Subclinical myopathy and colorectal cancer: identification and role of new muscle damage and regeneration biomarkers

Background Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting. Materials and Methods We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome. Results In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients compared to controls. Analyses on serum samples showed that, in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range and the mean value was significantly lower compared to that detected in controls. Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis. Cancer relapse was correlated with low serum levels of prealbumin and high levels of p62 in myofibers of cancer patients. Conclusions Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate that skeletal muscle fibers show nuclear abnormalities that seems to be associated to a better prognosis, while the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia

Mesenteric-Portal Vein Resection during Pancreatectomy for Pancreatic Cancer

The aim of the present study was to determine the outcome of patients undergoing pancreatic resection with (VR+) or without (VR 12) mesenteric-portal vein resection for pancreatic carcinoma. Between January 1998 and December 2012, 241 patients with pancreatic cancer underwent pancreatic resection: in 64 patients, surgery included venous resection for macroscopic invasion of mesenteric-portal vein axis. Morbidity and mortality did not differ between the two groups (VR+: 29% and 3%; VR 12: 30% and 4.0%, resp.). Radical resection was achieved in 55/64 (78%) in the VR+ group and in 126/177 (71%) in the VR 12 group. Vascular invasion was histologically proven in 44 (69%) of the VR+ group. Survival curves were not statistically different between the two groups. Mean and median survival time were 26 and 15 months, respectively, in VR 12 versus 20 and 14 months, respectively, in VR+ group . In the VR+ group, only histologically proven vascular invasion significantly impacted survival , while, in the VR 12 group, R0 resection and tumor\u2019s grading significantly influenced long-term survival. Vascular resection during pancreatectomy can be performed safely, with acceptable morbidity and mortality. Long-term survival was the same, with or without venous resection. Survival was worse for patients with histologically confirmed vascular infiltration

Para-aortic node involvement is not an independent predictor of survival after resection for pancreatic cancer

AIM To analyze the importance of para-aortic node status in a series of patients who underwent pancreaticoduodenectomy (PD) in a single Institution. METHODS Between January 2000 and December 2012, 151 patients underwent PD with para-aortic node dissection for pancreatic adenocarcinoma in our Institution. Patients were divided into two groups: patients with negative PALNs (PALNs-), and patients with metastatic PALNs (PALNs+). Pathologic factors, including stage, nodal status, number of positive nodes and lymph node ratio, invasion of para-aortic nodes, tumor\u2019s grading, and radicality of resection were studied by univariate and multivariate analysis. Survival curves were constructed with Kaplan-Meier method and compared with Log-rank test: significance was considered as P < 0.05. RESULTS A total of 107 patients (74%) had nodal metastases. Median number of pathologically assessed lymph nodes was 26 (range 14-63). Twenty-five patients (16.5%) had para-aortic lymph node involvement. Thirty-three patients (23%) underwent R1 pancreatic resection. One-hundred forty-one patients recurred and died for tumor recurrence, one is alive with recurrence, and 9 are alive and free of disease. Overall survival was significantly influenced by grading (P = 0.0001), radicality of resection (P = 0.001), stage (P = 0.03), lymph node status (P = 0.04), para-aortic nodes metastases (P = 0.02). Multivariate analysis showed that grading was an independent prognostic factor for overall survival (P = 0.0001), while grading (P = 0.0001) and radicality of resection (P = 0.01) were prognostic parameters for disease-free survival. Number of metastatic nodes, node ratio, and para-aortic nodes involvement were not independent predictors of disease-free and overall survival. CONCLUSION In this experience, lymph node status and para-aortic node metastases were associated with poor survival at univariate analysis, but they were not independent prognostic factors

Extra-gastrointestinal stromal tumor of the pancreas: case report and review of the literature

Primary extra-gastrointestinal stromal tumor (EGISTs) arising in the pancreas is extremely rare: only 20 cases have previously been reported in the English literature from 2000 to 2013. We reported a case of EGIST of the pancreas in a 69-year-old woman who presented with abdominal pain and with a solid, heterogeneously enhancing neoplasm in the uncinate process of the pancreas, revealed preoperatively by an abdominal computed tomography scan. A diagnosis of neuroendocrine tumor was suggested. Positron emission tomography with 68Ga-DOTATOC did not show pathological accumulation of the tracer in the pancreas. The patient underwent enucleation, under ultrasonic guidance, of the pancreatic tumor that emerged to the surface of the pancreas. Histopathology and immunohistochemical examination confirmed the final diagnosis of EGIST of the pancreas (CD117+), with one mitosis per 50 high-power fields. Although rarely, GIST can involve the pancreas as a primary site, and this tumor should be considered in the differential diagnosis of pancreatic neoplasms

CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles

Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50-70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20-30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e., mTOR, MAPK/PI3K, and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodeling, splicing, and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the downregulation of several genes involved in thrombin signaling and platelet activation. As a whole, these data support the model that CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients

miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34(+) cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34(+) cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41(+) MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF

Subclinical myopathy and colorectal cancer: identification and role of new muscle damage and regeneration biomarkers

