Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)-a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO.

INTRODUCTION: At the time of diagnosis, 15-20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5-20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients. Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario. METHODS: This study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery. DISCUSSION: Considering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03917173. Registered on 16 April 2019. PROTOCOL VERSION: v1, March 27, 2019. Protocol number: IRFMN-GCC-7813. EudraCT number: 2019-001478-27.

Diagnostic Approach to Acute Liver Failure in Children: A Position Paper by the SIGENP Liver Disease Working Group.

Acute liver failure (ALF) is a clinical condition characterized by the abrupt onset of coagulopathy and biochemical evidence of hepatocellular injury, leading to rapid deterioration of liver cell function. In children, ALF has been characterized by raised transaminases, coagulopathy, and no known evidence of pre-existing chronic liver disease; unlike in adults, the presence of hepatic encephalopathy is not required to establish the diagnosis. Although rare, ALF has a high mortality rate without liver transplantation (LT). Etiology of ALF varies with age and geographical location, although it may remain indeterminate in a significant proportion of cases. However, identifying its etiology is crucial to undertake disease-specific management and evaluate indication to LT. In this position statement, the Liver Disease Working Group of the Italian Society of Gastroenterology, Hepatology and Nutrition (SIGENP) reviewed the most relevant studies on pediatric ALF to provide recommendations on etiology, clinical features and diagnostic work-up of neonates, infants and children presenting with ALF. Recommendations on medical management and transplant candidacy will be discussed in a following consensus conference.

Hyperthermic intrathoracic chemotherapy combined to iterative cytoreductive surgery to treat a pleural carcinosis from psudomixoma peritonei. A case report.

Pseudomyxoma peritonei (PMP) is an uncommon disease with locally-invasive attitude. Intrathoracic spread is rarely reported and its management extremely challenging. A 51-year-old Caucasian female presented with left pleural carcinosis 9-months after two sequential abdominal surgical procedures combined with HIPEC for low-grade PMP. Cytoreductive surgery (pleurectomy/decortication) was followed by 60-minutes hyperthermic intrathoracic chemotherapy mitomycin-C (215 mg/m2) infusing at same temperature (42°C) and intrapleural pression (2-4 mmH2O). No intra-operative complication occurred, the post-op stay was uneventful and no sign of recurrence was observed 9-months after surgery. Cytoreductive thoracic surgery and hyperthermic chemotherapy (HITHOC) could be a feasible therapeutic option in very selected cases.

Subclinical atherosclerosis and endothelial dysfunction in patients with polymyalgia rheumatica: a pilot study.

Objective: The aim of the study was to investigate endothelial function in treatment-naïve polymyalgia rheumatica (PMR) patients and its modification during steroid therapy, in relation to changes in clinical and laboratory parameters.Method: This prospective observational study involved patients with a new diagnosis of PMR according to provisional American College of Rheumatology/European League Against Rheumatism 2012 criteria, who were naïve to steroid therapy, and control subjects matched for age, gender, and comorbidities. All participants underwent clinical and vascular ultrasound evaluations at baseline and after 1, 3, 6, and 12 months of steroid therapy. For the study of endothelial function, we evaluated the brachial artery reactivity, which has emerged as the most well-established technique used in adults, by assessing flow-mediated dilatation (FMD), which measures the endothelium-dependent vasodilatation.Results: Sixteen newly diagnosed PMR patients were compared with a population of 16 matched controls. FMD values in all subjects showed an inverse correlation with the values of erythrocyte sedimentation rate and C-reactive protein. At baseline, the FMD of PMR patients was significantly lower than controls and remained significantly lower with respect to controls until the sixth month of therapy, despite a clinical improvement already being evident after 1 month of therapy.Conclusions: PMR is characterized by an important chronic subclinical inflammatory component. This pilot study demonstrates that affected patients show endothelial dysfunction that slowly responds to steroid therapy. Further studies are needed to investigate the clinical relevance of these observations and, in particular, to monitor the cardiovascular risk profile of PMR patients.

Histotype influences emergency presentation and prognosis in colon cancer surgery.

