A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT. PATIENTS AND METHODS: Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT [7 weeks of radiotherapy (RT) with cisplatin 100 mg/m(2) on days 1, 22 and 43]; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF). RESULTS: In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6-20.4), 14.3 (95% CI, 11.8-19.3) and 13.8 months (95% CI, 11.0-17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9-11.8), 7.9 (95% CI, 6.5-11.8) and 8.2 months (95% CI, 6.7-12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable. CONCLUSION: Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN.

Efficacy of erlotinib in patients with relapsed gliobastoma multiforme who expressed EGFRVIII and PTEN determined by immunohistochemistry.

Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41-4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped.

Quorum sensing activity in Ophiostoma ulmi: effects of fusel oils and branched chain amino acids on yeast-mycelial dimorphism.

AIMS: For Ophiostoma (Ceratocystis) ulmi, the ability to undergo morphological change is a crucial factor for its virulence. To gain an understanding of quorum-sensing activity in O. ulmi as it relates to yeast-mycelium dimorphism control, this study examines the effects of branched-chain amino acids as well as their fusel alcohols and fusel acids as quorum sensing molecules. METHODS AND RESULTS: In a defined medium containing glucose, proline and salts, O. ulmi grew as yeasts when the culture was inoculated with a high density of spores (2 × 10(7) CFU ml(-1) ) and as mycelia when inoculated with a low spore density (4 × 10(5) CFU ml(-1) ). The cultures displaying yeast morphology secreted a quorum-sensing factor that shifted the morphology from mycelia to yeast. This quorum-sensing molecule was lipophilic and extractable by organic solvents from the spent medium. Using GC/MS analysis, it was determined that the major compound in the extract was 2-methyl-1-butanol. A similar effect was observed when the branched-chain amino acids (fusel alcohol precursors) were used as the nitrogen source. E, E-farnesol had no effect on the morphology of O. ulmi. CONCLUSIONS: Addition of the branched-chain amino acids or one of the compounds detected in the spent medium, 2-methyl-1-butanol or 4-hydroxyphenylacetic acid, or methylvaleric acid, decreased germ tube formation by more than 50%, thus demonstrating a quorum sensing molecule behaviour in O. ulmi cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents advances in the investigation of dimorphism in O. ulmi, complementing the existing scientific basis, for studying, understanding and controlling this phenomenon.

[Isolated nocturnal hypertension in individuals with human immunodeficiency virus]. / Hipertensión nocturna aislada en individuos con el virus de la inmunodeficiencia humana.

INTRODUCTION: Isolated nocturnal hypertension is associated with a greater number of cardiovascular events and target organ damage due to arterial hypertension. It has been observed that patients in the general population with this entity do not have high blood pressure figures in the office; and it is necessary to perform an outpatient measurement to unmask it. The prevalence in special populations is not fully described. The objective of the following study is to describe the prevalence of isolated nocturnal hypertension in a population living with the human immunodeficiency virus and to observe its relationship with the categories of office blood pressure and the phenotypes of the 24-hour ambulatory blood pressure measurement. METHODOLOGY: A retrospective cohort was carried out in a population with human immunodeficiency virus in a public hospital in Spain, clinical epidemiological characteristics, office blood pressure measurements and 24-hour ambulatory blood pressure measurement (ABPM) were recorded. An analysis was performed based on the different ABPM blood pressure phenotypes, as well as based on the different office blood pressure categories, the risks for isolated nocturnal hypertension were calculated. RESULTS: One hundred and sixteen individuals, without antihypertensive medication or history of established cardiovascular disease, were included in the analysis. A prevalence of nocturnal hypertension of 23.3% was described. It was not possible to demonstrate significant differences between phenotypes by ABPM of any variable specific to HIV. There were no adjusted risk differences between the different categories of office normotensives. CONCLUSIONS: Isolated nocturnal hypertension is more frequent in patients with HIV and office blood pressure values in normotensive patients are not sufficient to predict isolated nocturnal hypertension.

SEOM clinical guideline for the management of cutaneous melanoma (2020).

