Biomarker Identification through Proteomics in Colorectal Cancer.

Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer.

The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective.

Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.

Five-year follow-up mortality prognostic index for colorectal patients.

PURPOSE: To identify 5-year survival prognostic variables in patients with colorectal cancer (CRC) and to propose a survival prognostic score that also takes into account changes over time in the patient's health-related quality of life (HRQoL) status. METHODS: Prospective observational cohort study of CRC patients. We collected data from their diagnosis, intervention, and at 1, 2, 3, and 5 years following the index intervention, also collecting HRQoL data using the EuroQol-5D-5L (EQ-5D-5L), European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Multivariate Cox proportional models were used. RESULTS: We found predictors of mortality over the 5-year follow-up to be being older; being male; having a higher TNM stage; having a higher lymph node ratio; having a result of CRC surgery classified as R1 or R2; invasion of neighboring organs; having a higher score on the Charlson comorbidity index; having an ASA IV; and having worse scores, worse quality of life, on the EORTC and EQ-5D questionnaires, as compared to those with higher scores in each of those questionnaires respectively. CONCLUSIONS: These results allow preventive and controlling measures to be established on long-term follow-up of these patients, based on a few easily measurable variables. IMPLICATIONS FOR CANCER SURVIVORS: Patients with colorectal cancer should be monitored more closely depending on the severity of their disease and comorbidities as well as the perceived health-related quality of life, and preventive measures should be established to prevent adverse outcomes and therefore to ensure that better treatment is received. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02488161.

Reference values of EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L for women with non-metastatic breast cancer at diagnosis and 2 years after.

PURPOSE: To obtain reference norms of EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-5L, based on a population of Spanish non-metastatic breast cancer patients at diagnosis and 2 years after, according to relevant demographic and clinical characteristics. METHODS: Multicentric prospective cohort study including consecutive women aged ≥ 18 years with a diagnosis of incident non-metastatic breast cancer from April 2013 to May 2015. Health-related quality of life (HRQoL) questionnaires were administered between diagnosis and beginning the therapy, and 2 years after. HRQoL differences according to age, comorbidity and stage were tested with ANOVA or Chi Square test and multivariate linear regression models. RESULTS: 1276 patients were included, with a mean age of 58 years. Multivariate models of EORTC QLQ-C30 summary score and EQ-5D-5L index at diagnosis and at 2-year follow-up show the independent association of comorbidity and tumor stage with HRQoL. The standardized multivariate regression coefficient of EORTC QLQ-C30 summary score was lower (poorer HRQoL) for women with stage II and III than for those with stage 0 at diagnosis (- 0.11 and - 0.07, p < 0.05) and follow-up (- 0.15 and - 0.10, p < 0.01). The EQ-5D-5L index indicated poorer HRQoL for women with Charlson comorbidity index ≥ 2 than comorbidity 0 both at diagnosis (- 0.13, p < 0.001) and follow-up (- 0.18, p < 0.001). Therefore, we provided the reference norms at diagnosis and at the 2-year follow-up, stratified by age, comorbidity index, and tumor stage. CONCLUSION: These HRQoL reference norms can be useful to interpret the scores of women with non-metastatic breast cancer, comparing them with country-specific reference values for this population.

Clusterin Expression in Colorectal Carcinomas.

Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer.

Adherence of long-term breast cancer survivors to follow-up care guidelines: a study based on real-world data from the SURBCAN cohort.

PURPOSE: To identify adherence to follow-up recommendations in long-term breast cancer survivors (LTBCS) of the SURBCAN cohort and to identify its determinants, using real-world data. METHODS: We conducted a retrospective study using electronic health records from 2012 to 2016 of women diagnosed with incident breast cancer in Spain between 2000 and 2006 and surviving at least 5 years. Adherence to basic follow-up recommendations, adherence according to risk of recurrence, and overall adherence were calculated based on attendance at medical appointments and imaging surveillance, by year of survivorship. Logistic regression models were fitted to depict the association between adherence and its determinants. RESULTS: A total of 2079 LTBCS were followed up for a median of 4.97 years. Of them, 23.6% had survived ≥ 10 years at baseline. We estimated that 79.5% of LTBCS were overall adherent to at least one visit and one imaging test. Adherence to recommendations decreased over time and no differences were found according to recurrence risk. Determinants of better overall adherence were diagnosis in middle age (50-69 years old), living in a more-deprived area, having fewer years of survival, receiving primary treatment, and being alive at the end of follow-up. CONCLUSION: We identified women apparently not complying with surveillance visits and tests. Special attention should be paid to the youngest and eldest women at diagnosis and to those with longer survival.

