Proton pump inhibitors decrease efficacy of palbociclib in patients with metastatic breast.

OBJECTIVES: The objective of this investigation was to assess the impact of concurrent proton pump inhibitors (PPIs) on progression-free survival (PFS) in patients with hormone receptor-positive and HER2-negative metastatic breast cancer (mBC) who received palbociclib as first-line or successives therapy. MATERIALS AND METHODS: A retrospective observational study was conducted, enrolling patients diagnosed with estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, and eligible for palbociclib treatment. Patients were categorized as "concurrent PPIs" if they received PPIs for at least two-thirds of the palbociclib therapy duration, and as "no concurrent PPIs" if they did not receive PPIs during the course of palbociclib treatment. RESULTS: A total of 165 patients were included in the study. Among first-line patients treated with palbociclib, those using concurrent PPIs exhibited a PFS of 8.88 months, while patients using palbociclib without concurrent PPIs had a PFS of 67.81 months (p < 0.0001). In second-line or subsequent treatments, patients on palbociclib with concurrent PPIs had a PFS of 7.46 months, whereas those using palbociclib without concurrent PPIs had a PFS of 17.29 months (p = 0.122). CONCLUSION: This study demonstrates that the concurrent use of PPIs in mBC patients receiving palbociclib negatively affects PFS, particularly in the first-line setting. Nevertheless, further investigation is warranted to explore the impact of PPIs on cycle-dependent kinase 4/6 inhibitors.

Postoperative Critical Care Admission Was Not Associated with Improved Postoperative Outcomes in Elective Colorectal Surgery: Secondary Analysis Of POWER Trial.

BACKGROUND: The efficacy of routine admission of high-risk patients to a critical care unit after surgery is not clear. The aim of our study was to investigate the association between critical care admission after scheduled colorectal surgery and postoperative complications, 30-day mortality, and length of stay in hospital. METHODS: A pre-defined secondary substudy of POWER study was performed. POWER study was a prospective multicenter observational study of patients undergoing elective primary colorectal surgery during a single period of two months of recruitment between September and December 2017. RESULTS: A total of 2084 patients from 80 Spanish hospitals were included, of which 722 (34.6%) were admitted to critical care unit (CCU) after elective surgery. After adjusting for confounding factors in the multivariate analysis, postoperative CCU admission was independently associated with a higher incidence of moderate-to-severe postoperative complications (adjusted OR 1.951, 95% CI 1.570, 2.425; p < 0.001). Regarding secondary outcomes, postoperative critical care admission was independently associated with higher 30-day mortality (adjusted OR 6.736; 95% CI 2.507, 18.101; p < 0.001) and independently associated with an increased hospital length of stay (adjusted OR 1.143, 95% CI 1.112, 1.175; p < 0.001). CONCLUSIONS: Direct admission to CCU after scheduled colorectal surgery was not associated with a reduction in moderate-to-severe postoperative complications.

Relationship between air pollution exposure and the progression of idiopathic pulmonary fibrosis in Madrid: Chronic respiratory failure, hospitalizations, and mortality. A retrospective study.

Introduction: Air pollution has a significant impact on the morbidity and mortality of various respiratory diseases. However, this has not been widely studied in diffuse interstitial lung diseases, specifically in idiopathic pulmonary fibrosis. Objective: In this study we aimed to assess the relationship between four major air pollutants individually [carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), and nitrogen oxides (NOx)] and the development of chronic respiratory failure, hospitalization due to respiratory causes and mortality in patients with idiopathic pulmonary fibrosis. Methods: We conducted an exploratory retrospective panel study from 2011 to 2020 in 69 patients with idiopathic pulmonary fibrosis from the pulmonary medicine department of a tertiary hospital. Based on their geocoded residential address, levels of each pollutant were estimated 1, 3, 6, 12, and 36 months prior to each event (chronic respiratory failure, hospital admission and mortality). Data was collected from the air quality monitoring stations of the Community of Madrid located <3.5 km (2.2 miles) from each patient's home. Results: The increase in average values of CO [OR 1.62 (1.11-2.36) and OR 1.84 (1.1-3.06)], NO2 [OR 1.64 (1.01-2.66)], and NOx [OR 1.11 (1-1.23) and OR 1.19 (1.03-1.38)] were significantly associated with the probability of developing chronic respiratory failure in different periods. In addition, the averages of NO2, O3, and NOx were significantly associated with the probability of hospital admissions due to respiratory causes and mortality in these patients. Conclusion: Air pollution is associated with an increase in the probability of developing chronic respiratory failure, hospitalization due to respiratory causes and mortality in patients with idiopathic pulmonary fibrosis.