Melanoma affects about 6000 patients a year in Spain. A group of medical oncologists from Spanish Society of Medical Oncology (SEOM) and Spanish Multidisciplinary Melanoma Group (GEM) has designed these guidelines to homogenize the management of these patients. The diagnosis must be histological and determination of BRAF status has to be performed in patients with stage ≥ III. Stage I-III resectable melanomas will be treated surgically. In patients with stage III melanoma, adjuvant treatment with immunotherapy or targeted therapy is also recommended. Patients with unresectable or metastatic melanoma will receive treatment with immunotherapy or targeted therapy, the optimal sequence of these treatments remains unclear. Brain metastases require a separate consideration, since, in addition to systemic treatment, they may require local treatment. Patients must be followed up closely to receive or change treatment as soon as their previous clinical condition changes, since multiple therapeutic options are available.

Summary of recommendations and key points of the consensus of Spanish scientific societies (SEPAR, SEMICYUC, SEMES; SECIP, SENEO, SEDAR, SENP) on the use of non-invasive ventilation and high-flow oxygen therapy with nasal cannulas in adult, pediatric, and neonatal patients with severe acute respiratory failure. / Sumario de las recomendaciones y puntos clave del Consenso de las Sociedades Científicas Españolas (SEPAR, SEMICYUC, SEMES; SECIP, SENeo, SEDAR, SENP) para la utilización de la ventilación no invasiva y terapia de alto flujo con cánulas nasales en el paciente adulto, pediátrico y neonatal con insuficiencia respiratoria aguda grave.

Non-invasive respiratory support (NIRS) in adult, pediatric, and neonatal patients with acute respiratory failure (ARF) comprises two treatment modalities, non-invasive mechanical ventilation (NIMV) and high-flow nasal cannula (HFNC) therapy. However, experts from different specialties disagree on the benefit of these techniques in different clinical settings. The objective of this consensus was to develop a series of good clinical practice recommendations for the application of non-invasive support in patients with ARF, endorsed by all scientific societies involved in the management of adult and pediatric/neonatal patients with ARF. To this end, the different societies involved were contacted, and they in turn appointed a group of 26 professionals with sufficient experience in the use of these techniques. Three face-to-face meetings were held to agree on recommendations (up to a total of 71) based on a literature review and the latest evidence associated with 3 categories: indications, monitoring and follow-up of NIRS. Finally, the experts from each scientific society involved voted telematically on each of the recommendations. To classify the degree of agreement, an analogue classification system was chosen that was easy and intuitive to use and that clearly stated whether the each NIRS intervention should be applied, could be applied, or should not be applied.

Summary of recommendations and key points of the consensus of Spanish scientific societies (SEPAR, SEMICYUC, SEMES; SECIP, SENEO, SEDAR, SENP) on the use of non-invasive ventilation and high-flow oxygen therapy with nasal cannulas in adult, pediatric, and neonatal patients with severe acute respiratory failure.

Non-invasive respiratory support (NIRS) in adult, pediatric, and neonatal patients with acute respiratory failure (ARF) comprises two treatment modalities, non-invasive mechanical ventilation (NIMV) and high-flow nasal cannula (HFNC) therapy. However, experts from different specialties disagree on the benefit of these techniques in different clinical settings. The objective of this consensus was to develop a series of good clinical practice recommendations for the application of non-invasive support in patients with ARF, endorsed by all scientific societies involved in the management of adult and pediatric/neonatal patients with ARF. To this end, the different societies involved were contacted, and they in turn appointed a group of 26 professionals with sufficient experience in the use of these techniques. Three face-to-face meetings were held to agree on recommendations (up to a total of 71) based on a literature review and the latest evidence associated with 3 categories: indications, monitoring and follow-up of NIRS. Finally, the experts from each scientific society involved voted telematically on each of the recommendations. To classify the degree of agreement, an analogue classification system was chosen that was easy and intuitive to use and that clearly stated whether the each NIRS intervention should be applied, could be applied, or should not be applied.

Extended-schedule dose-dense temozolomide in refractory gliomas.

