SEOM-GEMCAD-TTD clinical guidelines for the adjuvant treatment of colon cancer (2023).

Colorectal cancer (CRC) has a 5-year overall survival rate of over 60%. The decrease in the rate of metastatic disease is due to screening programs and the population's awareness of healthy lifestyle. Similarly, advancements in surgical methods and the use of adjuvant chemotherapy have contributed to a decrease in the recurrence of resected disease. Before evaluating a patient's treatment, it is recommended to be discussed in a multidisciplinary tumor board. In stage II tumors, the pathologic characteristics of poor prognosis must be known (T4, number of lymph nodes analyzed less than 12, lymphovascular or perineural invasion, obstruction or perforation, poor histologic grade, presence of tumor budding) and it is mandatory to determine the MSI/MMR status for avoiding administering fluoropyridimidines in monotherapy to patients with MSI-H/dMMR tumors. In stage III tumors, the standard treatment consists of a combination of fluoropyrimidine (oral or intravenous) with oxaliplatin for 6 months although the administration of CAPOX can be considered for 3 months in low-risk tumors. Neoadjuvant treatment is not consolidated yet although immunotherapy is achieving very good preliminary results in MSI-H patients. The use of ctDNA to define the treatment and monitoring of resected tumors is only recommended within studies. These guidelines are intended to help decision-making to offer the best management of patients with non-metastatic colon cancer.

Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

8-Oxoguanine DNA Glycosylase 1 Upregulation as a Risk Factor for Obesity and Colorectal Cancer.

DNA damage has been extensively studied as a potentially helpful tool in assessing and preventing cancer, having been widely associated with the deregulation of DNA damage repair (DDR) genes and with an increased risk of cancer. Adipose tissue and tumoral cells engage in a reciprocal interaction to establish an inflammatory microenvironment that enhances cancer growth by modifying epigenetic and gene expression patterns. Here, we hypothesize that 8-oxoguanine DNA glycosylase 1 (OGG1)-a DNA repair enzyme-may represent an attractive target that connects colorectal cancer (CRC) and obesity. In order to understand the mechanisms underlying the development of CRC and obesity, the expression and methylation of DDR genes were analyzed in visceral adipose tissue from CRC and healthy participants. Gene expression analysis revealed an upregulation of OGG1 expression in CRC participants (p < 0.005) and a downregulation of OGG1 in normal-weight healthy patients (p < 0.05). Interestingly, the methylation analysis showed the hypermethylation of OGG1 in CRC patients (p < 0.05). Moreover, expression patterns of OGG1 were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that OGG1 can regulate CRC risk through obesity and may act as a biomarker for CRC.

Influence of Diagnostic Delay on Survival Rates for Patients with Colorectal Cancer.

Colorectal cancer affects men and women alike. Sometimes, due to clinical-pathological factors, the absence of symptoms or the failure to conduct screening tests, its diagnosis may be delayed. However, it has not been conclusively shown that such a delay, especially when attributable to the health system, affects survival. The aim of the present study is to evaluate the overall survival rate of patients with a delayed diagnosis of colorectal cancer. This observational, prospective, multicenter study was conducted at 22 public hospitals located in nine Spanish provinces. For this analysis, 1688 patients with complete information in essential variables were included. The association between diagnostic delay and overall survival at five years, stratified according to tumor location, was estimated by the Kaplan-Meier method. Hazard ratios for this association were estimated using multivariable Cox regression models. The diagnostic delay ≥ 30 days was presented in 944 patients. The presence of a diagnostic delay of more than 30 days was not associated with a worse prognosis, contrary to a delay of less than 30 days (HR: 0.76, 0.64-0.90). In the multivariate analysis, a short delay maintained its predictive value (HR: 0.80, 0.66-0.98) regardless of age, BMI, Charlson index or TNM stage. A diagnostic delay of less than 30 days is an independent factor for short survival in patients with CRC. This association may arise because the clinical management of tumors with severe clinical characteristics and with a poorer prognosis are generally conducted more quickly.

SEOM-GEMCAD-TTD Clinical Guideline for the diagnosis and treatment of esophageal cancer (2021).

Esophageal cancer is an aggressive tumor, and is the sixth-leading cause of death from cancer. Incidence is rising in Spain, particularly among men. Two main pathological different subtypes have been described: squamous cell carcinoma and adenocarcinoma. Growing evidence of their epidemiology and molecular differences explains their different response to novel treatments, and they are therefore likely to be treated as two separate entities in the near future. The best results are obtained with a multidisciplinary therapeutic strategy, and the introduction of immunotherapy is a promising new approach that will improve prognosis. In these guidelines, we review the evidence for the different methods of diagnosis and therapeutic strategies that form the basis of our standard of care.

Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice.

The impact of stressful events is especially important during early life, because certain cortical regions, especially the prefrontal cortex (PFC), are still developing. Consequently, aversive experiences that occur during the peripubertal period can cause long-term alterations in neural connectivity, physiology and related behaviors. Although sex influences the stress response and women are more likely to develop stress-related psychiatric disorders, knowledge about the effects of stress on females is still limited. In order to analyze the long-term effects of peripubertal stress (PPS) on the excitatory and inhibitory circuitry of the adult PFC, and whether these effects are sex-dependent, we applied an unpredictable chronic PPS protocol based on psychogenic stressors. Using two strains of transgenic mice with specific fluorescent cell reporters, we studied male and diestrus females to know how PPS affects the structure and connectivity of parvalbumin expressing (PV+) interneurons and pyramidal neurons. We also studied the expression of molecules related to excitatory and inhibitory neurotransmission, as well as alterations in the expression of plasticity-related molecules. The structure of pyramidal neurons was differentially affected by PPS in male and female mice: while the former had a decreased dendritic spine density, the latter displayed an increase in this parameter. PPS affected the density of puncta expressing excitatory and inhibitory synaptic markers exclusively in the female mPFC. Similarly, only in female mice we observed an increased complexity of the dendritic tree of PV+ neurons. Regarding the perisomatic innervation on pyramidal and PV + neurons by basket cells, we found a significant increase in the density of puncta in stressed animals, with interesting differences between the sexes and the type of basket cell analyzed. Finally, the PPS protocol also altered the total number of somata expressing the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) when we analyzed both sexes together. These results highlight the strong programming effects of aversive experiences during early life for the establishment of cortical circuitry and the special impact of these stressful events on females.

Incidence of COVID-19 in outpatients with cancer receiving active treatment in the context of a pandemic: An Andalusian cohort study.

BACKGROUND: Leading scientific societies have recommended delaying and/or suspending active cancer treatment during the COVID-19 pandemic. Nevertheless, data on this novel infection in patients with a diagnosis of cancer receiving active treatment are scarce and it is unknown if these recommendations could have repercussions on future progress of the disease. The main objective of this study is to learn the COVID-19 incidence rate in outpatients with cancer receiving active treatment. METHODS: This work is a retrospective cohort study that included all patients with a diagnosis of cancer who received active cancer treatment in two Andalusian hospitals between February 26 and May 13, 2020. Variables regarding the patient, tumor, and development of COVID-19 were collected. A descriptive analysis was performed and the cumulative incidence of COVID-19 in these patients was evaluated. RESULTS: A total of 673 patients were included. The median age was 62 years. There was a low rate of comorbidity and 12.1% had an ECOG >2. Breast cancer was the most common cancer (41%), followed by colorectal and lung cancer. Stage IV cancer was reported in 52.7% of patients. The most common treatment was chemotherapy (53.9%). Treatment was delayed or suspended in 6% of patients. Only three patients developed COVID-19. The cumulative incidence was 0.44% and one person died due to infection. CONCLUSIONS: In the present retrospective cohort study we found a low incidence of COVID-19 infection in patients with cancer receiving active treatment in an outpatient setting. The sociodemographic factors of Andalusia may explain why these results differ from those presented by other colleagues in Spain, but raise questions about whether universal recommendations may put the benefits of antineoplastic therapy at risk.

The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1+ tumour-infiltrating lymphocytes.

BACKGROUND: Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. METHODS: PD-1- and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. RESULTS: Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. CONCLUSION: We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

Impact of Tumor LINE-1 Methylation Level and Neoadjuvant Treatment and Its Association with Colorectal Cancer Survival.

Recent studies suggest that long-interspersed nucleotide element-1 (LINE-1) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation (p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients (p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

Tumour location and efficacy of first-line EGFR inhibitors in KRAS/RAS wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials.

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis. Methods: Patients with KRAS/RAS-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Patients with KRAS-wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with KRAS-wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the RAS-wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours. Conclusion: We observed significantly improved efficacy outcomes in patients with KRAS/RAS-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours. Trial registration numbers: NCT01161316 and NCT00885885.

First hospital contact via the Emergency Department is an independent predictor of overall survival and disease-free survival in patients with colorectal cancer.