A Novel Molecular Analysis Approach in Colorectal Cancer Suggests New Treatment Opportunities.

Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means-consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC disease.

Proteomics Characterization of Clear Cell Renal Cell Carcinoma.

PURPOSE: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. MATERIAL AND METHODS: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. RESULTS: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. CONCLUSIONS: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

Real-world outcomes of abiraterone and enzalutamide in first-line treatment of metastatic castration-resistant prostate cancer: which patients benefit most?

OBJECTIVES: Abiraterone and enzalutamide are two oral novel androgen receptor axis-targeted agents approved for the treatment of castration-resistant prostate cancer (mCRPC). Despite the availability of multiple treatments, there is a need to improve the knowledge and management of these drugs in the real-world setting, especially in patient groups under-represented in clinical trials. Our aim was to review the outcome of patients with chemotherapy-naïve mCRPC treated with abiraterone or enzalutamide in routine clinical practice in order to identify factors that are predictive for response. METHODS: This observational retrospective study was performed in a Spanish tertiary hospital and included men with chemotherapy-naïve mCPRC who started treatment with abiraterone or enzalutamide between September 2012 and November 2018. The study end date was 30 October 2020. RESULTS: Ninety patients with mCRPC were included, 57 with abiraterone and 33 with enzalutamide. Median overall survival (OS) was 26.87 months (95% CI 19.68 to 34.05), with no difference found between the two treatment groups. Nine variables were related to increased OS in the univariate analysis: Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), pain (need of opioids for cancer pain), visceral disease, ≥3 bone lesions, exclusively lymph node metastases, baseline prostate specific antigen (PSA) (<50 vs ≥50 ng/dL and <20 vs ≥20 ng/dL), haemoglobin (<12 vs ≥12 g/dL) and alkaline phosphatase (≤116 vs >116 IU/L). A PSA response >50% was observed in 65 patients (76.5%). In the multivariate analysis, ECOG performance status, pain, visceral disease and alkaline phosphatase provided independent prognostic information. Median OS by Kaplan-Meier analysis was significantly longer for patients with a PSA response (32.1 vs 17.9 months; HR 0.46, 95% CI 0.27 to 0.78; p=0.003). CONCLUSIONS: This study assessed the efficacy of abiraterone and enzalutamide in a real-world setting, including patients under-represented in pivotal studies. Some clinical factors were correlated with improved OS in chemotherapy-naïve men with mCPRC treated with these drugs.

Air pollution exposure and its effects on idiopathic pulmonary fibrosis: clinical worsening, lung function decline, and radiological deterioration.

Introduction: Major urban pollutants have a considerable influence on the natural history of lung disease. However, this effect is not well known in idiopathic pulmonary fibrosis (IPF). Aim: This study aimed to investigate the effects of air pollution on clinical worsening, lung function, and radiological deterioration in patients with IPF. Methods: This exploratory retrospective cohort study included 69 patients with IPF, monitored from 2011 to 2020. Data on air pollution levels, including carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter ≤ 2.5 µM (PM2.5), ozone (O3), and nitrogen oxides (NOx), were collected from the nearest air quality monitoring stations (<3.5 km from the patients' homes). Patient outcomes such as clinical worsening, lung function decline, and radiological deterioration were assessed over various exposure periods (1, 3, 6, 12, and 36 months). The statistical analyses were adjusted for various factors, including age, sex, smoking status, and treatment. Results: There was an association between higher O3 levels and an increased likelihood of clinical worsening over 6 and 36 months of exposure (odds ratio [OR] and 95% confidence interval [CI] = 1.16 [1.01-1.33] and OR and 95% CI = 1.80 [1.07-3.01], respectively). Increased CO levels were linked to lung function decline over 12-month exposure periods (OR and 95% CI 1.63 = [1.01-2.63]). Lastly, radiological deterioration was significantly associated with higher CO, NO2, and NOx levels over 6-month exposure periods (OR and 95% CI = 2.14 [1.33-3.44], OR and 95% CI = 1.76 [1.15-2.66] and OR and 95% CI = 1.16 [1.03-1.3], respectively). Conclusion: This study suggests that air pollution, specifically O3, CO, NO2, and NOx, could affect clinical worsening, lung function, and radiological outcomes in patients with IPF. These findings highlight the potential role of air pollution in the progression of IPF, emphasizing the need for further research and air quality control measures to mitigate its effects on respiratory health.

