, Mexico, Moscow, South Korea, and the United Arab Emirates, who convened and reviewed the literature, discussed the clinical practices across the participating regions, and formulated answers to key clinical questions for optimizing the management of HER2- mBC. In this review, evidence-based answers have been provided pertaining to (I) the specific mBC population to be considered for BRCA testing, optimal time point of BRCA testing, and genetic counselling in mBC patients; (II) the role of PARPi versus platinum therapy in HER2- mBC patients in the metastatic setting; (III) sequencing treatment in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive HER2- mBC patients, and defining the place of PARPi in the sequencing algorithms; and (IV) the need for a breast cancer registry for patients with HER2- mBC. This expert review will serve as a comprehensive guide to clinicians for optimizing BRCA testing and managing patients with BRCA mutation (BRCAm) and HER2- mBC. The data collected from the proposed HER2- mBC registry will help understand the treatment practices, identify unmet needs, and develop strategic policies regionally to help improve access to optimized care of HER2- mBC.

Correlation between PD-L1 expression (clones 28-8 and SP263) and histopathology in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related death worldwide. Recent advances in the management of non-small cell carcinoma are focused on the discovery of targeted therapies and novel immunotherapy strategies for patients with advanced disease. Treatment with anti PD-(L)1 immune checkpoint inhibitors requires the development of predictive biomarkers to select those patients that can most benefit from these therapies. Several immunohistochemical biomarkers have been developed in different technological platforms. However, the most useful and accessible for the daily clinical practice need to be selected. The objective of this study was to compare PD-L1 expression by automated immunohistochemistry in lung adenocarcinoma (ADC) FFPE samples with clones 28-8 and SP263 performed with the BenchMark GX automated staining instrument. To further determine interobserver agreement between two pathologists, and to correlate the results with histologic and pathology variables. FFPE tissue from 40 samples obtained from patients with lung ADC were reviewed retrospectively. Among all studied specimens, 53% of samples presented <1% of positive tumor cells with the 28-8 clone and 50% had <1% of PD-L1 expression in tumor cells with the SP263 clone; PD-L1 expression between ≥1 and <5% was observed in 18% and 24%; ≥5 and <50% PD-L1 expression in 18% and 21%; and ≥50% PD-L1 expression in 11% and 5% of samples, respectively. Similar results between antibodies were observed in 84% of cases for each of the four PD-L1 cutoff groups (Pearson's score 0.90, p < 0.00001). The interobserver degree of agreement calculated with Kappa was 0.75 (95%CI: 0.57-0.93), z = 7.08; p < 0.001. Lepidic, acinar and mucinous patterns had predominantly <1% PD-L1 expression, and the solid pattern subtype had high levels of PD-L1 staining using both clones. PD-L1 expression in less than 1% of tumor cells was similar in stages I/II compared to III/IV. No significant differences were observed in PD-L1 staining and quantification pattern between IHC antibodies 28-8 and SP263.

Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma.

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.

Breast Cancer in Young Women Presents With More Aggressive Pathologic Characteristics: Retrospective Analysis From an Argentine National Database.

PURPOSE: Multiple studies have reported that breast cancer in young patients is associated with aggressive characteristics, and it is suggested that prognosis is worse independently of pathologic variables. PATIENTS AND METHODS: We performed a retrospective analysis of the Breast Cancer Registry of the Argentinian Society of Mastology, including public and private centers. Patients ≤ 40 years of age at diagnosis were classified as "young," and patients ≤ 35 years of age at diagnosis were classified as "very young." Univariate and multivariate analyses were performed to detect differences between groups. RESULTS: Patients ≤ 40 years of age comprised 10.40% (739/7,105) of the participants, with an average age of 35.61 ± 4.04 years. Multivariate analysis showed that human epidermal growth factor receptor 2 (HER2)-positive tumor phenotype (odds ratio [OR], 1.82), nodal involvement (OR, 1.69), histologic grade (grade 3 OR, 1.41), and tumor size (T2 OR, 1.37; T3-T4, 1.47) were independently associated with younger age at diagnosis. Patients ≤ 35 years of age (n = 286), compared with patients 36 to 40 years of age, had a higher proportion of HER2 tumors (24.58% v 16.94%; P = .021), absence of progesterone receptor expression (29.85% v 22.95%; P = .043), and stage 3 cancer (29.34% v 18.52%; P < .001). Fewer breast-conserving surgeries (75.37% v 62.89%; P < .001) and more adjuvant chemotherapy (59.04% v 36.66%; P < 0.001) were reported in patients ≤ 40 years of age. CONCLUSION: In the population studied, breast cancer in young women was associated with aggressive pathologic features and locally advanced disease at the time of diagnosis. Moreover, tumor characteristics in very young patients with breast cancer nested in the population ≤ 40 years of age showed differences in important prognostic factors. More high-quality evidence is needed to improve treatment strategies in these patients.