AIM: To investigate whether differences in histotype in colon cancer correlate with clinical presentation and if they might influence oncological outcomes and survival. METHODS: Data regarding colon cancer patients operated both electively or in emergency between 2009 and 2014 were retrospectively collected from a prospectively maintained database and analyzed for the purpose of this study. Rectal cancer was excluded from this analysis. Statistical univariate and multivariate analyses were performed to investigate possible significant variables influencing clinical presentation, as well as oncological outcomes and survival. RESULTS: Data from 219 patients undergoing colorectal resection for cancer of the colon only were retrieved. One hundred seventy-four patients had an elective procedure and forty-five had an emergency colectomy. Emergency presentation was more likely to occur in mucinous (p < 0.05) and signet ring cell (p < 0.01) tumors. No definitive differences in 5-year overall (44.7% vs. 60.6%, p = 0.078) and disease-free (51.2% vs. 64.4%, p = 0.09) survival were found between the two groups as a whole, but the T3 emergency patients showed worse prognosis than the elective (p < 0.03). Lymph node invasion, laparoscopy, histology, and blood transfusions were independent variables found to influence survival. Distribution assessed for pTNM stage showed T3 cancers were more common in emergency (p < 0.01). CONCLUSIONS AND DISCUSSION: Mucinous and signet ring cell tumors are related to emergency presentation, pT3 stage, poorest outcomes, and survival. Disease-free survival in patients who had emergency surgery for T3 colon cancer seems related to the histotype.

Fertility preservation in chemo-radiotherapy for rectal cancer: A combined approach.

INTRODUCTION: Colorectal cancer is a very common form of cancer worldwide, affecting an increasing number of young women. Standard treatment for locally advanced rectal cancer (LARC) can pose a threat to fertility in these patients. CASE PRESENTATION: We present the case of a young woman affected by LARC who expressed a desire for child-bearing. The treatment she was proposed, according to guidelines, was neoadjuvant chemo-radiotherapy (CRT) followed by delayed surgery, carrying with it a high risk for amenorrhea. Counselling was performed before the initiation of treatment, with the aim of preserving fertility by the proposal of GnRH agonist administration, ovarian transposition and ovarian tissue cryopreservation, which the patient accepted. Treatment was then successfully completed. The patient presented regular menstrual period from before the surgery. DISCUSSION: Ovarian tissue is very sensitive to radiations. Transposition of the organ can prevent ovarian insufficiency by placing it outside the radiation field, while ovarian tissue cryopreservation and orthotopic transplantation offers the possibility to restore fertility in the case of organ failure. We performed both of the techniques. GnRH analogs administration allowed to diminish the risk of ovarian cytotoxicity. Radiation treatment plan was optimized in order to minimize the dose to organs at risk (ovary and vagina in particular); position of the uterus, which is quite radiosensitive too, was monitored with daily cone-beam CT (CBCT). CONCLUSION: The strategy proposed seemed safe and effective, resulting in radical treatment and persistence of regular menstrual period. Further studies are needed.

Synthetic small-molecule RNA ligands: future prospects as therapeutic agents.

RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified. Among the most important ones, one can mention prokaryotic ribosomal RNA which is the target of several marketed antibiotics, viral RNAs or oncogenic microRNAs that are tightly involved in the development and progression of various cancers. Oligonucleotides are efficient and specific RNA targeting agents but suffer from poor pharmacodynamic and pharmacokinetic properties. For this reason, a number of synthetic small-molecule ligands have been identified and studied upon screening of chemical libraries or focused design of RNA binders. In this review, we report the most relevant examples of synthetic compounds bearing sufficient selectivity to envisage clinical studies and future therapeutic applications with a particular attention for the main strategies that can be undertaken toward the improvement of selectivity and biological activity.

Association between peripheral arterial disease and cardiovascular risk factors: role of ultrasonography versus ankle-brachial index.

OBJECTIVE: Most studies on atherosclerotic processes include peripheral arterial disease diagnosis only if patients report symptoms suggestive of peripheral arterial disease and/or an instrumental demonstration of lower limbs perfusion deficit is provided, rather than the sole presence of atherosclerotic lesions localized at lower limbs, this attitude leading to ignore early stages of the disease. To overcome these limitations, we have proposed a new ultrasonographic semiquantitative score to better identify all disease stages. The aim of this study is to compare ultrasonography versus ankle-brachial index in the association between peripheral arterial disease and cardiovascular risk factors. PATIENTS AND METHODS: This cross-sectional observational study included subjects undergoing lower limbs evaluation through ultrasonography and ankle-brachial index determination because of symptoms suggestive of peripheral arterial disease or presence of known cardiovascular risk factors. Associations between ultrasonography and ankle-brachial index with cardiovascular risk factors were assessed by first fitting logistic regression models and then comparing the respective areas under the Receiver Operating Characteristic and 95% confidence intervals. RESULTS: The areas under the Receiver Operating Characteristic for each cardiovascular risk factors were consistently larger in magnitude for ultrasonography compared with ankle-brachial index, this comparison being statistically significant for age, male gender, smoking status, hypertension, diabetes mellitus and previous cardiovascular events. CONCLUSIONS: Our study demonstrates that ultrasonography is a better method to screen peripheral arterial disease respect to ankle-brachial index in order to identify all disease stages. These findings are useful in particular when including peripheral arterial disease as organ damage marker in cardiovascular risk stratification.