Are infections in children with juvenile idiopathic arthritis more frequent than in healthy children? A prospective multicenter observational study.

Background: Children with juvenile idiopathic arthritis (JIA) might be at a higher risk of infection. Our objectives are to describe and compare infection rates in patients with JIA vs. healthy patients. Methods: A prospective, multicenter observational study was performed in Spain from January 2017 to June 2019. Patients with JIA from 7 participating hospitals and children without JIA (siblings of patients with JIA, and non-JIA children from primary health centers) were followed up with quarterly questionnaires to record infection episodes. Tuberculosis, herpes zoster, and infections requiring hospital admission were considered severe infections. Rates of infection (episodes/patient/year) were compared using a generalized estimating equations model. Results: A total of 371 children (181 with and 190 without JIA) were included. The median age was 8.8 years (IQR 5.5-11.3); 75% of the patients with JIA received immunosuppressive treatment (24% methotrexate, 22% biologic, 26% both). A total of 667 infections were recorded; 15 (2.2%) were considered severe. The infection rate was 1.31 (95%CI 1.1-1.5) in JIA and 1.12 (95%CI 0.9-1.3) in non-JIA participants (p = 0.19). Age <4 years increased the infection rate by 2.5 times (2.72 vs. 1.12, p < 0.001) in both groups. The most frequent infection sites were upper respiratory (62.6% vs. 74.5%) and gastrointestinal (18.8% vs. 11.4%). There were no differences in severe infections (2.5% vs. 2%, p = 0.65) between the groups. In children with JIA, younger age and higher disease activity (JADAS71) were associated with a higher infection rate. Conclusion: We found no differences in the infection rate or infection severity between patients with and without JIA. Most infections were mild. An age younger than 4 years increased the infection risk in both groups. Higher disease activity was associated with a higher infection rate.

Humoral and cellular immune response to mRNA SARS-CoV-2 BNT162b2 vaccine in adolescents with rheumatic diseases.

BACKGROUND: Data about safety and efficacy of the mRNA SARS-CoV-2 vaccine in adolescents with rheumatic diseases (RD) is scarce and whether these patients generate a sufficient immune response to the vaccine remains an outstanding question. OBJECTIVE: To evaluate safety and humoral and cellular immunity of the BNT162b2 vaccine in adolescents 12 to 18 years with RD and immunosuppressive treatment compared with a healthy control group. METHODS: Adolescents from 12 to 18 years with RD followed at Hospital La Paz in Madrid (n = 40) receiving the BNT162b2 mRNA vaccination were assessed 3 weeks after complete vaccination. Healthy adolescents served as controls (n = 24). Humoral response was measured by IgG antiSpike antibodies, and cellular response by the quantity of IFN-γ and IL-2 present in whole blood stimulated with SARS-CoV-2 Spike and M proteins. RESULTS: There were no differences in spike-specific humoral or cellular response between groups (median IFN-γ response to S specific protein; 528.80 pg/ml in controls vs. 398.44 in RD patients, p 0.78, and median IL-2 response in controls: 635.68 pg/ml vs. 497.30 in RD patients, p 0.22. The most frequent diagnosis was juvenile idiopathic arthritis (26/40, 65%) followed by Lupus (6/40, 15%). 60% of cases (23/40) received TNF inhibitors and 35% (14/40) methotrexate. 40% of patients (26/64) had previous SARS-CoV-2 infection, 9 in the control group and 17 in the RD patients without differences. Of note, 70% of infections were asymptomatic. A higher IFN-γ production was found in COVID-19 recovered individuals than in naive subjects in both groups (controls: median 859 pg/ml in recovered patients vs. 450 in naïve p 0.017, and RD patients: 850 in recovered vs. 278 in naïve p 0.024). No serious adverse events or flares were reported following vaccination. CONCLUSIONS: We conclude that standard of care treatment for adolescents with RD including TNF inhibitors and methotrexate did not affect the humoral and the cellular immunity to BNT162b2 mRNA vaccination compared to a healthy control group. The previous contact with SARS-CoV-2 was the most relevant factor in the immune response.

The role of routine FIBERoptic bronchoscopy monitoring during percutaneous dilatational TRACHeostomy (FIBERTRACH): a study protocol for a randomized, controlled clinical trial.

