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.
Purpose
Among the prognostic factors relevant to the condition of oncological patients, nutritional status (NS) has the greatest single impact on quality of life (QL). The goals of our study were to ...evaluate the influence of NS, weight loss (WL), and the presence of cachexia, prior to the initiation of chemotherapy, on the patient’s QL.
Methods
Adult patients (aged ≥ 18 years) diagnosed with solid tumours for whom chemotherapy was started between April 2016 and June 2017 were eligible for inclusion in the study. They were asked to complete a QL questionnaire (Functional Assessment of Cancer Treatment (FACT-G)) at the beginning. The presence or absence of cachexia was evaluated at the outset, following the definition proposed by Fearon and nutritional assessment by the Patient-Generated Subjective Global Assessment (PG-SGA) scale.
Results
A total of 177 patients completed the FACT-G, the 60% receiving curative therapy. At the start of the treatment, 58.2% of patients had experienced WL, with an average of 4.4 ± 7.4%, and 19% were at risk of malnutrition. Patient who presented cachexia at diagnosis, were treated with palliative intention, had a Nutriscore ≥ 5 points or presented malnutrition in accordance with PG-SGA had a poorer QL (
p
< 0.05). Greater WL was associated with a worsened QL (
p
= 0.001). Breast cancer patients presented an inverse correlation between the %WL and the initial score in the FACT-G (
r
= − 0.304,
p
= 0.023), whereas no such correlation was observed for the other types of tumour (
r
= − 0.012,
p
= 0.892).
Conclusions
These results underline the relation of NS before starting chemotherapy and QL. Greater WL was associated with a worsened QL, especially in women with breast cancer.
The phase 3 KEYNOTE‐177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high ...(MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression‐free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE‐177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval CI 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio HR 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment‐related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune‐mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.
We report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis of the phase 3 KEYNOTE‐177 study which evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high(MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Median PFS was not reached (NR) with pembrolizumab versus 10.4 months with chemotherapy (hazard ratio HR 0.56, 95% confidence interval CI 0.26–1.20), median OS was NR versus 30.0 months (HR 0.65, 95% CI 0.27–1.55), ORR was 50% versus 46%, and grade 3/4 treatment‐related adverse events were reported by two patients (9%) versus 20 (80%). These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC.
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
expression in CRC participants (
< 0.005) and a downregulation of
in normal-weight healthy patients (
< 0.05). Interestingly, the methylation analysis showed the hypermethylation of
in CRC patients (
< 0.05). Moreover, expression patterns of
were found to be regulated by vitamin D and inflammatory genes. In general, our results showed evidence that
can regulate CRC risk through obesity and may act as a biomarker for CRC.
Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, ...many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies.
In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model.
:
F-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses.
: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample
-test and 2-way-ANOVA analyses, respectively.
A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala.
Our work showed
the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population.
Background
Alterations in the structure and physiology of interneurons in the prefrontal cortex (PFC) are important factors in the etiopathology of different psychiatric disorders. Among the ...interneuronal subpopulations, parvalbumin (PV) expressing cells appear to be specially affected. Interestingly, during development and adulthood the connectivity of these interneurons is regulated by the presence of perineuronal nets (PNNs), specialized regions of the extracellular matrix, which are frequently surrounding PV expressing neurons. Previous reports have found anomalies in the density of PNNs in the PFC of schizophrenic patients. However, although some studies have described alterations in PNNs in some extracortical regions of bipolar disorder patients, there are no studies focusing on the prefrontocortical PNNs of bipolar or major depression patients. For this reason, we have analyzed the density of PNNs in post-mortem sections of the dorsolateral PFC (DLPFC) from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients.
Results
We have not observed differences in the distribution of PV+ cells or PNNs, or in the percentage of PV+ interneurons surrounded by PNNs. The density of PV+ interneurons was similar in all the experimental groups, but there was a significantly lower density of PNNs in the DLPFC of bipolar disorder patients and a tendency towards a decrease in schizophrenic patients. No differences were found when evaluating the density of PV+ cells surrounded by PNNs. Interestingly, when assessing the influence of demographic data, we found an inverse correlation between the density of PNNs and the presence of psychosis.
Conclusions
The present results point to prefrontocortical PNNs and their role in the regulation of neuronal plasticity as putative players in the etiopathology of bipolar disorder and schizophrenia. Our findings also suggest a link between these specialized regions of the extracellular matrix and the presence of psychosis.
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.
Polysialic acid (polySia) is a complex sugar that in the nervous system appears mainly as a posttranslational modification of the neural cell adhesion molecule (NCAM). PolySia plays important roles ...during brain development, but also in its plasticity during adulthood. Two polysialyltransferases (polyST), ST8SIA2 and ST8SIA4, are involved in the synthesis and attachment of polySia. Both polyST are relevant for developmental migration of cortical interneurons and their establishment in the prefrontal cortex (PFC). In contrast, only ST8SIA4 appears to be important for the structural plasticity of a subpopulation of cortical interneurons in the adult. Interestingly,
and NCAM are candidate genes for schizophrenia, a disorder in which interneuronal circuits are altered. However, there is still no data on the effects of polyST depletion on the dendritic structure or the connectivity of cortical interneurons. Here, we studied the contribution of each polyST on these parameters in the medial PFC (mPFC) of polyST knock-out mice with GAD67-GFP-labeled interneurons. Genetic depletion of ST8SIA4, but not ST8SIA2, resulted in a decrease in the complexity of the dendritic arbor of interneurons. In contrast, ablation of either of the two polyST induced a decrease in the density of parvalbumin (PV) expressing perisomatic puncta on pyramidal neurons. Thus, the depletion of each polyST results in similar impairments of not only developmental migration but also efferent synaptic connectivity of interneurons. In contrast, the loss of ST8SIA4 has a unique effect on dendritic structure, hence on afferent connectivity, suggesting differential and independent contributions of each polyST to neuritogenesis and synaptogenesis.
Recent studies suggest that long-interspersed nucleotide element-1 (
) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of
...methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect
methylation. Thus, the aim of this study was to assess the prognostic value of tumor
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
methylation, as well as pathological and oncological variables. We also studied the association between
methylation and pathological features, and finally, we assessed the overall and disease-free survival of
methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions.
was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (
< 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,
methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated
tumors than those with normal
methylation (
= 0.004 and 0.0049, respectively). Indeed,
was hypermethylated more in the treated patients than in the non-treated patients (
< 0.05). The present study showed that tumor
hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor
methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.
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.
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.
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.
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.
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