This multicenter phase II study conducted by the Spanish Neuro-Oncology Group evaluated the activity of an extended, dose-dense temozolomide regimen in patients with temozolomide-refractory malignant glioma. Adult patients (at least 18 years of age) with WHO grade III or IV glioma and a Karnofsky Performance Status of 60 or higher were treated with temozolomide (85 mg/m(2)/day) for 21 consecutive days every 28-day cycle until disease progression or unacceptable toxicity. All patients had developed progressive disease either during or less than 3 months after completing previous temozolomide treatment. Forty-seven patients were treated with a median of 2 (range, 1-13) cycles of temozolomide. Before study entry, patients had received a median of 6 cycles of temozolomide: 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. Three patients (6.4%) had a partial response with durations of 8.0, 3.5, and 3.2 months; 15 patients (31.9%) had stable disease with a median duration of 2.1 months, including 2 patients with stable disease (SD) for greater than 6 months (14 and 16 months). Median time to progression was 2 months, and median overall survival from study entry was 5.1 months. The 6-month progression-free survival rate was 16.7%. The most common hematologic toxicities were lymphopenia, thrombocytopenia, and leukopenia. Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no opportunistic infections occurred. In conclusion, this extended dose-dense schedule of temozolomide appears to have modest activity in patients refractory to previous treatment with temozolomide and is associated with manageable toxicity.

Clinical and pathological findings of a sac-like formation in the tunica vaginalis of a Nelore (Bos indicus) bull.

A seven-month-old purebred Nelore calf was diagnosed with a bilateral finger-shaped swelling although more prominent at the left side of the scrotum, located longitudinal and parallel to epididymis corpus. The finding was present from 7 months of age up to castration (performed at 25 months of age). Scrotal circumference, testicular and epididymis consistency and symmetry as well as seminal quality were normal during the follow-up period. The ultrasonographic appearance of the scrotal wall, pampiniform plexus, gonad and epididymis was normal. However, an anechoic region surrounded by a wall forming a sac-like structure with a blind end at its dorsal pole was seen on the swelling area. The examination of fluid aspirated from the saccular contents revealed the presence of mononuclear cells mainly from lymphocytic and histiocytic type as well as some loosing degenerated mesothelial cells. Gross examination at castration revealed a blind sac-like appendix derived from an evagination in the parietal layer of the tunica vaginalis. The structure of approximately 5.0 cm in length extended from the dorsal edge of the epididymis cauda. No adherences with surrounded tissues were observed. Histopathology of the sac wall showed a smooth inner surface composed by scarce mesothelial cells forming in some areas papillary-like projections protruding to the vaginal cavity. Underneath, a thick layer of fibrous tissue mixed with collagen fibres and mononuclear inflammatory cells were seen. The potential consequences of this saccular formation at an older age in a bull are unknown.

SEOM clinical guideline for the management of immune-related adverse events in patients treated with immune checkpoint inhibitors (2019).

The use of immune checkpoint inhibitors has emerged as an effective treatment option for patients with several tumor types. By increasing the activity of the immune system, they can induce inflammatory side effects, which are often termed immune-related adverse events. These are pathophysiologically unique toxicities, compared with those from other anticancer therapies. In addition, the spectrum of the target organs is very broad. Immune-inflammatory adverse events can be life threatening. Prompt diagnosis and pharmacological intervention are instrumental to avoid progression to severe manifestations. Consequently, clinicians require new skills to successfully diagnose and manage these events. These SEOM guidelines have been developed with the consensus of ten medical oncologists. Relevant studies published in peer-review journals were used for the guideline elaboration. The Infectious Diseases Society of America grading system was used to assign levels of evidence and grades of recommendation.

SuperCam Calibration Targets: Design and Development.