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.

Immunotherapy at any line of treatment improves survival in patients with advanced metastatic non-small cell lung cancer (NSCLC) compared with chemotherapy (Quijote-CLICaP).

BACKGROUND: To compare survival outcomes of patients with advanced or metastatic non-small cell lung cancer (NSCLC) who received immunotherapy as first-, second- or beyond line, versus matched patients receiving standard chemotherapy with special characterization of hyperprogressors. METHODS: A retrospective cohort study of 296 patients with unresectable/metastatic NSCLC treated with either, first-, second-, third- or fourth-line of immunotherapy was conducted. A matched comparison with a historical cohort of first-line chemotherapy and a random forest tree analysis to characterize hyperprogressors was conducted. RESULTS: Median age was 64 years (range 34-90), 40.2% of patients were female. A total of 91.2% of patients had an Eastern Cooperative Oncology Group (ECOG) performance score ≤ 1. Immunotherapy as first-line was given to 39 patients (13.7%), second-line to 140 (48.8%), and as third-line and beyond to 108 (37.6%). Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival (PFS) of 4.27 months (95% CI 3.97-5.0). Factors associated with increased survival included treatment with immunotherapy as first-line (P < 0.001), type of response (P < 0.001) and PD-L1 status (P = 0.0039). Compared with the historical cohort, immunotherapy proved to be superior in terms of OS (P = 0.05) but not PFS (P = 0.2). A total of 44 hyperprogressors were documented (19.8%, [95% CI 14.5-25.1%]). Leukocyte count over 5.300 cells/dL was present in both hyperprogressors and long-term responders. CONCLUSIONS: Patients who receive immune-checkpoint inhibitors as part of their treatment for NSCLC have better overall survival (OS) compared with matched patients treated with standard chemotherapy, regardless of the line of treatment.

Spectrum of BRCA1/2 variants in 940 patients from Argentina including novel, deleterious and recurrent germline mutations: impact on healthcare and clinical practice.

BRCA1/2 mutations in Latin America are scarcely documented and in serious need of knowledge about the spectrum of BRCA pathogenic variants, information which may alter clinical practice and subsequently improve patient outcome. In addition, the search for data on testing policies in different regions constitutes a fundamental strength for the present study, which analyzes BRCA1/2 gene sequences and large rearrangements in 940 probands with familial and/or personal history of breast/ovary cancer (BOC). In non-mutated DNA samples, Multiplex Ligation-dependent Probe Amplification assays (MLPA) were used for the analysis of large rearrangements. Our studies detected 179 deleterious mutations out of 940 (19.04%) probands, including 5 large rearrangements and 22 novel mutations. The recurrent mutations accounted for 15.08% of the total and only 2.87% of the probands analyzed, very different from a Hispanic panel previously described. IN CONCLUSION: a) this first comprehensive description of the spectrum in BRCA1/2 sheds light on the low frequency of recurrent mutations; b) this information is key in clinical practice to select adequate sequencing studies in our population, subsequently improve patient outcome and prevent damage associated to false normal reports resulting from the use of invalid population panels; c) panels of mutations from other populations should be cautiously validated before imported, even those of apparently similar origin, a concept to be considered beyond significance in Argentina.

[Clinical-pathological features and gene profile in colorectal cancer]. / Caracteres clínico-patológicos y perfil genético en el carcinoma colorrectal.

Colorectal cancer is the third most frequent cancer in men and the second most frequent in women, with a worldwide incidence of approximately 1.2 million new cases per year. Our primary objective was to study the relationship between clinical and histological features of individuals with colorectal cancer and the mutational status of codons 12 and 13 of the KRAS gene (7 validated mutations), in order to find a histopathological marker to mutated tumors. The secondary objective was to determine how many patients had additional mutations in codons 15 and 61 of the KRAS gene, and codon 600 of the BRAF gene, which could modify the tumor phenotype. Sixty individuals with colorectal cancer (30 wild-type subjects and 30 with validated mutations in codons 12 and 13 of the KRAS gene) were selected. Exons 2 and 3 of the KRAS gene, and exon 15 of the BRAF gene were amplified and sequenced. The data collected were reviewed by a descriptive, univariate and/or multivariate analysis, as appropriate. In conclusion, no relation was found between clinical and histological features of individuals with colorectal cancer and their mutational status for codons 12 and 13 of the KRAS gene. This suggests that those easily available data do not allow predicting the response to anti-EGFR therapy. In patients with advanced colorectal adenocarcinomas and KRAS wild-type status, further study of codon 600 of the BRAF gene could be required.