Influence of depression on survival of colorectal cancer patients drawn from a large prospective cohort.

OBJECTIVE: The prevalence of depressive symptoms immediately after the diagnosis of colorectal cancer (CRC) is high and has important implications both psychologically and on the course of the disease. The aim of this study is to analyse the association between depressive symptoms and CRC survival at 5 years after diagnosis. METHODS: This multicentre, prospective, observational cohort study was conducted on a sample of 2602 patients with CRC who completed the Hospital Anxiety and Depression Scale (HADS-D) at 5 years of follow-up. Survival was analysed using the Kaplan-Meier method and Cox regression models. RESULTS: According to our analysis, the prevalence of depressive symptoms after a CRC diagnosis was 23.8%. The Cox regression analysis identified depression as an independent risk factor for survival (HR = 1.47; 95% CI: 1.21-1.8), a finding which persisted after adjusting for sex (female: HR = 0.63; 95% CI: 0.51-0.76), age (>70 years: HR = 3.78; 95% CI: 1.94-7.36), need for help (yes: HR = 1.43; 95% CI: 1.17-1.74), provision of social assistance (yes: HR = 1.46; 95% CI: 1.16-1.82), tumour size (T3-T4: HR = 1.56; 95% CI: 1.22-1.99), nodule staging (N1-N2: HR = 2.46; 95% CI: 2.04-2.96), and diagnosis during a screening test (yes: HR = 0.71; 95% CI: 0.55-0.91). CONCLUSIONS: There is a high prevalence of depressive symptoms in patients diagnosed with CRC. These symptoms were negatively associated with the survival rate independently of other clinical variables. Therefore, patients diagnosed with CRC should be screened for depressive symptoms to ensure appropriate treatment can be provided.

Anxiety, depression, health-related quality of life, and mortality among colorectal patients: 5-year follow-up.

PURPOSE: Health-related quality of life (HRQoL) measurement represents an important outcome in cancer patients. We describe the evolution of HRQoL over a 5-year period in colorectal cancer patients, identifying predictors of change and how they relate to mortality. METHODS: Prospective observational cohort study including colorectal cancer (CRC) patients having undergone surgery in nineteen public hospitals who were monitored from their diagnosis, intervention and at 1-, 2-, 3-, and 5-year periods thereafter by gathering HRQoL data using the EuroQol-5D-5L (EQ-5D-5L), European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), and Hospital Anxiety and Depression Scale (HADS) questionnaires. Multivariable generalized linear mixed models were used. RESULTS: Predictors of Euroqol-5D-5L (EQ-5D-5L) changes were having worse baseline HRQoL; being female; higher Charlson index score (more comorbidities); complications during admission and 1 month after surgery; having a stoma after surgery; and needing or being in receipt of social support at baseline. For EORTC-QLQ-C30, predictors of changes were worse baseline EORTC-QLQ-C30 score; being female; higher Charlson score; complications during admission and 1 month after admission; receiving adjuvant chemotherapy; and having a family history of CRC. Predictors of changes in HADS anxiety were being female and having received adjuvant chemotherapy. Greater depression was associated with greater baseline depression; being female; higher Charlson score; having complications 1 month after intervention; and having a stoma. A deterioration in all HRQoL questionnaires in the previous year was related to death in the following year. CONCLUSIONS: These findings should enable preventive follow-up programs to be established for such patients in order to reduce their psychological distress and improve their HRQoL to as great an extent as possible. GOV IDENTIFIER: NCT02488161.

Effect of comorbidities on long-term outcomes of colorectal cancer patients.