BACKGROUND: Tracheostomy is one of the most frequent techniques in intensive care units (ICU). Fiberoptic bronchoscopy (FB) is a safety measure when performing a percutaneous dilatational tracheostomy (PDT), but the controversy surrounding the routine use of FB as part of the procedure remains open. National surveys in some European countries showed that the use of FB is non-standardized. Retrospective studies have not shown a significant difference in complications between procedures performed with or without a bronchoscope. International guidelines have not been able to establish recommendations regarding the use of FB in PDT due to lack of evidence. DESIGN: This is a multicenter (three centers at the time of  publishing this paper) randomized controlled clinical trial to examine the safety of percutaneous tracheostomy using FB. We will include all consecutive adult patients admitted to the ICU in whom percutaneous tracheostomy for prolonged mechanical ventilation is indicated and with no exclusion criteria for using FB. Eligible patients will be randomly assigned to receive blind PDT or PDT under endoscopic guidance. All procedures will be performed by experienced intensivists in PDT and FB. A Data Safety and Monitoring Board (DSMB) will monitor the trial. The primary outcome is the incidence of perioperative complications. DISCUSSION: FB is a safe technique when performing PDT although its use is not universally accepted in all ICUs as a routine practice. Should PDT be monitored routinely with endoscopic guidance? This study will assess the role of FB monitoring during PDT. TRIAL REGISTRATION: ClinicalTrials.gov NCT04265625. Registered on February 11, 2020.

Development and Validation of an Early Mortality Risk Score for Older Patients Treated with Chemotherapy for Cancer.

Background: Estimation of life expectancy in older patients is relevant to select the best treatment strategy. We aimed to develop and validate a score to predict early mortality in older patients with cancer. Patients and Methods: A total of 749 patients over 70 years starting new chemotherapy regimens were prospectively included. A prechemotherapy assessment that included sociodemographic variables, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and early death was examined using multivariable logistic regression. Score points were assigned to each risk factor. External validation was performed on an independent cohort. Results: In the training cohort, the independent predictors of 6-month mortality were metastatic stage (OR 4.8, 95% CI [2.4-9.6]), ECOG-PS 2 (OR 2.3, 95% CI [1.1-5.2]), ADL ≤ 5 (OR 1.7, 95% CI [1.1-3.5]), serum albumin levels ≤ 3.5 g/dL (OR 3.4, 95% CI [1.7-6.6]), BMI < 23 kg/m2 (OR 2.5, 95% CI [1.3-4.9]), and hemoglobin levels < 11 g/dL (OR 2.4, 95% CI (1.2-4.7)). With these results, we built a prognostic score. The area under the ROC curve was 0.78 (95% CI, 0.73 to 0.84), and in the validation set, it was 0.73 (95% CI: 0.67-0.79). Conclusions: This simple and highly accurate tool can help physicians making decisions in elderly patients with cancer who are planned to initiate chemotherapy treatment.

Haploidentical transplantation in pediatric non-malignant diseases: A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH).

OBJECTIVE: Describe the GETH haploidentical stem cell transplantation (haplo-HSCT) activity in non-malignant disease (NMDs). METHODS: We retrospectively analyzed data from children with NMDs who underwent haplo-HSCT. RESULTS: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo-HSCT through ex vivo T cell-depleted (TCD) graft platforms or post-transplantation cyclophosphamide (PT-Cy) at 7 Spanish centers. Five cases employed unmanipulated PT-Cy haplo-HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+ CD19+ depletion, TCRαß+ CD19+ selection or naive CD45RA+ T-cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo-HSCT, and bone marrow was the source for one PT-Cy haplo-HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1-year cumulative incidence of graft failure was 27.4%. The 1-year III-IV acute graft-versus-host disease (GvHD) and 1-year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2-year overall survival was 44.9% for PIDs, and the 2-year graft-versus-host disease-free and relapse-free survival rate was 37.6% for the other NMDs. The transplantation-related mortality at day 100 was 30.8%. CONCLUSION: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise.

Bayesian networks established functional differences between breast cancer subtypes.

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which had a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 96 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as mitochondrial function or extracellular matrix between breast cancer subtypes, including our new defined subtype TN-like. In addition, one of the components, mainly related with extracellular matrix processes, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.

Predicting Chemotherapy Toxicity in Older Patients with Cancer: A Multicenter Prospective Study.