Ambulatory Surgery for Perianal Crohn's Disease: Study of Feasibility.

BACKGROUND: One-third of Crohn's disease (CD) patients present perianal fistula. The gold standard in the diagnosis and treatment of symptomatic perianal disease (PAD) in CD is the exploration of the anal canal and distal rectum under anesthesia (EUA). This procedure is mainly conducted as a day case surgery. Unfortunately, it is not always possible to proceed within the ideal timing and any delay may well represent a relevant clinical issue. The aim of this study was to evaluate the feasibility of outpatient treatment of symptomatic perianal fistulas in CD patients. METHODS: All CD patients under regular follow-up at our inflammatory bowel disease referral center, presenting with symptomatic perianal fistulas, were offered surgical consultation. The data of patients were prospectively collected for three years (February 2014 to February 2017) for the purpose of the study. All clinical information, including previous EUA and/or records from MRI and endoscopic ultrasound, was included. Outpatient anal canal and distal rectum exploration and treatment (OE) were undertaken during the specialist surgical consultation. Fistulas were classified according to Parks's classification; the type of outpatient treatment and compliance of patients were recorded. Pain was assessed by VAS at the time of the procedure and during the first control. Patients were followed up in the surgical clinic in relation to the study. RESULTS: Ninety-two CD patients with symptomatic perianal fistulas had surgical consultation during the study period. OE was offered to all but 18 patients who fulfilled the exclusion criteria or had an extremely severe disease; six patients refused the OE (8.11%). Of the 68 patients undergoing OE, eleven (16.18%) had previous surgery for perianal disease. The OE was accomplished in sixty-one patients (89.71%), while in 7 patients, it was abandoned for scarce compliance. Nine patients (14.75%) underwent drainage of perianal abscess; in 3 of them, it was possible to probe the fistula tract, find the internal orifice, and pass a loose seton. Overall, setonage was performed in 50 patients (81.97%). Rectovaginal setons were placed in 3 patients and more than one seton (up to 3) in 6 cases. Fistulotomy was performed in 4 simple subcutaneous fistulous tracts. Concordance with the preoperative findings was found in 54 out of 61 patients. EUA was scheduled at the time of OE for the 7 patients who did not complete the procedure. All sixty-one patients who had the OE were followed up for a minimum of 12 months. CONCLUSIONS: This preliminary study indicates that OE in CD patients with symptomatic perianal fistulas is safe and feasible in a high-volume referral center. It might provide several benefits, including patients' logistics, reduce or remove patients' symptoms and discomfort, allow for a timely start of medical therapy, and avoid further complications.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Comparison of cholecystectomy and percutaneous cholecystostomy in acute cholecystitis: results of a retrospective study.

OBJECTIVE: To retrospectively compare the clinical outcomes of percutaneous cholecystostomy (PC) and cholecystectomy in patients with acute cholecystitis admitted to an urban University Hospital. PATIENTS AND METHODS: We studied 646 patients with acute cholecystitis. Ninety patients had placement of a PC at their index hospitalization, and 556 underwent cholecystectomy. Of the 90 patients with PC, 13 underwent subsequent elective cholecystectomy. RESULTS: Overall, in-hospital mortality and postoperative complications were significantly higher in patients who received PC than in those who underwent cholecystectomy. In the ASA score 1-2 group, patients with PC were significantly older and had a longer postoperative stay while their mortality and morbidity were similar to patients who underwent cholecystectomy. In patients with ASA score of 3, PC and cholecystectomy did not differ significantly for demographic variables and clinical outcomes such as hospital stay, in-hospital mortality, postoperative complications and distribution of complications according to the classification of Clavien-Dildo. In mild, moderate, and severe cholecystitis, patients who underwent PC were significantly older than those who received cholecystectomy. In general, in mild, moderate and severe cholecystitis, the clinical outcomes did not differ significantly between patients who received PC and cholecystectomy. Morbidity was higher in patients with mild cholecystitis who underwent PC. Of the 77 patients dismissed from the hospital with drainage, 12 (15.6%) developed biliary complications and 5 needed substitutions of the drainage itself. CONCLUSIONS: PC does not offer advantages compared to cholecystectomy in the treatment of acute cholecystitis. Its routine use is therefore questioned. There is need of an adequate, randomized study that compares PC and cholecystectomy in high-risk patients with moderate-severe cholecystitis.