OBJECTIVE: The objective of this work is to evaluate the association of comorbidities with various outcomes in patients diagnosed with colon or rectal cancer. METHODS: We conducted a prospective cohort study of patients diagnosed with colon or rectal cancer who underwent surgery. Data were gathered on sociodemographic, clinical characteristics, disease course, and the EuroQol EQ-5D and EORTC QLQ-C30 scores, up to 5 years after surgery. The main outcomes of the study were mortality, complications, readmissions, reoperations, and changes in PROMs up to 5 years. Multivariable multilevel logistic regression models were used in the analyses. RESULTS: Mortality at some point during the 5-year follow-up was related to cardiocerebrovascular, hemiplegia and/or stroke, chronic obstructive pulmonary disease (COPD), diabetes, cancer, and dementia. Similarly, complications were related to cardiovascular disease, COPD, diabetes, hepatitis, hepatic or renal pathologies, and dementia; readmissions to cardiovascular disease, COPD, and hepatic pathologies; and reoperations to cerebrovascular and diabetes. Finally, changes in EQ-5D scores at some point during follow-up were related to cardiocerebrovascular disease, COPD, diabetes, pre-existing cancer, hepatic and gastrointestinal pathologies, and changes in EORTC QLQ-C30 scores to cardiovascular disease, COPD, diabetes, and hepatic and gastrointestinal pathologies. CONCLUSIONS: Optimising the management of the comorbidities most strongly related to adverse outcomes may help to reduce those events in these patients.

Multimorbidity clusters among long-term breast cancer survivors in Spain: Results of the SURBCAN study.

The disease management of long-term breast cancer survivors (BCS) is hampered by the scarce knowledge of multimorbidity patterns. The aim of our study was to identify multimorbidity clusters among long-term BCS and assess their impact on mortality and health services use. We conducted a retrospective study using electronic health records of 6512 BCS from Spain surviving at least 5 years. Hierarchical cluster analysis was used to identify groups of similar patients based on their chronic diagnoses, which were assessed using the Clinical Classifications Software. As a result, multimorbidity clusters were obtained, clinically defined and named according to the comorbidities with higher observed/expected prevalence ratios. Multivariable Cox and negative binomial regression models were fitted to estimate overall mortality risk and probability of contacting health services according to the clusters identified. 83.7% of BCS presented multimorbidity, essential hypertension (34.5%) and obesity and other metabolic disorders (27.4%) being the most prevalent chronic diseases at the beginning of follow-up. Five multimorbidity clusters were identified: C1-unspecific (29.9%), C2-metabolic and neurodegenerative (28.3%), C3-anxiety and fractures (9.7%), C4-musculoskeletal and cardiovascular (9.6%) and C5-thyroid disorders (5.3%). All clusters except C5-thyroid disorders were associated with higher mortality compared to BCS without comorbidities. The risk of mortality in C4 was increased by 64% (adjusted hazard ratio 1.64, 95% confidence interval 1.52-2.07). Stratified analysis showed an increased risk of death among BCS with 5 to 10 years of survival in all clusters. These results help to identify subgroups of long-term BCS with specific needs and mortality risks and to guide BCS clinical practice regarding multimorbidity.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

Risk scores to predict mortality 2 and 5 years after surgery for colorectal cancer in elderly patients.

BACKGROUND: The aim of this study was to identify predictors of mortality in elderly patients undergoing colorectal cancer surgery and to develop a risk score. METHODS: This was an observational prospective cohort study. Individuals over 80 years diagnosed with colorectal cancer and treated surgically were recruited in 18 hospitals in the Spanish National Health Service, between June 2010 and December 2012, and were followed up 1, 2, 3, and 5 years after surgery. Sociodemographic and clinical data were collected. The primary outcomes were mortality at 2 and between 2 and 5 years after the index admission. RESULTS: The predictors of mortality 2 years after surgery were haemoglobin ≤ 10 g/dl and colon locations (HR 1.02; CI 0.51-2.02), ASA class of IV (HR 3.55; CI 1.91-6.58), residual tumour classification of R2 (HR 7.82; CI 3.11-19.62), TNM stage of III (HR 2.14; CI 1.23-3.72) or IV (HR 3.21; CI 1.47-7), LODDS of more than - 0.53 (HR 3.08; CI 1.62-5.86)) and complications during admission (HR 1.73; CI 1.07-2.80). Between 2 and 5 years of follow-up, the predictors were no tests performed within the first year of follow-up (HR 2.58; CI 1.21-5.46), any complication due to the treatment within the 2 years of follow-up (HR 2.47; CI 1.27-4.81), being between 85 and 89 and not having radiotherapy within the second year of follow-up (HR 1.60; CI 1.01-2.55), no colostomy closure within the 2 years of follow-up (HR 4.93; CI 1.48-16.41), medical complications (HR 1.61; CI 1.06-2.44), tumour recurrence within the 2 years of follow-up period (HR 3.19; CI 1.96-5.18), and readmissions at 1 or 2 years of follow-up after surgery (HR 1.44; CI 0.86-2.41). CONCLUSION: We have identified variables that, in our sample, predict mortality 2 and between 2 and 5 years after surgery for colorectal cancer older patients. We have also created risks scores, which could support the decision-making process. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02488161 .