SuperCam is a highly integrated remote-sensing instrumental suite for NASA's Mars 2020 mission. It consists of a co-aligned combination of Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), Visible and Infrared Spectroscopy (VISIR), together with sound recording (MIC) and high-magnification imaging techniques (RMI). They provide information on the mineralogy, geochemistry and mineral context around the Perseverance Rover. The calibration of this complex suite is a major challenge. Not only does each technique require its own standards or references, their combination also introduces new requirements to obtain optimal scientific output. Elemental composition, molecular vibrational features, fluorescence, morphology and texture provide a full picture of the sample with spectral information that needs to be co-aligned, correlated, and individually calibrated. The resulting hardware includes different kinds of targets, each one covering different needs of the instrument. Standards for imaging calibration, geological samples for mineral identification and chemometric calculations or spectral references to calibrate and evaluate the health of the instrument, are all included in the SuperCam Calibration Target (SCCT). The system also includes a specifically designed assembly in which the samples are mounted. This hardware allows the targets to survive the harsh environmental conditions of the launch, cruise, landing and operation on Mars during the whole mission. Here we summarize the design, development, integration, verification and functional testing of the SCCT. This work includes some key results obtained to verify the scientific outcome of the SuperCam system.

Clinical Consensus Recommendations Regarding Non-Invasive Respiratory Support in the Adult Patient with Acute Respiratory Failure Secondary to SARS-CoV-2 infection. / Recomendaciones de consenso respecto al soporte respiratorio no invasivo en el paciente adulto con insuficiencia respiratoria aguda secundaria a infección por SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus, that was first recognized in Wuhan, China, in December 2019. Currently, the World Health Organization (WHO) has defined the infection as a global pandemic and there is a health and social emergency for the management of this new infection. While most people with COVID-19 develop only mild or uncomplicated illness, approximately 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute respiratory distress syndrome (ARDS), sepsis and septic shock, and multiorgan failure. This consensus document has been prepared on evidence-informed guidelines developed by a multidisciplinary panel of health care providers from four Spanish scientific societies (Spanish Society of Intensive Care Medicine [SEMICYUC], Spanish Society of Pulmonologists [SEPAR], Spanish Society of Emergency [SEMES], Spanish Society of Anesthesiology, Reanimation, and Pain [SEDAR]) with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS, as well as sepsis and ARDS. The document provides clinical recommendations for the noninvasive respiratory support (noninvasive ventilation, high flow oxygen therapy with nasal cannula) in any patient with suspected or confirmed presentation of COVID-19 with acute respiratory failure. This consensus guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival and to allow for reliable comparison of investigational therapeutic interventions as part of randomized controlled trials.

The Coriolis mass flow meter as a volume meter for the custody transfer in liquid hydrocarbons logistics.

In recent years, the Coriolis mass flow meters (CMF), devices based on the Coriolis effect over a vibrating pipe, have developed better metrological performance and they are now a reasonable alternative for the custody transfer measurements. Nowadays, many custody transfer operations require measurement of the net volume (volume measured at a certain reference temperature) and, therefore, it is not feasible to use the CMF as a mass flow meter. However, the actual CMF can be used as net volume meters because they have special equipment to measure density and temperature, and a flow computer. In this work, firstly a mathematical simplification of the physical model is proposed for the CMF. We part from the dimensional analysis of the flow-phase relationship produced by the Coriolis force, the main physical principle behind these devices. A simplified formula is obtained and it permits identifying the magnitudes of influence of the CMF as a mass meter. Secondly, its metrological properties are characterized. For such purpose, a 4" straight tube commercial meter has been calibrated in volume, in the 50 to 165 m3/h range against a standard container and a bidirectional prover, employing gas oil and kerosene (JET-A1). These calibrations have turned out to be compatible with the ones performed by the manufacturer in mass and using water. Then it is verified that the CMF fulfills the requisites of the legal metrology: maximum error allowed, linearity and repeatability. Skewness is observed in the relative error (expressed in %) of the CMF and it has been researched to be due to systematic effects related to constructive parameters of the meter. Lineal correlation is verified between relative error and temperature, and between relative error and flow rate, with negative slopes of -0.03% °C-1 and -0.001% h/m3 respectively.

A retrospective chart review study describing metastatic melanoma patients profile and treatment patterns in Spain.