Caracteres clínico-patológicos y perfil genético en el carcinoma colorrectal / Clinical-pathological features and gene profile in colorectal cancer

El cáncer colorrectal es el tercer cáncer más frecuente en hombres y el segundo más frecuente en mujeres, con una incidencia mundial aproximada de 1.2 millones de casos nuevos por año. Nuestro objetivo primario fue estudiar la relación existente entre las características clínico-histológicas en individuos con cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS (7 mutaciones validadas), con el fin de hallar un marcador histopatológico para los tumores mutados. El objetivo secundario fue determinar cuántos pacientes tenían mutaciones adicionales en los codones 15 y 61 del gen KRAS y 600 del gen BRAF que podrían modificar el fenotipo tumoral. Fueron seleccionados 60 individuos con cáncer colorrectal (30 wild-type y 30 con mutaciones validadas en los codones 12 y 13 del gen KRAS). Se amplificaron y secuenciaron del gen KRAS los exones 2 y 3, y del gen BRAF el exón 15. La información recolectada se examinó mediante un análisis descriptivo, análisis univariado y/o análisis multivariado, según correspondiese. En conclusión, no se encontró relación entre las características clínico-histológicas de los tumores de individuos con diagnóstico de cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS. No hallamos un marcador histopatológico para los tumores mutados. En pacientes con adenocarcinomas colorrectales avanzados y KRAS wild-type resulta de interés considerar el estudio del codón 600 del gen BRAF.

Colorectal cancer is the third most frequent cancer in men and the second most frequent in women, with a worldwide incidence of approximately 1.2 million new cases per year. Our primary objective was to study the relationship between clinical and histological features of individuals with colorectal cancer and the mutational status of codons 12 and 13 of the KRAS gene (7 validated mutations), in order to find a histopathological marker to mutated tumors. The secondary objective was to determine how many patients had additional mutations in codons 15 and 61 of the KRAS gene, and codon 600 of the BRAF gene, which could modify the tumor phenotype. Sixty individuals with colorectal cancer (30 wild-type subjects and 30 with validated mutations in codons 12 and 13 of the KRAS gene) were selected. Exons 2 and 3 of the KRAS gene, and exon 15 of the BRAF gene were amplified and sequenced. The data collected were reviewed by a descriptive, univariate and/or multivariate analysis, as appropriate. In conclusion, no relation was found between clinical and histological features of individuals with colorectal cancer and their mutational status for codons 12 and 13 of the KRAS gene. This suggests that those easily available data do not allow predicting the response to anti-EGFR therapy. In patients with advanced colorectal adenocarcinomas and KRAS wild-type status, further study of codon 600 of the BRAF gene could be required.

Caracteres clínico-patológicos y perfil genético en el carcinoma colorrectal / Clinical-pathological features and gene profile in colorectal cancer

El cáncer colorrectal es el tercer cáncer más frecuente en hombres y el segundo más frecuente en mujeres, con una incidencia mundial aproximada de 1.2 millones de casos nuevos por año. Nuestro objetivo primario fue estudiar la relación existente entre las características clínico-histológicas en individuos con cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS (7 mutaciones validadas), con el fin de hallar un marcador histopatológico para los tumores mutados. El objetivo secundario fue determinar cuántos pacientes tenían mutaciones adicionales en los codones 15 y 61 del gen KRAS y 600 del gen BRAF que podrían modificar el fenotipo tumoral. Fueron seleccionados 60 individuos con cáncer colorrectal (30 wild-type y 30 con mutaciones validadas en los codones 12 y 13 del gen KRAS). Se amplificaron y secuenciaron del gen KRAS los exones 2 y 3, y del gen BRAF el exón 15. La información recolectada se examinó mediante un análisis descriptivo, análisis univariado y/o análisis multivariado, según correspondiese. En conclusión, no se encontró relación entre las características clínico-histológicas de los tumores de individuos con diagnóstico de cáncer colorrectal y el estado mutacional de los codones 12 y 13 del gen KRAS. No hallamos un marcador histopatológico para los tumores mutados. En pacientes con adenocarcinomas colorrectales avanzados y KRAS wild-type resulta de interés considerar el estudio del codón 600 del gen BRAF.(AU)

Colorectal cancer is the third most frequent cancer in men and the second most frequent in women, with a worldwide incidence of approximately 1.2 million new cases per year. Our primary objective was to study the relationship between clinical and histological features of individuals with colorectal cancer and the mutational status of codons 12 and 13 of the KRAS gene (7 validated mutations), in order to find a histopathological marker to mutated tumors. The secondary objective was to determine how many patients had additional mutations in codons 15 and 61 of the KRAS gene, and codon 600 of the BRAF gene, which could modify the tumor phenotype. Sixty individuals with colorectal cancer (30 wild-type subjects and 30 with validated mutations in codons 12 and 13 of the KRAS gene) were selected. Exons 2 and 3 of the KRAS gene, and exon 15 of the BRAF gene were amplified and sequenced. The data collected were reviewed by a descriptive, univariate and/or multivariate analysis, as appropriate. In conclusion, no relation was found between clinical and histological features of individuals with colorectal cancer and their mutational status for codons 12 and 13 of the KRAS gene. This suggests that those easily available data do not allow predicting the response to anti-EGFR therapy. In patients with advanced colorectal adenocarcinomas and KRAS wild-type status, further study of codon 600 of the BRAF gene could be required.(AU)