Predictors of readmission and reoperation in patients with colorectal cancer.

PURPOSE: To assess the impact of readmission and reoperation on colon or rectal cancer patients in clinical and patient-reported outcome measures (PROMs) and to identify predictors of these events up to 1 year after surgery. METHODS: Prospective cohort study of patients diagnosed with colon or rectal cancer who underwent surgery at 1 of 22 hospitals. Medical history, clinical parameters, and PROMs were evaluated as possible predictors. Multivariable multilevel logistic regression and survival models were used in the analyses to create the clinical prediction rules. Models were developed in a derivation sample and validated in a different sample. RESULTS: Readmission and reoperation were related to clinical outcomes and changes in some PROMs. Predictors of readmission in colon cancer were ASA class (odds ratio (OR) 4.5), TNM (OR for TNM III 3.24, TNM IV 4.55), evidence of residual tumor (R2) (OR 3.96), and medical (OR 1.96) and infectious (OR 2.01) complications within 30 days after surgery, while for rectal cancer, the predictors identified were age (OR 1.03), R2 (OR 6.48), infectious complications within 30 days (OR 2.29), hemoglobin (OR 3.26), lymph node ratio (OR 2.35), and surgical complications within 1 month (OR 3.04). Predictors of reoperation were TNM IV (OR 5.06), surgical complications within 30 days (OR 1.98), and type and site of tumor (OR 1.72) in colon cancer and being male (OR 1.52), age (OR 1.80), stoma (OR 1.87), and surgical complications within 1 month (OR 1.95) in rectal cancer. CONCLUSIONS: Our clinical prediction rule models are easy to use and could help to develop and implement interventions to reduce preventable readmissions and reoperations. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02488161 Identifier: NCT02488161.

Stage- and age-adjusted cost-effectiveness analysis of laparoscopic surgery in rectal cancer.

BACKGROUND: It has been argued that laparoscopy should be a standard treatment in rectal cancer due to its greater technical complexity. The objective of this study was to conduct a cost-effectiveness analysis to compare laparoscopy with open surgery for rectal cancer adjusting for age and clinical stage. METHODS: A real-world prospective cost-effectiveness cohort study was conducted with data on costs and effectiveness at individual patient level. A "genetic matching" algorithm was used to correct for selection bias. After balancing the sample groups, combined multivariate analysis of total costs and quality-adjusted life years (QALYs) was performed using seemingly unrelated regression (SUR) models. These models were first constructed without interactions and, subsequently, effects of any age-stage interaction were analyzed. RESULTS: The sample included 601 patients (400 by laparoscopy and 201 by open surgery). Crude cost-effectiveness analysis indicated that overall laparoscopy was cheaper and associated with higher QALYs. The SUR models without interactions showed that while laparoscopy remained dominant, the incremental effectiveness decreased to the point that it offered no statistically significant benefits over open surgery. In the subgroup analysis, at advanced stages of the disease, although none of the coefficients were significant, the mean incremental effectiveness (QALYs value) for laparoscopy was positive in younger patients and negative in older patients. Further, for advanced stages, the mean cost of open surgery was lower in both age subgroups but differences did not reach statistical significance. In early stages, laparoscopy cost was significantly lower in the subgroup younger than 70 and higher in the older subgroup. CONCLUSIONS: The cost-effectiveness of laparoscopy in surgery for rectal cancer justifies this being the standard surgical procedure in young patients and those at initial stages. The choice of procedure should be discussed with patients who are older and/or in advanced stages of the disease. Trial registration ClinicalTrials.gov Identifier: NCT02488161.

Factors associated with colon cancer early, intermediate and late recurrence after surgery for stage I-III: A 5-year prospective study.

