Multi-omics Characterization of Response to PD-1 Inhibitors in Advanced Melanoma.

Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.

Sorting Transcriptomics Immune Information from Tumor Molecular Features Allows Prediction of Response to Anti-PD1 Therapy in Patients with Advanced Melanoma.

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy.

Beneficios de la urea oral en pacientes con hiponatremiae insuficiencia cardiaca / Benefits of oral urea in patients with hyponatremia and heart failure

Objectives: To assess the efficacy and safety of oral urea in patients with hyponatremia and heart failure (HF).Methods and Results: This is a retrospective observational study of hospitalized and non-hospitalized patients with HF and hyponatremia(serum Na+ < 135 mEq/L) followed by the Heart Failure Unit between January 2013 and May 2018. The study evaluated sodium normalization levels (Na+ = 135 ± 3 mEq/L) after treatment with oral urea. Thirty-four patients were included in the study, and all were on standardtreatment for HF. Natremia at the beginning of treatment with oral urea was 126.34 ± 5.41 mEq/L, and the mean on the day of normalizationwas 136.45 ± 3.22 mEq/L (p < 0.001). The mean time to achieve sodium normalization was 4.28 ± 2.37 days. Blood urea at the beginning oftreatment with urea was 85.77 ± 50.51 mg/dl, and the mean on the day of Na+ normalization was 137.90 ± 56.66 mg/dl (p < 0.001). Therewas an increase in diuresis (p < 0.006) and plasma osmolarity (p < 0.001) as well as a slight decrease in serum potassium (p < 0.001). Themean dose of oral urea was 22.5 g/day. There were no important adverse effects, nor were there significant changes in creatinine levels orthe estimated glomerular filtration rate by the MDRD formula.Conclusions: When added to the standard treatment for short periods of time, treatment with oral urea is safe and effective at correctingnatremia and improving diuresis in patients with hypervolemic HF with hyponatremia. (AU)

Durable Response to Vemurafenib and Cobimetinib for the Treatment of BRAF-Mutated Metastatic Melanoma in Routine Clinical Practice.

BACKGROUND: The combination of BRAF and MEK inhibitors delays the onset of resistance and provides more sustained and dramatic responses in comparison with a BRAF inhibitor in monotherapy. The objective of the study was to evaluate the effectiveness of the combination therapy with vemurafenib/cobimetinib in terms of durability, and to describe differential characteristics in patients associated to durable responses in real-world settings. PATIENTS AND METHODS: Retrospective, observational, cross-sectional, multicenter study involving 41 patients with advanced melanoma harboring a BRAF V600 mutation who initiated a combination therapy with vemurafenib/cobimetinib between May 2018 and March 2019. Participants were differentiated regarding the durability of the response: durable (complete response, CR, or a partial response, PR, for at least 12 months) and non-durable (stable disease, SD, progressive disease, PD, or CR/PR <12 months). Secondary endpoints included treatment adherence, labor productivity, anxiety/depression, and safety profile. RESULTS: During the combination therapy, 12 patients (29.3%) had a CR, 19 a PR (46.3%), 5 showed SD (12.2%), and 5 had PD. A total of 12 patients (29.3%) were considered as achieving a durable response and 29 (70.7%) as a non-durable one. Practically all sociodemographic and clinical characteristics were similar between patients. Body mass index was the only differential factor (with higher body mass index achieving a non-durable response). The treatment adherence was 100% in patients with durable response and 66.7% in those with non-durable. CONCLUSION: The combination treatment with vemurafenib/cobimetinib results in an important impact on long-term survival, leading to a steady CR in one-third of the patients.

Implicaciones médico-legales de las perforaciones corporales / Medical-legal implications of body piercings

La perforación corporal es una actividad cada vez más común en nuestro medio, por lo tanto es de importancia tanto para el médico como para el especialista en medicina legal pues ya se les exige que tengan un amplio conocimiento acerca de la técnica correcta de la perforación corporal, de los cuidados necesarios y las principales complicaciones de los piercings. En la prática hospitalaria hoy día es frecuente encontrarse con personas que consultan ya sea porque desean colocarse un piercing y quieren escuchar un consejo de su médico o personas que consultan a causa de las múltiples complicaciones que pueden ocurrir.

A phase II study of sequential docetaxel followed by doxorubicin/cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

This phase II study assessed the activity and toxicity profile of the sequential administration of 3 cycles of docetaxel (100 mg/m2 every 3 weeks) followed by 3 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2 every 3 weeks) as first-line chemotherapy in 30 patients with metastatic breast cancer. The response rate was 60% after docetaxel and 73% after AC. This reflected an increase in the rate of complete response (from 7% after docetaxel to 17% after AC). The median duration of response was 10.5 months, and the median time to progression was 12.6 months. The median survival time had not been reached after a median follow-up of 23.2 months. The sequential treatment was generally well tolerated, with grade 3/4 neutropenia found in 20% and 14% of patients treated with docetaxel and AC, respectively. No cumulative myelosuppression was detected. The incidence of grade 3/4 nonhematologic toxicities was low. The sequential administration of docetaxel followed by AC showed a high antitumor activity and a good safety profile. The hematologic toxicity found is markedly lower than that found using concomitant chemotherapy with the same drugs. Our results support the design of phase III trials that directly compare a sequential schedule with a concomitant schedule of docetaxel plus AC (or with doxorubicin only), focusing on the toxicity profile.

Increasing-dose gemcitabine plus low-dose cisplatin in metastatic non-small cell lung cancer.

UNLABELLED: Gemcitabine, a pyrimidine analog active in non-small cell lung cancer (NSCLC), is widely used with cisplatin. The potential activity of the combination has not been fully assessed: gemcitabine is not used at its maximum tolerated dose (MTD) and cisplatin shows a clearly dose-related toxicity. This trial was designed to assess the MTD and dose-limiting toxicity (DLT) of low-dose cisplatin and increasing gemcitabine dose. CHEMOTHERAPY: cisplatin 50 mg/m2 on day 1, gemcitabine starting at 1400 mg/m on days 1 and 8 every 21 days. Subsequent levels were increased by 200 mg/m2. Forty-two patients with metastatic NSCLC were enrolled (37 males; median age 61 years; squamous cell carcinoma 19 patients; performance status 2, in 13 patients; 18 patients had significant weight loss). MTD was found to be 2600 mg/m2 because of DLT in three of six patients: two neutropenic fever and one massive bleeding. Overall toxicity was generally mild consisting mainly of neutropenia. Asthenia was the most common non-hematological effect. Overall response rate was 19 out of 41 patients (46.3%) and median survival was 31 weeks. We conclude that the recommended dose for a phase II dose is gemcitabine 2400 mg/m2 days 1 and 8 as a 30-min infusion when given with cisplatin 50 mg/m2.