Background Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting. Materials and Methods We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome. Results In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients compared to controls. Analyses on serum samples showed that, in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range and the mean value was significantly lower compared to that detected in controls. Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis. Cancer relapse was correlated with low serum levels of prealbumin and high levels of p62 in myofibers of cancer patients. Conclusions Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate that skeletal muscle fibers show nuclear abnormalities that seems to be associated to a better prognosis, while the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia.Introduzione Il muscolo scheletrico rappresenta la principale riserva proteica del corpo e può essere compromesso in varie affezioni metaboliche e di alterato turnover proteico, quale il cancro. Benchè una severa perdita di massa sia generalmente presente in quadri neoplastici avanzati, in alcuni casi può essere già evidente in una fase di malattia iniziale. L’autofagia è stata recentemente descritta come uno dei possibili fattori responsabili del processo catabolico. Materiali e Metodi 50 pazienti sottoposti ad intervento chirurgico per neoplasia colorettale e 25 pazienti operati per patologia benigna non infiammatoria, in assenza di segni clinici di miopatia, sono stati sottoposti a biopsia muscolare su cui sono state eseguite analisi di carattere morfometrico ed istochimico. Sono state, inoltre, eseguite analisi biochimiche e molecolari al fine di valutare l’assetto proteico e lo stato di attivazione del processo autofagico e la loro correlazione con l’outcome clinico dei pazienti. Risultati Nei pazienti neoplastici abbiamo riscontrato la presenza di una miopatia subclinica, caratterizzata dalla presenza di fibre muscolari con un’anomala localizzazione del nucleo cellulare al centro della fibra, significativamente maggiore rispetto ai controlli. L’analisi dell’assetto proteico ha dimostrato valori sierici di albumina e prealbumina significativamente più bassi nei pazienti oncologici, mentre l’analisi molecolare ha documentato elevati livelli di p62 nelle fibre muscolari dei pazienti affetti da carcinoma colorettale, rispetto ai controlli. La valutazione dell’outcome clinico ha dimostrato una correlazione inversa tra la percentuale di miofibre anomale e l’insorgenza di metastasi linfonodali, mentre bassi livelli sierici di prealbumina ed alti livelli di p62 nelle fibre muscolari sono risultati correlati con un aumentato rischio di ripresa di malattia Conclusioni I pazienti affetti da carcinoma colorettale presentano una miopatia subclinica già all’insorgenza della malattia, caratterizzata dalla presenza di fibre con alterata posizione del nucleo nella cellula. In assenza di infiammazione sistemica e tissutale, i pazienti oncologici presentano bassi livelli sierici di albumina e prealbumina, come espressione di un alterato turnover proteico, nonché elevati livelli di p62 nelle fibre muscolari, a dimostrazione dell’attivazione del processo autofagico che risulta tuttavia compromesso. Tali dati suggeriscono, pertanto, un verosimile ruolo protettivo per le anomalie nucleari descritte, mentre un alterato turnover proteico ed una compromissione del normale flusso autofagico, in concomitanza dell’insorgenza della neoplasia, costituiscono un potenziale fattore predittivo negativo in termini di ripresa di malattia ed evoluzione verso uno stato cachettico

Carotid endarterectomy protects elderly patients from cognitive decline: A prospective study

IF: 3.406 Background. Carotid endarterectomy (CEA) reduces the risk of stroke in selected patients with symptomatic and asymptomatic carotid disease, but its beneficial influence on cognitive performance in the elderly remains debatable. This prospective study sought to determine early and long-term neurocognitive outcomes after CEA for severe unilateral carotid artery stenosis. Methods. From July 2006 to December 2008, 75 symptomatic (group A) and 70 asymptomatic patients (group B) aged 65 years and older underwent CEA under general anesthesia. Sixty-eight age- and sex-matched individuals who underwent laparoscopic cholecystectomy during the same period at our institution served as a control group (group H). Patients with contralateral severe carotid stenosis or occlusion and those with dementia, depression, or a history of major stroke were excluded. Cognitive function was assessed using 2 neuropsychological tests (the Mini-Mental State Examination [MMSE] and the Montreal Cognitive Assessment [MoCA]) performed preoperatively (T0) and then 3 (T1) and 12 months (T2) after operation. A change of at least 2 points between the scores at T0 and T2 was arbitrarily considered as clinically significant. Results. At T0, group A revealed significant cognitive impairments in both mean test scores by comparison with group H (P = .005 and P < .01, respectively), whereas there were no significant differences between groups A and B, or between groups B and H. Postoperatively, symptomatic patients had significant improvements in their mean cognitive performance scores in both tests (P < .01 and P < .01, respectively), whereas there were no changes in the asymptomatic and control patients\u2019 scores. No significant differences emerged for the MMSE scores in the 3 groups, whereas there was a marginally significant difference in the MoCA scores between groups A and H (P = .08), but not for A versus B or B versus H when clinically significant scores were considered. Conclusion. Our study showed that only elderly symptomatic patients with severe carotid lesions had a significant improvement in cognitive performance scores after CEA, although the benefit was considered clinically not significant. This suggests that CEA does not diminish neurocognitive functions, but it might provide some protection against cognitive decline in the elderly