BACKGROUND: Standard oncology tools are inadequate to distinguish which older patients are at higher risk of developing chemotherapy-related complications. MATERIALS AND METHODS: Patients over 70 years of age starting new chemotherapy regimens were prospectively included in a multicenter study. A prechemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and the development of grade 3-5 toxicity was examined by using logistic regression. RESULTS: A total of 551 patients were accrued. Chemotherapy doses (odds ratio [OR] 1.834; 95% confidence interval [CI] 1.237-2.719) and creatinine clearance (OR 0.989; 95% CI 0.981-0.997) were the only factors independently associated with toxicity. Only 19% of patients who received reduced doses of chemotherapy and had a creatinine clearance ≥40 mL/minute had grade 3-4 toxicity, compared with 38% of those who received standard doses or had a creatinine clearance <40 mL/minute (p < .0001). However, no satisfactory multivariate model was obtained using different selection approaches. CONCLUSION: Chemotherapy doses and renal function were identified as the major risk factors for developing severe toxicity in the older patient. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up in these patients. IMPLICATIONS FOR PRACTICE: Older patients are more vulnerable to chemotherapy toxicity. However, standard tools are inadequate to identify who is at higher risk of developing chemotherapy-related complications. Chemotherapy doses (standard vs. reduced) and renal function were identified as the major risk factors for developing severe toxicity in the elderly. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up.

Computational models applied to metabolomics data hints at the relevance of glutamine metabolism in breast cancer.

BACKGROUND: Metabolomics has a great potential in the development of new biomarkers in cancer and it has experiment recent technical advances. METHODS: In this study, metabolomics and gene expression data from 67 localized (stage I to IIIB) breast cancer tumor samples were analyzed, using (1) probabilistic graphical models to define associations using quantitative data without other a priori information; and (2) Flux Balance Analysis and flux activities to characterize differences in metabolic pathways. RESULTS: On the one hand, both analyses highlighted the importance of glutamine in breast cancer. Moreover, cell experiments showed that treating breast cancer cells with drugs targeting glutamine metabolism significantly affects cell viability. On the other hand, these computational methods suggested some hypotheses and have demonstrated their utility in the analysis of metabolomics data and in associating metabolomics with patient's clinical outcome. CONCLUSIONS: Computational analyses applied to metabolomics data suggested that glutamine metabolism is a relevant process in breast cancer. Cell experiments confirmed this hypothesis. In addition, these computational analyses allow associating metabolomics data with patient prognosis.

Haploidentical transplantation in high-risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH).

A total of 192 pediatric patients, median age 8.6 years, with high-risk hematological malignancies, underwent haploidentical stem cell transplantation (haplo-HSCT) using post-transplantation cyclophosphamide (PT-Cy), or ex vivo T cell-depleted (TCD) graft platforms, from January 1999 to December 2016 in 10 centers in Spain. Some 41 patients received an unmanipulated graft followed by PT-Cy for graft-vs-host disease (GvHD) prophylaxis. A total of 151 patients were transplanted with CD3-depleted peripheral blood stem cells (PBSCs) by either CD34+ selection, CD3+ CD19+ depletion, TCRαß+ CD19+ depletion or CD45RA+ depletion, added to CD34+ selection for GvHD prophylaxis. The PBSCs were the only source in patients following ex vivo TCD haplo-HSCT; bone marrow was the source in 9 of 41 patients following PT-CY haplo-HSCT. Engraftment was achieved in 91.3% of cases. A donor younger than 30 years, and the development of chronic GvHD were positive factors influencing survival, whereas positive minimal residual disease (MRD) before transplant and lymphoid disease were negative factors. The probability of relapse increased with lymphoid malignancies, a donor killer-cell immunoglobulin-like receptor (KIR) haplotype A and positive MRD pretransplant. No difference was found in overall survival, disease-free survival or relapse incidence between the two platforms. Relapse is still of concern in both platforms, and it should be the focus of future efforts. In conclusion, both platforms for haplo-HSCT were effective and could be utilized depending on the comfort level of the center.

Computational metabolism modeling predicts risk of distant relapse-free survival in breast cancer patients.

Aim: Differences in metabolism among breast cancer subtypes suggest that metabolism plays an important role in this disease. Flux balance analysis is used to explore these differences as well as drug response. Materials & methods: Proteomics data from breast tumors were obtained by mass-spectrometry. Flux balance analysis was performed to study metabolic networks. Flux activities from metabolic pathways were calculated and used to build prognostic models. Results: Flux activities of vitamin A, tetrahydrobiopterin and ß-alanine metabolism pathways split our population into low- and high-risk patients. Additionally, flux activities of glycolysis and glutamate metabolism split triple negative tumors into low- and high-risk groups. Conclusion: Flux activities summarize flux balance analysis data and can be associated with prognosis in cancer.

