Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Human gut microbiota analysis of cystic fibrosis infants using metaproteomics.

We report a metaproteomic analysis of the gut microbiota of eight infants with cystic fibrosis, during the first year of life. This is the first study in this disease that uses metaproteomics to analyze stool samples from patients at such a young age.

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.

Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice.

PURPOSE: Intestinal dysbiosis has emerged as a biomarker of response to immune checkpoint inhibitors (ICIs). It can be caused by antibiotics, although it may also result from the use of other drugs that have been studied to a lesser extent. The objective of our study was to analyze the association between the use of potentially dysbiosis-related drugs and survival in patients treated with ICIs in the clinical practice. MATERIALS AND METHODS: A retrospective, multicenter, cohort study was conducted. Clinicopathological variables were collected and the concomitant use of drugs was analyzed. A descriptive analysis of variables and overall survival, estimated by the Kaplan-Meier method, was performed, and association with various independent variables was assessed using Cox regression. RESULTS: We included 253 patients, mainly with non-small cell lung cancer and melanoma. The most commonly used drugs were acid reducers, prescribed to 55.3% of patients, followed by corticosteroids (37.9%), anxiolytic drugs (35.6%), and antibiotics (20.5%). The use of acid reducers (9 vs. 18 months, P < .0001), antibiotics (7 vs. 15 months, P < .017), anxiolytic drugs (8 vs. 16 months, P < .015), and corticosteroids (6 vs. 19 months, P < .00001) was associated with poorer overall survival. Furthermore, the greater the number of drugs used concomitantly with ICIs, the higher the risk of death (1 drug: hazard ratio, 1.88; CI 95%, 1.07-3.30; 4 drugs: hazard ratio, 4.19; CI9 5%, 1.77-9.92; P < .001). CONCLUSION: Response to ICIs may be influenced by the use of drugs that lead to intestinal dysbiosis. Although a confirmatory prospective controlled study is required, our findings should be taken into account when analyzing ICI efficacy.

Second complete remission induced by cyclophosphamide plus bevacizumab in two patients with heavily pre-treated ovarian cancer.

During the last decade we have been developing new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of the molecular biology. New drugs like bevacizumab are showing antiangiogenic antitumour activity in ovarian cancer in preclinical models and in clinical trials. Bevacizumab is a monoclonal human antibody that has showed activity in both monotherapy and in combination with other therapies. We present the outcome of two patient cases with recurring heavily pre-treated ovarian cancer that were treated with cyclophosphamide and bevacizumab in combination and showed a complete remission of disease. After interruption of the treatment with bevacizumab, both patients had a disease relapse. Despite poor prognosis of the disease, in both cases a second complete and maintained remission was achieved, again with the same regimen.

[Oxygen therapy in acute and chronic conditions: Indications, oxygen systems, assessement and follow-up]. / Fundamentos de la oxigenoterapia en situaciones agudas y crónicas: indicaciones, métodos, controles y seguimiento.

Oxygen therapy has become a major tool for infants with acute and chronic respiratory failure. Appropriate goals when prescribing supplemental oxygen are reduction and prevention of hypoxemia, prevention and treatment of pulmonary hypertension and decrease in respiratory and cardiac overload. This is commonplace in the acute setting and is also becoming widespread in chronic pathologies. However, there is a lack of consensus on many fundamental issues, such as appropriate indications, desirable targets and outcome measures amongst centres, reflecting a variety of clinical practices. The Techniques Group of the Spanish Society of Pediatric Pneumology undertook to design recommendations for a rational approach to oxygen therapy, reviewing the existing literature in order to establish its indications, benefits and potential risks as well as its cost-effectivenes. General aspects of oxygen treatment are reviewed including physiological mechanisms, indications, delivery systems and assessment methods. Management of patients on home oxygen therapy is also addressed with discussion of benefits and potential risks of supplemental oxygen use.

SEOM clinical guidelines to primary prevention of cancer (2018).

Cancer is the leading social and healthcare problem of the twenty-first century. The aim of primary prevention is to decrease the incidence of cancer by avoiding the known causes and risk factors. Nevertheless, it has been estimated that cancer diagnoses could be halved through primary prevention measures. A comprehensive review of the scientific evidence regarding the main carcinogens and risk factors and primary prevention recommendations have been put forth based on this evidence. The GRADE scale has been used to classify the grade of evidence. We present the scientific evidence and recommendations for primary prevention of the major modifiable risk factors: smoking, alcohol, diet, obesity, physical activity, occupational and environmental factors, ultraviolet radiation, infections, and socioeconomic factors. Primary prevention is a simple, effective means to lower the incidence of cancer. Preventive measures must be circulated in the fight against cancer.

Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

INTRODUCTION: This study aimed to describe the efficacy of fulvestrant 500 mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. MATERIALS AND METHODS: Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500 mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. RESULTS: A total of 263 women were evaluated (median age, 65.8 years). At a median follow-up of 21.5 months, median PFS and OS were 10.6 and 43.2 months, respectively. PFS according to 1st, 2nd, 3rd, and ≥ 4th lines were 11.5, 10.6, 9.9, and 8.5 months, respectively (p = 0.0245). PFS in patients with visceral involvement was 10 months vs 10.6 months in patients without visceral involvement (p = 0.6604), 9.6 months in patients with high Ki67 vs 10 months in patients with low Ki67 (p = 0.7224), and 10.2 months in HER2+ patients vs 10.3 months in HER2- patients (p = 0.6809). The CBR was 56.5% and the DoCB was 18.4 months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). CONCLUSIONS: Fulvestrant 500 mg administered in clinical practice was shown to be effective (PFS, 10.6 months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

Correction to: Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

A sentence under 'Results' heading in the Abstract section was published incorrectly. The correct sentence should read as follows.

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.

Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population.

OBJECTIVES: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. MATERIAL AND METHODS: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]). CONCLUSION: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Epidemiological characteristics of a Spanish cohort of patients diagnosed with squamous cell carcinoma of head and neck: distribution of risk factors by tumor location.

PURPOSE: Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations. METHODS/PATIENTS: A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012-2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location. RESULTS: Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10-140 g: OR 2.53, p = 0.012; 141-280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21-40 packs: OR 0.46, p = 0.045; 41-70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015). CONCLUSIONS: The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors.

[Outcome of two patients with Hurler's syndrome under enzyme replacement therapy with human recombinant alpha-L-iduronidase]. / Evolución de dos pacientes con síndrome de Hurler en tratamiento con enzima recombinante humana alpha-L-iduronidasa.

We performed a prospective study of two patients with Hurler's syndrome (aged 4.8 years and 17 months at the beginning of the intervention) under enzyme replacement therapy with human recombinant alpha-L-iduronidase for 452 and 28 weeks respectively. The aim of this study was to analyze the safety and efficacy of the intervention during the treatment periods. Several diagnostic imaging tests, clinical examinations, and serial laboratory determinations were performed to demonstrate the effectiveness of the therapy in both patients. In patient 1 (a boy aged 4.8 years, homozygote W402X), the treatment was always intended to be palliative because of the advanced stage of the disease. In patient 2 (a 17-month-old girl, heterozygote W402X) the treatment was initiated early with subsequent clinical stabilization without acquisition of regressive factors. Bone marrow transplantation from an unrelated donor was successful. Currently, because of the lack of histocompatible bone marrow donors, transplantation of hematopoietic stem cells from umbilical cord blood or peripheral blood are being performed with satisfactory results. In the future, gene therapy may be able to prevent the diseases associated with Hurler's syndrome and halt the neurocognitive deterioration characteristic of these patients.

Ara h 1 protein-antibody dissociation study: evidence for binding inhomogeneities on a molecular scale.

The characterization of biomolecular interactions is essential when designing novel biosensors, since the interaction between the bioreceptor and the ligand determines important biosensing parameters such as sensitivity and selectivity. In this paper we study the interaction of the trimeric Ara h 1 protein with a monoclonal anti-Ara h 1 antibody by means of magnetic force-induced dissociation. The proteins were bound to magnetic particles and polystyrene surfaces by EDC/NHS reaction chemistry and by physisorption, respectively. Two different molecular configurations have been investigated, with either the Ara h 1 protein on the particles or the Ara h 1 protein on the polystyrene surface. A model with a Gaussian distribution of energy barriers for dissociation gives an adequate description for the measured multi-exponential decays. We hypothesize that distributions of molecular orientations as well as experimentally induced variations may underlay the observed distributions. The two molecular configurations show a different peak value of the energy distribution. Similarly, SPR experiments for two distinct configurations (either Ara h 1 protein on the surface, or anti-Ara h 1 antibody on the surface) also show clear differences in dissociation behavior. We hypothesize that the multivalency of the involved molecules leads to different modes of binding. The results of this work highlight the importance of molecular inhomogeneities when studying the interaction processes of biomolecular complexes.

[Endoscopic evaluation of endobronchial tuberculosis in children]. / Valoración endoscópica de la tuberculosis endobronquial infantil.

The aim of this study was to determine the role of fiberoptic bronchoscopy (FB) in pulmonary tuberculosis in children. We assessed bronchoscopic findings of 36 procedures performed in 30 children who presented the following abnormalities on chest films: lobular or segmentary atelectasis (17), paratracheal or parahilar adenopathies (14), parenchymatous consolidation (9) and localized hyperinflation (5). Premedication for FB included intravenous atropine and diazepam plus ketamine for sedation, as well as lidocaine 2 and 5% in aerosol form for topical anesthesia. FB results showed that involvement was endobronchial in 29 patients. In the 18 patients with X-rays suggestive of endobronchial tuberculosis (EBT), the diagnosis was confirmed by FB. Significantly, EBT was found by FB in 11 (36.6%) patients with no clinical or radiological signs of such involvement. EBT was in the early stages in 3 (10%) patients and was advanced in 8 (26.6%). M. tuberculosis was isolated in 9 (30%) of the 30 patients. Culture was of bronchoalveolar lavage in three, of gastric lavage in four and of endobronchial biopsy in two. We conclude that FB is a safe, important tool for the confirmation of EBT in the management of pulmonary tuberculosis in children. It serves as a guide for the start of steroid treatment, especially in children with no radiological suggestion of EBT.

[Usefulness of fiberoptic bronchoscopy in critical pediatric care]. / Utilidad de la fibrobroncoscopia en el paciente crítico pediátrico.

UNLABELLED: Fiberoptic bronchoscopy (FB) is being applied increasingly in pediatrics as a therapeutic and diagnostic technique. OBJECTIVE: To analyze the contribution of FB to the diagnosis and treatment of respiratory disease in patients admitted to the pediatric intensive care unit (PICU). PATIENTS AND METHOD: We reviewed FB performed with 3.5 and 2.2 mm external diameter instruments between January 1989 and October 1998 in patients admitted to the PICU. Underlying disease and purpose of and indications for FB were analyzed. We also analyzed route of insertion, findings of airway inspection and bronco-alveolar lavage (BAL), complications and the contribution of FB to patient management. RESULTS: A total of 51 procedures in 47 patients aged between ten days and 12 years old were performed. Twenty-one children (41%) were under one year old. The initial indications for FB were diagnostic in 73% and therapeutic in 27%. Airway inspection showed abnormality in 65%. BAL was performed in 18 cases, with microbiological findings in 8 of the 18. The patients benefited directly from the technique in 75% of cases. CONCLUSIONS: FB is useful diagnostic and therapeutic procedure in PICU patients and is generally well tolerated.

[Carbohydrate metabolic changes in cystic fibrosis]. / Alteraciones del metabolismo hidrocarbonado en la fibrosis quística.

OBJECTIVES: To assess the prevalence of impaired glucose tolerance and diabetes mellitus in a group of patients with cystic fibrosis and to compare insulin secretion, haemoglobin A1c, age, gender, genotype, and clinical status related variables between the groups with abnormal (impaired glucose tolerance and diabetes mellitus) and normal carbohydrate metabolism. PATIENTS AND METHODS: 66 patients with cystic fibrosis (age 1-38 years). Plasma glucose, insulin and C peptide determinations during an oral glucose tolerance test (OGTT) in 65 patients (one was previously known as diabetic). Based on the Expert Committee from the American Diabetes Association (1997), patients were classified as having impaired glucose tolerance and diabetes mellitus. Haemoglobin A1c, presence of delta F508 mutation, date of diagnosis and first sputum colonization, scores of National Institutes of Health, Schwachman and Chrispin-Norman, pancreatic enzyme intake, weight, body mass index, forced expiratory volume in one second and forced vital capacity determinations in every patient. Comparative analysis of these variables in both groups of patients was performed by Student test. RESULTS: Nine patients (13.6%) showed impaired tolerance glucose and one diabetes mellitus following OGTT, so we have two diabetics in our cystic fibrosis group (3.0%). When compared to cystic fibrosis patients with normal glucose tolerance, tolerance glucose and diabetes mellitus patients had significantly reduced basal insulin levels (8.6 [3.8] vs 15.0 [22.2] microU/ml; p < 0.0001), increased glucose stimulated insulin and C peptide levels (50.2 [19.3] vs 21.4 [19.3] microU/ml; p < 0.0001, and 9.0 [5.9] vs 4.4 [3.2] ng/ml; p < 0.0001), they were older (18.0 [7.5] vs 12.7 [7.3] years old; p < 0.05) and had longer time since diagnosis and since first sputum colonization. The remaining variables did not differ between the two groups. All patients with exocrine pancreatic sufficiency showed normal glucose tolerance. CONCLUSIONS: Abnormalities in carbohydrate metabolism were present in 16.6% of cystic fibrosis patients. These patients had reduced basal but increased glucose stimulated insulin levels. Age, time since diagnosis of cystic fibrosis, time since first sputum colonization and exocrine pancreatic insufficiency are the variables being associated with carbohydrate metabolism abnormalities.

[Techniques and complementary techniques. Fiberoptic bronchoscopy in mechanically ventilated children]. / Técnicas y tratamientos complementarios. Fribroncoscopia en el niño con ventilación mecánica.

Fiberoptic bronchoscopy can be performed at the patient's bedside. This technique allows direct visualization of the upper and lower airways up to the segmental and subsegmental bronchi. Its most frequent indications are airway examination ot evaluate damage produced by toxins or the endotracheal tube, patency of the endotracheal tube and extubation failure. It is also used to obtain microbiological samples, facilitate intubation when difficult, aspirate airway sections or mucus plugs, perform bronchoalveolar lavage and administer drugs. With prior preparation, adequate monitoring and sedation, material according to the size of the patient and correct techniques, there are few complications. However, the procedure can produce trauma and obstruction of the airway, bronchial hemorrhage, barotrauma, loss of alveolar recruitment, bronchospasm, hypoxemia, bradycardia, and bronchopulmonary infection.