AIMS: the aim of this study was to examine the possible association between the type of hospital admission and subsequent survival of the patient, as well as the pathological features recorded in a large population of patients with colorectal cancer. METHODS: the study included 1,079 patients diagnosed with colon or rectal cancer in the Hospital Costa del Sol (Marbella, Spain). The relationship between patient survival rate and type of first admission to the hospital (elective or emergency admission) was assessed. The following variables were studied: age, gender, tumor location, pathological stage, differentiation grade, chemotherapy before surgery and survival. RESULTS: colon tumors are more common in patients admitted to hospital for the first time via the emergency service (63.7%) and the tumors tend to be poorly differentiated (64.2%) and metastatic (70%). These patients also present a more aggressive disease and a poorer prognosis than patients with an elective admission. With regard to patients from the Emergency Department, a Cox regression analysis showed a risk-ratio (RR) of 1.36 (confidence interval [CI] 95%: 1.11-1.66) for disease-free survival and of 1.41 (95% CI: 1.14-1.76) for overall survival. CONCLUSIONS: hospital admission via the Emergency Department is an indicator of aggressiveness and poorer prognosis compared to patients who enter via programmed routes.

Biological and prognostic differences between symptomatic colorectal carcinomas and those detected by screening.

INTRODUCTION: Few studies have been conducted to establish the relationship between colorectal cancer screening programmes and survival adjusting by stage and, to determine whether there are differences, at a biological level, between the tumours of asymptomatic and symptomatic patients. Accordingly, the aim of this study is to evaluate clinical, biological and survival differences between symptomatic colorectal tumours and those detected by screening. STUDY METHOD: A prospective cohort study was performed of patients subjected to surgical intervention during the period 2010-2012, at different hospitals in Spain. In every case, clinical, pathological, biological and survival-related variables were obtained. RESULTS: A total of 2634 patients from the CARESS-CCR cohort were analysed; of these, 220 were diagnosed through screening. The asymptomatic patients were younger, had a higher Body Mass Index (BMI), a lower degree of perineural invasion and a less advanced T stage and nodular stage, and the tumour was frequently located on the right side of the colon. All of these differences were statistically significant. The serum tumour marker carbohydrate antigen 19.9 (CA 19.9) was found more frequently in the symptomatic patients (p < 0.05). However, no significant differences were found regarding the markers of tumour biology: Ki67 (proliferation), CD105 (angiogenesis) and the Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay (apoptosis). The patients with asymptomatic tumours had a lower mortality at five years than those diagnosed presenting symptoms. CONCLUSIONS: The detection method employed influenced the survival of patients with colorectal cancer and there were no significant biological differences between the study groups.

Factors Associated with Prolonged Patient-Attributable Delay in the Diagnosis of Colorectal Cancer.

PURPOSE: The delayed diagnosis of colorectal cancer (CRC) may be attributable to sociodemographic characteristics, to aspects of tumour histopathology or to the functioning of the health system. We seek to determine which of these factors most influences prolonged patient-attributable delay (PPAD) in the diagnosis and treatment of CRC. MATERIALS AND METHODS: A prospective, multicentre observational study was conducted in 22 Spanish hospitals. In total, 1,785 patients were recruited to the study between 2010 and 2012 and underwent elective or urgent surgery. PPAD is considered to occur when the time elapsed between a patient presenting the symptom and him/her seeking attention from the primary care physician or hospital emergency department exceeds 180 days. A bivariate analysis was performed to assess differences in variables segmented by tumour location and patient delay. Multivariate logistic regression analysis was performed on the outcome variable, PPAD. RESULTS: The rate of PPAD among this population was 12.1%. PPAD was significantly associated with altered bowel rhythm (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.02 to 1.83) and with adenocarcinoma histology, in comparison with mucinous adenocarcinoma (OR, 2.03; 95% CI, 1.11 to 3.71). Other sociocultural factors and clinicopathological features were not independent predictors of PPAD. CONCLUSION: Many patients do not consider altered bowel rhythm an alarming symptom, warranting a visit to the doctor. PPAD could be reduced by improving health education, raising awareness of CRC-related symptoms.

Efficacy and safety of aflibercept in metastatic colorectal cancer pretreated with bevacizumab: A report of five cases.

Aflibercept is a recombinant fusion protein that acts by inhibiting tumoural angiogenesis. Efficacy data obtained in the VELOUR randomised study has contributed to the approval of aflibercept as a second-line metastatic colorectal cancer (mCRC) treatment following an oxaliplatin-based regimen. The present study reports a case series of five patients with mCRC, who were treated in two centres since 2011 in the Compassionate Use Program for aflibercept. All patients had a KRAS mutation and previously received palliative fluoropyrimidine-oxaliplatin-based chemotherapy with bevacizumab. A doublet with irinotecan combined with aflibercept was administered until progression of disease. The majority of patients received a greater number of aflibercept cycles than the median reported in the VELOUR study (12 vs. 7 cycles), with manageable and reversible toxicity. The most frequent adverse events observed were diarrhoea, neutropenia, fatigue, proteinuria and hypertension. Most cases obtained a progression-free survival greater than the median reported in the VELOUR study (11 vs. 6.9 months) and, in a subgroup of patients previously treated with bevacizumab, and a median survival time of ~47 months was reached from the initial treatment of the disease. The present study contrasts the efficacy and safety results obtained from the pivotal VELOUR trial, and confirms that aflibercept, used in routine clinical practice outside of the clinical trial environment, is active and well-tolerated following bevacizumab treatment.