OBJECTIVE: To identify factors associated with early, intermediate or late recurrence colon cancer recurrence. METHODS: A total of 1,732 consecutive patients with colon cancer were recruited and followed for a period of 5 years. Recurrence at 1 year (early), from 1 to 2 (early), from 2 to 3 (intermediate) and from 3 to 5 years (late) was the main outcome measures. RESULTS: Predictors of early recurrence (AUC (95% CI):0.74 (0.70-0.78) were as follows: TNM stage II and III, more than one type of invasion, haemoglobin <10 g/dl, residual tumour (R1), ASA IV, log odds of positive lymph nodes ratio ≥-0.53, perforation, neoadjuvant chemotherapy, infectious complications within 1 year and CEA pre- and post-intervention. These factors remained significant for predicting intermediate (AUC [95% CI]: 0.72 [0.67-0.77]) and late (AUC [95% CI]: 0.68 [0.63-0.74]) recurrence, except for ASA class, log lymph node ratio, perforation and neoadjuvant chemotherapy. Additionally, laterality (left) and medical complications up to 2 years were significant. CONCLUSIONS: These risk factors show good predictive ability of early, intermediate and late recurrence, confirming factors established by guidelines and adding some others. They could serve to provide more appropriate and accurate treatment and follow-up tailored to patient characteristics.

Clinical-pathological characteristics and short-term follow-up associated with proliferation, apoptosis and angiogenesis in a prospective cohort of patients with colorectal tumours.

We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical-pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27-0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.

Clinical and sociodemographic factors that may influence the resilience of women surviving breast cancer: cross-sectional study.

PURPOSE: Breast cancer is one of the most common diseases, affecting many thousands of women. Although more than 80% of women survive the experience, very few studies have been conducted to examine the question of resilience among long-term survivors of breast cancer. The aim of this study is to describe the clinical and sociodemographic factors that correlate with greater resilience in women survivors of breast cancer, in the Costa del Sol Health Area (Spain). METHODS: Accordingly, a descriptive cross-sectional study was conducted, with respect to 59 survivors of breast cancer, who each completed a questionnaire for analysis according to the Connor-Davidson Resilience Scale (CD-RISC). RESULTS: The median resilience score was 77 (interquartile range 70-80). The group of patients who had survived for six or more years since the diagnosis had a higher score for total resilience (90: IR 76-92) than those diagnosed more recently (74: IR 65.7-83.7) (p = 0.012). Regarding the patients' education background, the group with no formal qualifications or only primary studies had a score of 72 (IR 64-84), versus 79 (IR 74-89.7) for the group with higher levels of education (p = 0.016). Of the clinical variables, only the administration of chemotherapy was significantly associated with the score obtained on the CD-RISC scale (p = 0.012). CONCLUSIONS: The results obtained in this study lead us to conclude that sociodemographic and clinical factors have a positive impact on the level of resilience among women resident in the Costa del Sol Health Area and who are long-term survivors of breast cancer.

Risk factors affecting hospital stay among patients undergoing colon cancer surgery: a prospective cohort study.

PURPOSE: To identify and validate risk factors that contribute to prolonged length of hospital stay (LOS) in patients undergoing resection for colorectal cancer. METHODS: This prospective cohort study included 1955 patients admitted to 22 hospitals for primary resection of colorectal cancer. Multivariate analyses were used to identify and validate risk factors, randomizing patients into a derivation and a validation cohort. Multiple correspondence and cluster analysis were performed to identify clinical subtypes based on LOS. RESULTS: The strongest independent predictors of prolonged LOS were postoperative reintervention, surgical site infection, open surgery, and distant metastasis. The multiple correspondence and cluster analysis provided three groups of patients in relation to prolonged LOS: patients with the longest LOS included the highest percentage of patients with open surgery, distant metastasis, deep surgical site infections, emergency admissions, additional diagnostic factors, and highly contaminated surgical sites. Patients with prolonged LOS (> 14 days) were more likely to develop adverse outcomes within 30 days after discharge. CONCLUSIONS: Patients undergoing resection of colorectal cancer cluster into different groups based on LOS of the index admission. Those with prolonged LOS were more likely to develop adverse outcomes within 30 days after discharge. Some of the strongest independent predictors of prolonged LOS, such as surgical infections or open surgery, could be modified to reduce LOS and, in turn, other adverse outcomes. TRIAL REGISTRATION: NCT02488161.

Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy.

The interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as a great promise for cancer treatment, increasing total survival compared to standard therapy in different tumors. Despite the hopefulness of these results, a significant percentage of patients do not respond to such therapy or will end up evolving toward a progressive disease. Besides their role in PD-L1 expression, altered protein kinases in tumor cells can limit the effectiveness of PD-1/PD-L1 blocking therapies at different levels. In this review, we describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments.