Lymphovascular invasion (LVI) and perineural invasion (PNI) can indicate poor survival outcomes in colorectal cancer, but few studies have focused on stage III colon cancer. The current study aimed ...to confirm the prognostic value of LVI and PNI and identify patients who could benefit from a complete duration of adjuvant chemotherapy based on the two pathological factors.
We enrolled 402 consecutive patients with stage III colon cancer who received colon tumor resection from November 2007 to June 2016 at Sun Yat-sen University Cancer Center. Survival analyses were performed by using Kaplan-Meier method with log-rank tests. Risk factors related to disease-free survival (DFS) and overall survival (OS) were identified through Cox proportional hazards analysis.
141 (35.1%) patients presented with LVI, and 108 (26.9%) patients with PNI. The LVI-positive group was associated with poorer 3-year DFS (86.5% vs. 76.3%, P = 0.001) and OS (96.0% vs. 89.1%, P = 0.003) rates compared with the LVI-negative group. The PNI-positive group showed a worse outcome compared with the PNI-negative group in 3-year DFS rate (72.5% vs. 86.7%, P < 0.001). Moreover, LVI-positive group present better 3-year DFS and OS rate in patients completing 6-8 cycles of adjuvant chemotherapy than those less than 6 cycles (3-year DFS: 80.0% vs. 64.9%, P = 0.019; 3-year OS: 93.2% vs. 76.3%, P = 0.002).
LVI is a superior prognostic factor to PNI in stage III colon cancer patients undergoing curative treatment. PNI status can noly predict the 3-year DFS wihout affecting the 3-year OS. Furthermore, LVI also represents an effective indicator for adjuvant chemotherapy duration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Patients with initially unresectable colorectal liver metastases (CRLM) could achieve survival benefit from successful conversion therapy. Recently, Tumor Burden Score (TBS) was proposed ...as a valuable index to predict outcome following resection of CRLM. The study is aimed to investigate the association of TBS with conversion outcome.
Methods:
A total of 234 patients who underwent first-line treatment in our center were enrolled as training cohort. The validation cohort was developed from 89 patients in our previous study. Cut-off value of TBS was calculated to stratify patients into two groups. Significance test and logistic regression model were used to examine the prediction value of TBS for conversion outcome after first-line systemic therapy. Kaplan–Meier method and Cox proportional hazard model were applied to assess the prognostic value of TBS.
Results:
TBS showed good discriminatory power area under curve (AUC) 0.726, p < 0.001 with cut-off value defined as 14.3 in training cohort, which was validated in the validation cohort. Increasing TBS was related to adverse chemotherapy response and conversion outcome. Low TBS group had three times higher conversion rate than that in high TBS group (57.3% versus 19.0%, p < 0.001). Multivariate analysis indicated that high TBS odds ratio (OR) = 3.676, 95% confidence interval (CI) 1.671–8.429, p = 0.002, first-line treatment response as stable disease (SD) or progressive disease (PD) (OR = 9.247; 95% CI 4.736–18.846, p < 0.001), and absence of targeted therapy (OR = 2.453, 95% CI 1.139–5.455, p = 0.024) were three independent risk factors for failure conversion outcome. High TBS was significantly associated with conversion outcome whatever chemotherapy response, addition of targeted therapy, and Kirsten rat sarcoma viral oncogene homolog (KRAS) status. High TBS was also associated with worse overall survival.
Conclusion:
TBS should be applied in clinical practice to predict conversion outcome in patients with initially unresectable CRLM.
Background: The prognostic nutritional index (PNI) has been widely applied for predicting survival outcomes of patients with various malignant tumors. Although a low PNI predicts poor prognosis in ...patients with colorectal cancer after tumor resection, the prognostic value remains unknown in patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy. This study aimed to investigate the prognostic value of PNI in patients with stage III colon cancer. Methods: Medical records of 274 consecutive patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December 2013 were reviewed. The optimal PNI cutoff value was determined using receiver operating characteristic (ROC) curve analysis. The associations of PNI with systemic inflammatory response markers, including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) level, and clinicopathologic characteristics were assessed using the Chi square or Fisher’s exact test. Correlation analysis was performed using Spearman’s correlation coefficient. Disease-free survival (DFS) and overall survival (OS) stratified by PNI were analyzed using Kaplan–Meier method and log-rank test, and prognostic factors were identified by Cox regression analyses. Results: The preoperative PNI was positively correlated with LMR (r = 0.483, P < 0.001) and negatively correlated with NLR (r = ? 0.441, P < 0.001), PLR (r = ? 0.607, P < 0.001), and CRP level (r = ? 0.333, P < 0.001). A low PNI (≤ 49.22) was significantly associated with short OS and DFS in patients with stage IIIC colon cancer but not in patients with stage IIIA/IIIB colon cancer. In addition, patients with a low PNI achieved a longer OS and DFS after being treated with 6–8 cycles of adjuvant chemotherapy than did those with < 6 cycles. Multivariate analyses revealed that PNI was independently associated with DFS (hazard ratios 2.001; 95% confidence interval 1.157–3.462; P = 0.013). Conclusion: The present study identified preoperative PNI as a valuable predictor for survival outcomes in patients with stage III colon cancer receiving curative tumor resection followed by adjuvant chemotherapy.
The delta-opioid receptor (DOR) belongs to the superfamily of G-protein-coupled receptors (GPCRs) with seven transmembrane domains, and its membrane trafficking is regulated by intracellular sorting ...processes involving its C-tail motifs, intracellular sorting proteins, and several intracellular signaling pathways. In the quiescent state, DOR is generally located in the intracellular compartments in central neurons. However, chronic stimulation, such as chronic pain and sustained opioid exposure, may induce membrane trafficking of DOR and its translocation to surface membrane. The emerged functional DOR on cell membrane is actively involved in pain modulation and opioid analgesia. This article reviews current understanding of the mechanisms underlying GPCRs and DOR membrane trafficking, and the analgesic function of emerged DOR through membrane trafficking under certain pathophysiological circumstances.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Opioids are commonly used for pain relief, but their strong rewarding effects drive opioid misuse and abuse. How pain affects the liability of opioid abuse is unknown at present. In this study, we ...identified an epigenetic regulating cascade activated by both pain and the opioid morphine. Both persistent pain and repeated morphine upregulated the transcriptional regulator MeCP2 in mouse central nucleus of the amygdala (CeA). Chromatin immunoprecipitation analysis revealed that MeCP2 bound to and repressed the transcriptional repressor histone dimethyltransferase G9a, reducing G9a-catalyzed repressive mark H3K9me2 in CeA. Repression of G9a activity increased expression of brain-derived neurotrophic factor (BDNF). Behaviorally, persistent inflammatory pain increased the sensitivity to acquiring morphine-induced, reward-related behavior of conditioned place preference in mice. Local viral vector-mediated MeCP2 overexpression, Cre-induced G9a knockdown, and CeA application of BDNF mimicked, whereas MeCP2 knockdown inhibited, the pain effect. These results suggest that MeCP2 directly represses G9a as a shared mechanism in central amygdala for regulation of emotional responses to pain and opioid reward, and for their behavioral interaction.
As long-term opioids are increasingly used for control of chronic pain, how pain affects the rewarding effect of opioids and hence risk of prescription opioid misuse and abuse remains a healthcare ...concern and a challenging issue in current pain management. In this study, using a rat model of morphine self-administration, we investigated the molecular mechanisms underlying the impact of pain on operant behavior of morphine intake and morphine seeking before and after morphine withdrawal. We found that rats with persistent pain consumed a similar amount of daily morphine to that in control rats without pain, but maintained their level-pressing behavior of morphine seeking after abstinence of morphine at 0.2 mg/kg, whereas this behavior was gradually diminished in control rats. In the central nucleus of amygdala (CeA), a limbic structure critically involved in the affective dimension of pain, proteins of GluA1 subunits of glutamate AMPA receptors were upregulated during morphine withdrawal, and viral knockdown of CeA GluA1 eliminated the morphine-seeking behavior in withdrawn rats of the pain group. Chromatin immunoprecipitation analysis revealed that the methyl CpG-binding protein 2 (MeCP2) was enriched in the promoter region of Gria1 encoding GluA1 and this enrichment was significantly attenuated in withdrawn rats of the pain group. Furthermore, viral overexpression of CeA MeCP2 repressed the GluA1 level and eliminated the maintenance of morphine-seeking behavior after morphine withdrawal. These results suggest direct MeCp2 repression of GluA1 function as a likely mechanism for morphine-seeking behavior maintained by long-lasting affective pain after morphine withdrawal.
Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability ...to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•The female offspring from maternal mice with pain displayed pain sensitization.•MeCP2 mediates pain transgenerational transmission in female mice.•MeCP2 regulates S1 glutamatergic neuronal ...activity.•MeCP2 regulates gene expression in S1 glutamatergic neurons in pain states.
Pain symptoms can be transmitted across generations, but the mechanisms underlying these outcomes remain poorly understood. Here, we identified an essential role for primary somatosensory cortical (S1) glutamate neuronal DNA methyl-CpG binding protein 2 (MeCP2) in the transgenerational transmission of pain. In a female mouse chronic pain model, the offspring displayed significant pain sensitization. In these mice, MeCP2 expression was increased in S1 glutamate (GluS1) neurons, correlating with increased neuronal activity. Downregulation of GluS1 neuronal MeCP2 in maternal mice with pain abolished offspring pain sensitization, whereas overexpression of MeCP2 in naïve maternal mice induced pain sensitization in offspring. Notably, single-cell sequencing and chromatin immunoprecipitation analysis showed that the expression of a wide range of genes was changed in offspring and maternal GluS1 neurons, some of which were regulated by MeCP2. These results collectively demonstrate the putative importance of MeCP2 as a key regulator in pain transgenerational transmission through actions on GluS1 neuronal maladaptation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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