Successful management of acute liver failure in Italian children: A 16-year experience at a referral centre for paediatric liver transplantation.

BACKGROUND: Identifying the causes of acute liver failure (ALF) and predictors of death or liver transplantation (LTX) is crucial to decide its management. We aimed to describe features and outcome of ALF in Italian children. METHODS: Retrospective review of cases presenting between 1996-2012. ALF was defined by high transaminases, INR ≥2.0 regardless of hepatic encephalopathy (HE), no evidence of underlying chronic liver disease. RESULTS: 55 children (median age 2.6 years, range 0.1-15.1; M/F=31/24) had ALF due to autoimmune hepatitis (AIH) in 10 (18%), metabolic disorders in 9 (17%), paracetamol overdose in 6 (11%), mushroom poisoning in 3 (5%), viral infection in 1 (2%), indeterminate in 26 (47%); 25/55 recovered with supportive management (45%); 28/55 underwent LTX and 2 died on the waiting list (55%). On multivariate analysis severity of HE grade 3-4 and bilirubin ≥12mg/dl were independent predictors of death or LTX (p<0.05). After a median follow up of 4 years (range 2-15.0 years) the overall survival rate was 93%. CONCLUSION: Children with ALF can be managed successfully with combined medical treatment and transplantation, warranting a survival rate similar to children transplanted because of chronic conditions. In our cohort of patients severe HE and high bilirubin on admission were independent predictors of the need of LTX.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Out-of-the-box pelvic surgery including iliopsoas resection for recurrent gynecological malignancies: Does that make sense? A single-institution case-series.

OBJECTIVE: To report morbidity and oncological outcomes in a consecutive series of lateral isolated recurrent gynecological cancer involving the pelvic side wall (PSW) including the iliopsoas muscle. MATERIAL AND METHODS: We retrospectively evaluated a consecutive series between 6/2013 and 12/2015 of lateral isolated recurrent gynecological malignancies treated with a lateral endopelvic resection (LEPR). LEPR was defined as an en-bloc lateral resection of a pelvic tumor with sidewall muscle, and/or bone, and/or major nerve, and/or major vascular structure. Post-surgical complications, quality of life (QoL) and survivals were computed. RESULTS: Seventy-four women with pelvic isolated relapse were admitted for surgery during the study period. Among them, 8 cases (10.8%) showed lateral isolated relapse involving the iliopsoas muscle and were treated with LEPR. R0 resection was achieved in 6/8 patients (75.0%), while the pathologic margins were microscopically and macroscopically positive in 1 patient (12.5%), respectively. There were no perioperative mortalities. Major postoperative complications occurred in 3 patients (37.5%) through peripheral neuropathies, thrombosis of the vascular graft and compartment syndrome of the leg. Median follow-up time was 21 months (range, 12-28). The 2-year overall survival (OS) was 88% improving up to 100% if R0 resection was achieved. In patients with positive pathologic margins (n = 2), the 2-year OS was 50%. All women showed an improved QoL after surgery. CONCLUSION: LEPR with iliopsoas resection can be safely performed in selected cases with lateral isolated gynecological relapse involving the PSW and was associated with improved QoL and prolonged survival when an R0 resection was achieved.

Biomarkers of low-grade inflammation in primary varicose veins of the lower limbs.