The role and prognostic value of apoptosis in colorectal carcinoma.

BACKGROUND: Alterations to apoptosis are a common occurrence in human tumours. The aim of our study was to determine the influence of apoptotic variations on the carcinogenesis and prognosis of colorectal carcinomas (CRCs). METHODS: A TUNEL assay was performed on archival material from 103 colorectal carcinomas, 26 adenomas and 20 samples of normal epithelia. RESULTS: The number of apoptotic cells was higher in CRCs (1.09 ± 0.13) than in adenomas (0.38 ± 0.23, p = 0.059) and normal epithelium (0.06 ± 0.04, p = 0.001). In addition, the apoptotic index (AI) was greater in metastatic disease (stage IV) than in other stages (p = 0.017). No relationship was found between apoptotic rates and age, gender or tumour grade. However, patients with tumours that showed higher AI values had a significantly lower disease-free survival (DFS) and overall survival (OS) than those with tumours that had lower AIs (p = 0.020 and p = 0.027). In a multivariate Cox proportional hazards model, AI remained a significant independent predictor of survival. CONCLUSIONS: We conclude that disregulated apoptosis is an important event during CRC development and progression. Higher AIs are associated with more aggressive tumours and a poorer prognosis for patients with CRC.

Clusterin expression is associated with decreased disease-free survival of patients with colorectal carcinomas.

AIMS: It has been demonstrated that increased clusterin expression is involved in malignant progression and that anticlusterin treatment leads to selective apoptosis. The aim of this study was to determine the clinicopathological significance of clusterin expression in human colorectal carcinomas. METHODS AND RESULTS: The expression of clusterin was examined in 31 adenomas and 103 colorectal carcinomas. Normal epithelial cells were always negative for clusterin expression, but clusterin expression was present in 16% (5/31) of adenomas and this percentage increased in colorectal carcinomas (30%, 31/103). Immunopositivity always presented an apical cytoplasmic pattern. The expression level of clusterin did not correlate with age, gender, grade or stage. However, its expression was significantly associated with a decrease in disease-free survival (P < 0.05). In a multivariate Cox proportional hazards model, clusterin expression remained a significant independent predictor. CONCLUSIONS: Clusterin expression may have a role in colonic carcinogenesis and may help identify patients with more aggressive tumours who may benefit from targeted therapy.

A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status.

OBJECTIVE: We conducted a phase II trial to evaluate the efficacy and toxicity of a combination consisting of second-line docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. ELIGIBILITY CRITERIA: histologically confirmed advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function. Treatment consisted of docetaxel 36 mg/m(2) i.v. over 60 min followed by gemcitabine 1000 mg/m(2) i.v. over 30 min on days 1 and 8 of each 3-week cycle for a planned six cycles or unacceptable toxicity. RESULTS: Of the 52 patients enrolled, 50 were evaluable for response and toxicity. The mean age was 59 years (range 42-79), 46 male and 4 female. Histology subtypes were: adenocarcinoma 26 patients, bronchioloalveolar 1 patient, large cell carcinoma 5 patients, and squamous cell carcinoma 18 patients. Thirty-eight patients had ECOG PS 1 and 12 patients had PS 0. The median number of cycles administered was four (range 2-6). The overall response rate was 28%. The median follow-up was 9 months (range 5-34 months). The median survival time (MST) was 8.2 months (95% CI, 4-12%), and the 1-year survival was 25%. The median progression-free survival was 4.4 months (95% CI, 2-6%). In the Cox regression model, survival was only significantly affected by the PS. The median survival in patients with PS 0 was 17.8 months (95% CI, 18.8-21.8%) compared with a median survival for patients with PS 1 of 6.1 months (95% CI, 4.1-8.2%) (P=0.0057). TOXICITY: three patients had grade 3 anemia, three patients had grade 3 thrombocytopenia, four patients had grade 3 neutropenia and only one patient developed grade 4 febrile neutropenia. Non-hematologic toxicity was also mild; the most frequent was asthenia, with grade 3 in eight patients (16%), and one patient with grade 4. CONCLUSION: This regimen of docetaxel in combination with gemcitabine in advanced second-line NSCLC is an active and safe regimen.