Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

The neutrophil-lymphocyte ratio and its utilisation for the management of cancer patients in early clinical trials.

BACKGROUND: Inflammation is critical to the pathogenesis and progression of cancer, with a high neutrophil-lymphocyte ratio (NLR) associated with poor prognosis. The utility of studying NLR in early clinical trials is unknown. METHODS: This retrospective study evaluated 1300 patients treated in phase 1 clinical trials between July 2004 and February 2014 at the Royal Marsden Hospital (RMH), UK. Data were collected on patient characteristics and baseline laboratory parameters. RESULTS: The test cohort recruited 300 patients; 53% were female, 35% ECOG 0 and 64% ECOG 1. RMH score was 0-1 in 66% and 2-3 in 34%. The median NLR was 3.08 (IQR 2.06-4.49). Median OS for the NLR quartiles was 10.5 months for quartile-1, 10.3 months for quartile-2, 7.9 months for quartile-3 and 6.5 months for quartile-4 (P<0.0001). Univariate analysis identified RMH score (HR=0.55, P<0.0001), ECOG (HR=0.62, P=0.002) and neutrophils (HR=0.65, P=0.003) to be associated with OS. In multivariate analysis, adjusting for RMH score, ECOG, neutrophils and tumour type, NLR remained significantly associated with OS (P=0.002), with no association with therapeutic steroid use. These results were validated in a further 1000 cancer patients. In the validation cohort, NLR was able to discriminate for OS (P=0.004), as was the RMH score. This was further improved on in the RMH score+NLR50 and RMH score+Log10NLR models, with an optimal NLR cutoff of 3.0. CONCLUSIONS: NLR is a validated independent prognostic factor for OS in patients treated in phase 1 trials. Combining the NLR with the RMH score improves the discriminating ability for OS.

Risk factors and survival outcomes in patients with brain metastases from breast cancer.

Development of central nervous system (CNS) metastases in breast cancer (BC) is associated with poor prognosis. The incidence of CNS metastases in metastatic BC is reported to be about 10-16 %, but different subtypes of BC are associated with different risk of developing CNS metastases. We retrospectively analysed the risk of CNS metastases and the outcome in a cohort of 473 patients with metastatic BC. CNS metastases were diagnosed in 15.6 % of patients and median survival from diagnosis of CNS metastases was 7.53 (25th-75th 2.8-18.9) months. The risk of developing CNS metastases was higher in patients with grade 3, hormone receptor negative, HER2-positive, high Ki-67 BC. When compared to luminal A subtype, only HER2-positive BC was associated with increased risk of CNS metastases. Survival from diagnosis of CNS metastases was longer in patients with HER2-positive BC, while it was shorter in patients that did not receive any locoregional treatment, or with extra-CNS disease, or with more than 3 CNS lesions.

The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis.

BACKGROUND: Myeloproliferative disorders (MPDs) represent a risk factor for thrombosis in the portal, mesenteric, and hepatic districts. OBJECTIVE: We aimed to assess whether the Janus kinase 2 (JAK2) V617F mutation, an acquired mutation that occurs in MPD patients, is a risk factor for portal and mesenteric venous thrombosis (PMVT) independently of the presence of overt MPDs. PATIENTS AND METHODS: The medical histories of 99 patients presenting with PMVT were obtained. The presence of the JAK2 V617F and VHL 598C > T mutations was determined by polymerase chain reaction followed by restriction enzyme analysis and direct cycle sequence analysis. RESULTS: Over a 10-year period of observation, of the 99 patients presenting with PMVT, the JAK2 V617F mutation was detected in heterozygous state in 17 individuals [17.2%; 95% confidence interval (95% CI) 10.9-25.9]. None of the patients presenting with the JAK2 V617F mutation carried an inherited thrombophilic risk factor. Seven patients with (43.8%; 95% CI 19.8-70.1) and two without (2.4%; 95% CI 0.3-8.4) the JAK2 V617F mutation had a diagnosis of MPD at the occurrence of the venous thrombotic event. After a median follow-up of 41 months (range 3-114 months), three out of the 10 patients carrying the JAK2 V617F mutation were then diagnosed as having idiopathic myelofibrosis (n = 2) or polycythemia vera (n = 1), whereas in seven patients a MPD was not detected. Two of the 83 patients without the JAK2 V617F mutation went on to develop MPDs. CONCLUSIONS: Determination of the JAK2 V617F mutation may contribute to the search for genetic determinants of PMVT and may be useful to recognize patients who should be carefully observed for the subsequent development of overt MPDs.

Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine in myeloproliferative disorders: relationship with splanchnic vein thrombosis and arterial disease.

The contribution of pro-thrombotic factors towards the development of arterial disease (AD) and splanchnic vein thrombosis (SVT) was retrospectively evaluated in 79 patients (39M, 40F, mean age 55 +/- 16 years) with myeloproliferative disorders (MPD) (essential thrombocythemia [n = 26], primary proliferative polycythemia [n = 27], and idiopathic myelofibrosis [n = 26]). Of these, 18 had AD and 17 SVT, the remaining 44 were non-thrombotic (NT). Plasma concentrations of natural anticoagulants, plasma homocysteine (HC), IgG anticardiolipin antibodies (aCL), and thrombophilic genotypes (methylenetetrahydrofolate reductase C(677)T, factor V Leiden, prothrombin G(20210)-->A) were determined. Isolated protein C deficiency was found in 23% of patients from the SVT group, in 5% from the AD group, in 6.8% from the NT group, and in 1% of historical controls (P = 0.0001). The prevalence of thrombophilic genotypes and that of the other natural anticoagulants did not differ across the groups. The proportion of patients with elevated plasma HC was 66% in the AD group, 27% in the non-thrombotic group, 12% in the SVT group and 4.5% in the control group (P < 0.0001). Patients with AD had higher plasma HC (24.4 +/- 23 micromol/L) than NT patients (12.3 +/- 7.7 micromol/L), SVT patients (9 +/- 4.9 micromol/L), and healthy controls (7.9 +/- 3 micromol/L) (P < 0.0001). In a logistic regression model lower protein C was independently associated with SVT, whereas elevated plasma HC was independently associated with AD. Measurement of plasma HC and protein C in MPD may identify patients more likely to suffer arterial disease and splanchnic vein thrombosis and who may require plasma HC lowering in the former case.

Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.

BACKGROUND AND STUDY AIMS: Portal vein thrombosis is a rare event in patients with liver cirrhosis in the absence of a related neoplasm. Endoscopic sclerotherapy of esophageal varices has been anecdotally associated with the development of portal vein thrombosis. We tested the hypothesis that genetic thrombophilia plays a role in the development of portal vein thrombosis in patients with liver cirrhosis undergoing endoscopic sclerotherapy. PATIENTS AND METHODS: From June 1998 to December 1999, 61 consecutive patients underwent multiple sessions of endoscopic sclerotherapy for bleeding esophageal varices. Doppler ultrasound of the portal vein was performed before sclerotherapy and every 3 months thereafter. Antiphospholipid antibodies, factor V Leiden (FVL) mutation, prothrombin mutation G20210A (PTHRA20210) and mutation TT677 of methylenetetrahydrofolate reductase (MTHFR C677T) were evaluated in all patients. RESULTS: Portal vein thrombosis developed in 16 % of the patients (10 of 61) after a mean follow-up period of 16 months. A genetic cause for thrombosis was found in 70 % of patients with liver cirrhosis who developed portal vein occlusion, but only in 8 % of patients without this complication. CONCLUSIONS: Endoscopic sclerotherapy of esophageal varices may represent a trigger factor for portal vein thrombosis in cirrhotic patients with genetic thrombophilia.

Multiple thrombophilic factors in a patient with Budd-Chiari syndrome.

Myeloproliferative disorders are the main cause of Budd-Chiari syndrome in western countries. Inherited or acquired thrombophilic factors have also been implicated. A novel mutation of the prothrombin gene (G-->A20210) has only been described in a few cases of Budd-Chiari syndrome so far. Venous thrombosis is often the result of multiple concomitant thrombophilic factors. We report the case of a patient with essential thrombocythemia and Budd-Chiari syndrome in which heterozygosity for both factor V Leiden and the mutation G20210A of the prothrombin gene were identified.

Diffusion of knowledge about Helicobacter pylori as assessed in an open-access endoscopy system: a prospective observational study based on the Maastricht guidelines.

BACKGROUND/AIM: Aim of the present study is to assess, according to the guidelines of the Maastricht Consensus Conference, the appropriateness and diagnostic yield of upper gastrointestinal endoscopy in an open-access endoscopy system, in order to evaluate the diffusion of knowledge about Helicobacter pylori among different types of physicians. METHODS: Patients undergoing endoscopy because of dyspeptic symptoms were prospectively considered in 21 endoscopy services of Campania during two different 1-week periods in 1998 and 2001. The following data were recorded: age, sex, symptoms, history of peptic ulcer with regard to previous endoscopic or radiographic examinations and treatment, endoscopic diagnosis, and H. pylori status. The indication for endoscopy was evaluated according to Maastricht guidelines and current medical knowledge. RESULTS: In the two periods, 1998 and 2001, 706 and 520 patients were, respectively, considered. The two series were matched for demographic characteristics, symptoms, and endoscopic diagnosis. Endoscopy was considered not indicated in 398 patients (56.4%) in 1998 and in 265 patients (50.9%) in 2001 (p = NS). The majority of them, 288/398 (72.3%) in 1998 and 162/265 (61.1%) in 2001 (p = 0.001), had recently undergone endoscopy or radiology and empiric antisecretory treatment or eradication. They had been referred to endoscopy because of recurrence of symptoms or to assess healing. In 110 cases in 1998 (27.6%) and in 103 cases in 2001 (38.9%; p = 0.001) endoscopy was performed in dyspeptic patients younger than 45 years without alarm symptoms. CONCLUSIONS: 4 years after the Maastricht Conference, a large number of endoscopic examinations are not indicated and could be avoided following the Maastricht guidelines. In 2001, in comparison to 1998, a larger number of physicians are likely to investigate and treat correctly the H.-pylori-related diseases, but there are still some problems with the application of the 'test-and-treat policy'.

Endoscopic management of foreign bodies in the upper gastrointestinal tract: report on a series of 414 adult patients.

BACKGROUND AND STUDY AIMS: Ingestion of foreign bodies is a common occurrence. Few papers in the literature report experience and outcome at tertiary centers. The aim of this paper is to report the management and the outcomes in 414 patients admitted for suspected ingestion of foreign body between May 1995 and December 1999. METHODS: A plain radiographic film of the neck, chest or abdomen was obtained in the case of radiopaque objects, and in order to rule out suspected perforation: in such cases a computed tomography (CT) study was also performed. All patients were asked to give their informed consent, which was refused by three patients. Anesthesia was always used, either conscious sedation (86.8 %), or general anesthesia in the case of poor patient tolerance (13.2 %). All patients underwent an endoscopic procedure within six hours of admission. A flexible scope was used in all patients and a wide range of endoscopic devices was employed. RESULTS: Foreign bodies were found in 64.5 % of our patients. Almost all were found in the esophagus. The types of foreign body were very different, but they were chiefly food boluses, bones or cartilages, dental prostheses or fish bones. In three patients (1.1 %) it was impossible to endoscopically remove the foreign body, which was located in the cervical esophagus: all these three patients required surgery. No complications relating to the endoscopic procedure were observed, but 30.7 % of patients had an underlying esophageal disease, such as a stricture. Only eight patients required a second endoscopic procedure, performed by a more experienced endoscopist. CONCLUSION: Foreign body ingestion represents a frequent reason for emergency endoscopy. The endoscopic procedure is a successful technique which allows the removal of the foreign bodies in almost all cases without significant complications. Surgery is rarely required.

High prevalence of thrombophilic genotypes in patients with acute mesenteric vein thrombosis.

OBJECTIVES: Mesenteric vein thrombosis is a rare but severe abdominal emergency, often requiring intestinal resection. New genetic prothrombotic defects such as factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype have been described in association with venous thrombosis. Our goal was to assess prevalence and clinical significance of genetic thrombophilia in mesenteric vein thrombosis. METHODS: Twelve patients with acute mesenteric vein thrombosis were compared with 431 healthy people from the same geographical area. The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype were identified by polymerase chain reaction and restriction analysis. RESULTS: A thrombophilic genotype was present in 9 patients (75%): the methylenetetrahydrofolate reductase TT677 genotype was present in 6 (50%), the factor V Leiden in 3 (25%), and the prothrombin transition G20210A in 3 (25%). Combined mutations were present in 4 (33%) patients. CONCLUSIONS: The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype are important predisposing factors in the pathogenesis of mesenteric vein thrombosis. Their identification bears strong clinical implications for management of patients with mesenteric vein thrombosis.

Late biliary tract complications after orthotopic liver transplantation: diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography.

BACKGROUND: Biliary tract complications are frequent after orthotopic liver transplantation. Late biliary tract complications occurring after T-tube removal mostly include stones and strictures which may be associated with sepsis and worsening of the liver function. Endoscopic retrograde cholangiopancreatography (ERCP) has a role in the diagnosis and therapy of these complications. The aim of our study was to report our experience of endoscopic diagnosis and treatment of late biliary tract complications in liver-transplanted patients. METHODS AND RESULTS: One hundred and thirty-six adult liver-transplanted patients have been followed since 1988. Seventeen patients (12.5%) needed a total of 30 ERCP because of evidence of clinical and/or biochemical cholestasis: eight with biliary stricture; six with biliary stones; one with both stricture and stones; and two with normal ERCP findings. Interventional endoscopic procedures included 14 sphincterotomies, six stone removals, seven biliary balloon dilatations, seven biliary stent placements, 11 biliary stent replacements, seven nasobiliary catheter placements and one mechanical lithotripsy. No complications were seen. In all cases, ERCP was able to identify the location, entity and dimension of the late biliary tract complication, thus allowing a therapeutic strategy to be used. Two patients had medical cholestasis. Forty-seven per cent of patients with late biliary tract complications could definitely be cured by ERCP alone. The ERCP improved the patients' condition to allow subsequent surgery in five patients (33%). CONCLUSIONS: These results confirms that ERCP is a valuable diagnostic tool and should be considered as the first step in the non-surgical management of late biliary tract complications after orthotopic liver transplantation.

Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.

The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with cirrhosis without hepatocellular carcinoma are not clearly defined. The role of thrombophilic genetic factors is well established in other venous thrombotic diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin [PTHR A(20210)], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR C677-->T]) have been identified and associated with increased risk of venous thrombosis. The aim of our study was to investigate the role of these thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty-three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons served as controls. The FVL, PTHR A(20210), and MTHFR C(677)-->T genotypes were identified by a polymerase chain reaction and restriction analysis. The frequencies of FVL, PTHR A(20210) mutation, and homozygous MTHFR C(677)-->T were 13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in cirrhotic patients without PVT, respectively. Five patients in the former group had associated defects. A thrombophilic genotype was detected in 69.5% of the patients with PVT. Identification of this high-risk group may have implications in patients who are candidates for major surgery or liver transplantation, and may influence the duration of oral anticoagulation.

Cortico-spinal pathways and inhibitory mechanisms in hepatic encephalopathy.

Transcranial magnetic stimulation of the cerebral cortex was used to study motor system function in 31 cirrhotics (29 post-necrotic and 2 cryptogenic) with and without hepatic encephalopathy (HE). The results were compared with those of 14 healthy subjects matched for age. A significant increase of central motor conduction time, a significant raising of the motor evoked potential (MEP) threshold at rest and a significant reduction of the MEP/muscle action potential (MAP) amplitude ratio were found only in patients with chronic stable (12 patients) and recurrent (9 patients) HE. Vice versa, a significant shortening of the central silent period was observed in all 31 cirrhotic patients. The peripheral silent period was normal in all instances. These results indicate that the damage to the cortico-spinal pathways is related to the progression of cirrhosis to HE, and that cirrhotic patients present a dysfunction of the inhibitory motor mechanisms before HE is clinically manifest.

Reversal of extrahepatic membrane cholesterol deposition in patients with chronic liver diseases by S-adenosyl-L-methionine.

1. S-Adenosyl-L-methionine is reported to improve serum liver function tests in chronic liver disease. Because liver disease is complicated by cholesterol deposition in hepatic and extrahepatic membranes, we have assessed whether oral administration of S-adenosyl-L-methionine to patients with hepatic disease can reverse the cholesterol enrichment of their erythrocytes. 2. The mean erythrocyte cholesterol-to-phospholipid molar ratio in 13 jaundiced patients was reduced 2 weeks after oral administration of S-adenosyl-L-methionine (from 0.874 +/- 0.112 to 0.844 +/- 0.102, P < 0.05) with 10 of the patients (77%) showing a decrease. By contrast, only four of 11 untreated patients (36%) had a reduced erythrocyte cholesterol-to-phospholipid molar ratio after 2 weeks and the mean values did not differ. 3. The plasma and erythrocyte cholesterol-to-phospholipid molar ratios remained closely correlated (r = 0.77, P < 0.01) before and after treatment, suggesting that S-adenosyl-L-methionine had not acted directly on the cells but rather had improved their lipoprotein milieu. Further support for this concept was provided by following one patient, who initially failed to respond, during an additional 3 weeks of S-adenosyl-L-methionine administration. The plasma cholesterol-to-phospholipid molar ratio fell steadily from week 1 to week 5 and was accompanied by a progressive decrease in the erythrocyte cholesterol-to-phospholipid molar ratio. Moreover, the initially suppressed acetylcholinesterase activity of the erythrocyte membranes returned towards normal during this period. 4. This preliminary study is the first evidence in jaundiced patients that a drug can help to reverse the deposition of cholesterol in an extrahepatic membrane.(ABSTRACT TRUNCATED AT 250 WORDS)