OBJECTIVE: To analyze serum biomarkers of CVD in selected patients with primary axial reflux of great saphenous vein in one or both lower limbs. PATIENTS AND METHODS: Ninety-six patients affected by uncomplicated varicose veins, were enrolled in the study. A unilateral, primary axial reflux in great saphenous veins was detected in 54 patients (U-CVD group) and a bilateral one in 42 (B-CVD group). Sixty-five age and sex-matched subjects without venous reflux were enrolled as controls. Mean venous pressure of both lower limbs at the distal great saphenous vein (mGSVP) and venous reflux were measured by continuous-wave Doppler ultrasound and echoduplex scanning, respectively. Reactive Oxygen Species (ROS), tissue Plasminogen Activator (t-PA) and its Inhibitor 1 (PAI-1) activities, Hematocrit (HTC), White Blood Cells (WBC), Neutrophyls (NEU), Platelets (PLT), Fibrinogen (FIB) and Blood Viscosity (BV) were assessed in blood samples drawn from the antecubital vein. RESULTS: B-CVD group showed higher fibrinogen values (p < 0.005) and higher mean venous pressure (0 < 0.0001) in comparison to controls, while U-CVD did not. No difference was found between both groups and controls for all the other parameters. CONCLUSIONS: Increased fibrinogen levels in patients with bilateral varicose veins may represent an early warning signal, as it could be associated to the long-term progression of chronic venous disease.

Fulminant hepatic failure of autoimmune aetiology in children.

OBJECTIVE: Autoimmune hepatitis (AIH) is considered an underdiagnosed cause of fulminant hepatic failure (FHF). Autoimmune FHF (AI-FHF) is believed to lead invariably to liver transplantation (LTX) or death. We aimed to describe the autoimmune features of children diagnosed as having AI-FHF and indeterminate FHF (ID-FHF), and describe the outcome of patients with AI-FHF treated with immunosuppressive drugs. METHODS: In this case-control study, the files of patients with AI-FHF and ID-FHF were reviewed and compared. AIH was diagnosed based on positive autoantibodies, raised immunoglobulin G, and histology when available. FHF was defined by raised transaminases, international normalised ratio ≥ 2.0, presence of encephalopathy, and no previously recognised liver disease. RESULTS: A total of 46 children with FHF were managed in the last 15 years: 10/46 (22%) had AI-FHF, 20/46 (43%) ID-FHF, and 16 had other diagnosis. The mean follow-up time was 4.6 years. AI-FHF and ID-FHF differed for the presence of autoantibodies (10/10, 6/10 liver/kidney microsome [LKM]-type, vs 3/20, none LKM, P < 0.0001), immunoglobulin G level (1845 vs 880 mg/dL, P < 0.001), median age at diagnosis (6.4 vs 1.8 years, P = 0.017), and alanine aminotransferase level (1020 vs 2386 IU/L, P = 0.029). Liver histology did not allow to differentiate the 2 conditions. Among the patients with AI-FHF, 4/9 who received steroids recovered; 5/9 required LTX and 1 died awaiting treatment. CONCLUSIONS: AIH is a much more common cause of FHF than previously suggested, and a complete autoantibody testing including LKM-type is essential in this setting. Autoantibodies are uncommon in ID-FHF, and histology cannot distinguish it from AI-FHF. A cautious steroid trial may avoid LTX in some of the patients with AI-FHF.

Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.

Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases.

PURPOSE: A major problem in treating patients with peritoneal spread from colorectal cancer is that at diagnosis wide peritoneal involvement often precludes all curative attempts. A possible solution is to identify those patients at risk for peritoneal metastases and intervene early to prevent locoregional disease spread before it develops and, thus, to improve outcome. METHODS: We analyzed long-term results from a previous study and compared outcomes in 25 patients with advanced colon cancer considered at high risk for peritoneal spread (pT3/pT4 and mucinous or signet ring cell histology) prospectively included and managed with a proactive surgical approach including target organ resection for peritoneal spread plus hyperthermic intraperitoneal chemotherapy (HIPEC) and in 50 retrospectively well-matched controls who underwent standard surgical resection during the same period and in the same hospital by different surgical teams. RESULTS: At 48 months after the study closed, peritoneal metastases and local recurrence developed significantly less often in proactively managed patients than in controls (4 vs 28%) (p < 0.03). Patients in the proactive group also survived longer than control patients (median overall survival 59.5 vs 52 months). Despite similar morbidity, Kaplan-Meier survival curves disclosed significantly longer disease-free and overall survival in the proactive than in the control group (p < 0.05 and <0.04). CONCLUSIONS: In patients with advanced colon cancer at risk for peritoneal recurrence, the proactive surgical approach plus HIPEC seems to achieve good locoregional control preventing peritoneal spread thus improving outcome without increasing morbidity. These advantages merit investigation in a multicentric randomized trial.