Biological molecular layer classification of muscle-invasive bladder cancer opens new treatment opportunities.

BACKGROUND: Muscle-invasive bladder tumors are associated with a high risk of relapse and metastasis even after neoadjuvant chemotherapy and radical cystectomy. Therefore, further therapeutic options are needed and molecular characterization of the disease may help to identify new targets. The aim of this study was to characterize muscle-invasive bladder tumors at the molecular level using computational analyses. METHODS: The TCGA cohort of muscle-invasive bladder cancer patients was used to describe these tumors. Probabilistic graphical models, layer analyses based on sparse k-means coupled with Consensus Cluster, and Flux Balance Analysis were applied to characterize muscle-invasive bladder tumors at a functional level. RESULTS: Luminal and Basal groups were identified, and an immune molecular layer with independent value was also described. Luminal tumors showed decreased activity in the nodes of epidermis development and extracellular matrix, and increased activity in the node of steroid metabolism leading to a higher expression of the androgen receptor. This fact points to the androgen receptor as a therapeutic target in this group. Basal tumors were highly proliferative according to Flux Balance Analysis, which makes these tumors good candidates for neoadjuvant chemotherapy. The Immune-high group showed a higher degree of expression of immune biomarkers, suggesting that this group may benefit from immune therapy. CONCLUSIONS: Our approach, based on layer analyses, established a Luminal group candidate for therapy with androgen receptor inhibitors, a proliferative Basal group which seems to be a good candidate for chemotherapy, and an immune-high group candidate for immunotherapy.

Melanoma proteomics suggests functional differences related to mutational status.

Melanoma is the most lethal cutaneous cancer. New drugs have recently appeared; however, not all patients obtain a benefit of these new drugs. For this reason, it is still necessary to characterize melanoma at molecular level. The aim of this study was to explore the molecular differences between melanoma tumor subtypes, based on BRAF and NRAS mutational status. Fourteen formalin-fixed, paraffin-embedded melanoma samples were analyzed using a high-throughput proteomics approach, combined with probabilistic graphical models and Flux Balance Analysis, to characterize these differences. Proteomics analyses showed differences in expression of proteins related with fatty acid metabolism, melanogenesis and extracellular space between BRAF mutated and BRAF non-mutated melanoma tumors. Additionally, probabilistic graphical models showed differences between melanoma subgroups at biological processes such as melanogenesis or metabolism. On the other hand, Flux Balance Analysis predicts a higher tumor growth rate in BRAF mutated melanoma samples. In conclusion, differential biological processes between melanomas showing a specific mutational status can be detected using combined proteomics and computational approaches.

A novel approach to triple-negative breast cancer molecular classification reveals a luminal immune-positive subgroup with good prognoses.

Triple-negative breast cancer is a heterogeneous disease characterized by a lack of hormonal receptors and HER2 overexpression. It is the only breast cancer subgroup that does not benefit from targeted therapies, and its prognosis is poor. Several studies have developed specific molecular classifications for triple-negative breast cancer. However, these molecular subtypes have had little impact in the clinical setting. Gene expression data and clinical information from 494 triple-negative breast tumors were obtained from public databases. First, a probabilistic graphical model approach to associate gene expression profiles was performed. Then, sparse k-means was used to establish a new molecular classification. Results were then verified in a second database including 153 triple-negative breast tumors treated with neoadjuvant chemotherapy. Clinical and gene expression data from 494 triple-negative breast tumors were analyzed. Tumors in the dataset were divided into four subgroups (luminal-androgen receptor expressing, basal, claudin-low and claudin-high), using the cancer stem cell hypothesis as reference. These four subgroups were defined and characterized through hierarchical clustering and probabilistic graphical models and compared with previously defined classifications. In addition, two subgroups related to immune activity were defined. This immune activity showed prognostic value in the whole cohort and in the luminal subgroup. The claudin-high subgroup showed poor response to neoadjuvant chemotherapy. Through a novel analytical approach we proved that there are at least two independent sources of biological information: cellular and immune. Thus, we developed two different and overlapping triple-negative breast cancer classifications and showed that the luminal immune-positive subgroup had better prognoses than the luminal immune-negative. Finally, this work paves the way for using the defined classifications as predictive features in the neoadjuvant scenario.