PURPOSE: To describe patient characteristics by disease stage, resectability status and current treatment management after first diagnosis of IIIB to IV1c advanced (AM)/metastatic melanoma (MM). METHODS/PATIENTS: Multicentre, retrospective study based on data from medical charts of patients > 18 years at MM first diagnosis, visited by oncologists at 4 reference centres in Spain: Hospital Universitario Gregorio Marañón (Madrid), Hospital General de Valencia (Valencia), Clínica Universidad de Navarra (Pamplona), and Hospital Clínic (Barcelona). RESULTS: Metastatic non-visceral melanoma (IIIB, IIIC, IV M1a) was reported in 139 (48.6%) patients and 40.9% (n = 117) were diagnosed with IV-M1c disease. 160 (55.9%) metastases were resectable. Available therapies under clinical practice were used in 210 patients; 74 were treated under clinical trials (CT). Intention-to-cure surgery (47.6%) was the most common treatment at time of MM diagnosis. Systemic (45.1% overall) therapy included chemo-, targeted- and immunotherapy (19.6%, 14.3%, 8.4%, respectively). At time of data collection, 26 patients were still alive and 120 had progressed to IV-M1c. Median overall survival (OS) was significantly larger in IIIB patients, 28.9 m (25.2-32.7); the shortest for IV-M1c patients, 11.0 m (8.7-13.3). CONCLUSIONS: Novel treatments are undoubtedly a major step forward in AM/MM, however these are often only available in the CT setting because early stages of development or country-specific regulations. Further prospective studies and multifactorial analysis should be performed to clearly identify possible clinical associations for outcome in Spanish patients with AM/MM.

Experience in the management of ECMO therapy as a mortality risk factor. / Experiencia en el manejo de terapia ECMO como factor de riesgo de mortalidad.

INTRODUCTION: The extracorporeal oxygenation membrane (ECMO) is a system that provides circulatory and respiratory assistance to patients in cardiac or respiratory failure refractory to conventional treatment. It is a therapy with numerous associated complications and high mortality. Multidisciplinary management and experienced teams increase survival. OBJECTIVE: Our purpose is to evaluate and analyse the effect of the learning curve on mortality. METHODS: Retrospective and observational study of 31 patients, from January 2012 to December 2015. Patients were separated into 2periods. These periods were divided by the establishment of an ECMO protocol. We compared the quantitative variables by performing the Mann-Whitney U test. For the categorical qualitative variables we performed the chi-square test or Fisher exact statistic as appropriate. The survival curve was computed using the Kaplan-Meier method, and the analysis of statistical significance using the Log-rank test. Data analysis was performed with the STATA programme 14. RESULTS: Survival curves show the tendency to lower mortality in the subsequent period (P=0.0601). The overall mortality rate in the initial period was higher than in the subsequent period (P=0.042). In another analysis, we compared the characteristics of the 2groups and concluded that they were homogeneous. CONCLUSION: The degree of experience is an independent factor for mortality. The application of a care protocol is fundamental to facilitate the management of ECMO therapy.

This is a call to oncologists for action.

Cancer cases are growing in an exponential way, likewise the prices of new cancer drugs. Continuing in this way, in the near future, it will be impossible to provide optimum care for all cancer patients. Therefore, it is important to establish mechanisms that enable the National Health Systems to provide the best options of treatment, either through the elaboration of decision-binding frameworks or through other initiatives that guarantee the best quality care for all oncology patients to overcome, in the best possible way, this difficult illness. Here, we review current proposals that have been established by different cancer organizations worldwide, their similarities, their differences and whether they are helpful in a real clinical setting. Facing present reality and despite these organizations' huge efforts, these proposals are not being implemented at all and it does not seem feasible that they will in the short run. In the same way, we support and argue why oncologists should have a crucial and a preponderant role to establish the best way of guaranteeing an equal access to the latest oncology care.

SEOM clinical guideline for the management of malignant melanoma (2017).

All melanoma suspected patients must be confirmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic melanoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams.

Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients.

PURPOSE: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. PATIENTS AND METHODS: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. RESULTS: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. CONCLUSION: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.