Pertuzumab, primer inhibidor de la dimerización HER / Pertuzumab, first HER dimerization inhibitor

Entre un 15 y un 20% de pacientes con cáncer de mama presentan amplificación o sobre expresión de HER2, lo que le confiere un comportamiento más agresivo. Pese a que el advenimiento del trastuzumab, primer agente dirigido contra HER2, mejoró significativamente el pronóstico de este grupo de pacientes, el 50% de ellas aún progresa dentro del año de tratamiento. Pertuzumab, el primer inhibidor de la dimerización de HER2, muestra un mecanismo de acción complementario a trastuzumab, logrando mejores resultados clínicos en pacientes tratadas con ambos agentes anti-HER2 y quimioterapia. El presente trabajo repasa las propiedades de pertuzumab y su desarrollo clínico.

Approximately 15 to 20% of breast cancers present amplificationor overexpression of HER2, and these tumoursshow a more aggressive behavior. Trastuzumab, the firsttargeted agent against HER2, significantly improved prognosisfor these patients, but still around 50% shows diseaseprogression within the first year of treatment. Pertuzumab,the first HER2 dimerization inhibitor, has a mechanismof action that is complementary to that of trastuzumab,achieving enhanced efficacy for patients treated with bothanti-HER2 agents and chemotepapy. This work reviews themain aspects of pertuzumab and its clinical development.

Caracteres clínico-patológicos y perfil genético en el carcinoma colorrectal. / [Clinical-pathological features and gene profile in colorectal cancer].

Colorectal cancer is the third most frequent cancer in men and the second most frequent in women, with a worldwide incidence of approximately 1.2 million new cases per year. Our primary objective was to study the relationship between clinical and histological features of individuals with colorectal cancer and the mutational status of codons 12 and 13 of the KRAS gene (7 validated mutations), in order to find a histopathological marker to mutated tumors. The secondary objective was to determine how many patients had additional mutations in codons 15 and 61 of the KRAS gene, and codon 600 of the BRAF gene, which could modify the tumor phenotype. Sixty individuals with colorectal cancer (30 wild-type subjects and 30 with validated mutations in codons 12 and 13 of the KRAS gene) were selected. Exons 2 and 3 of the KRAS gene, and exon 15 of the BRAF gene were amplified and sequenced. The data collected were reviewed by a descriptive, univariate and/or multivariate analysis, as appropriate. In conclusion, no relation was found between clinical and histological features of individuals with colorectal cancer and their mutational status for codons 12 and 13 of the KRAS gene. This suggests that those easily available data do not allow predicting the response to anti-EGFR therapy. In patients with advanced colorectal adenocarcinomas and KRAS wild-type status, further study of codon 600 of the BRAF gene could be required.

Immunohistochemical characterization of neoplastic cells of breast origin.

BACKGROUND: After skin cancer, breast cancer is the most common malignancy in women. Tumors of unknown origin account for 5-15% of malignant neoplasms, with 1.5% being breast cancer. An immunohistochemical panel with conventional and newer markers, such as mammaglobin, was selected for the detection of neoplastic cells of breast origin. The specific objectives are: 1) to determine the sensitivity and specificity of the panel, with a special emphasis on the inclusion of the mammaglobin marker, and 2) to compare immunohistochemistry performed on whole tissue sections and on tissue micro-array. METHODS: Twenty-nine metastatic breast tumors were included and assumed as tumors of unknown origin. Other 48 biopsies of diverse tissues were selected and assumed as negative controls. Tissue Micro-Array was performed. Immunohistochemistry for mammaglobin, gross cystic disease fluid protein-15, estrogen receptor, progesterone receptor and cytokeratin 7 was done. RESULTS: Mammaglobin positive staining was observed in 10/29 cases, in 13/29 cases for gross cystic disease fluid protein-15, in 20/29 cases for estrogen receptor, in 9/29 cases for progesterone receptor, and in 25/29 cases for cytokeratin 7. Among the negative controls, mammaglobin was positive in 2/48, and gross cystic disease fluid protein-15 in 4/48. CONCLUSIONS: The inclusion of MAG antibody in the immunohistochemical panel for the detection of tumors of unknown origin contributed to the detection of metastasis of breast cancer. The diagnostic strategy with the highest positive predictive value (88%) included hormone receptors and mammaglobin in serial manner.