Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m², and capecitabine 2000 mg/m² repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3–4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n?=?34; 55%), as well as those with left colon primary tumors (n?=?66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.     

Structures et propriétés diélectriques des poly(α-acétoxystyréne)s parasubstitués

The relations between structure and isothermal, dielectric properties of poly(α-acetoxystyrene)s substituted in para position by ? OCOCH₃ ( 1a ), ? OCOCH₂CH₃ ( 1b ), ? OCOCH₂CH₂CH₃ ( 1c ), ? OCOC₆H₅ ( 1d ), ? OCOCH₂CH₂Cl ( 1f ) and ? OCOOCH₃ ( 1g ) were studied. The dielectric constants, at 10⁵ Hz and 20 ± 2°C, were found to be: 3,79 ( 1a ), 3,36 ( 1b ), 3,18 ( 1c ), 3,51 ( 1d ), 3,36 ( 1e ), 3,65 ( 1f ) and 3,07 ( 1g ). The polymers 1a – 1g do not show any α- or β-transition. Increasing bulkiness of the para substituent gives rise to a decreasing dielectric constant due to an increase of the degree of syndiotacticity, as determined from ¹H and ¹³C NMR spectra.     

Iatrogenic hyperhomocysteinemia in patients with metabolic syndrome: A systematic review and metaanalysis

Metabolic syndrome (MetS) is associated with increased cardiovascular mortality and its management incorporates hypolipidemic, antidiabetic and antihypertensive drugs. However, several classes of these drugs, such as biguanides, fibrates and hydrochlorothiazide have been reported to raise circulating total homocysteine (tHcy) levels. During the last decades, numerous large-scale epidemiological studies have identified Hcy as a moderate independent cardiovascular risk factor. Therefore, drug-induced hyperhomocysteinemia in MetS patients may add one cardiovascular risk factor in these high-risk patients. The present systematic review summarizes data from studies which investigated the effects of the above-mentioned drugs on tHcy, and calculates the treatment effect of each drug class on tHcy levels. We also discuss the underlying pathophysiology and the issues that should be addressed in the future.     

Helicobacter pylori infection upregulates endothelial nitric oxide synthase expression and induces angiogenesis in gastric mucosa of dyspeptic patients

BACKGROUND: Helicobacter pylori (H. pylori) infection induces nitric acid (NO) overproduction through inducible NO synthase (NOS) expression, subsequent DNA damage and enhanced antiapoptosis signal transduction sequence in the human gastric mucosa, whereas its possible effect on endothelial nitric oxide synthase (eNOS) expression has not as yet been investigated. The aim of this study was to evaluate the effect of H. pylori infection in the expression of eNOS in gastric mucosa. PATIENTS AND METHODS: We prospectively studied 30 nonsmoking dyspeptic patients (12 men, 18 women, mean age 54.26+/-12.89 years). The diagnosis of H. pylori infection was based mainly on histology. The histological grading of H. pylori infection was evaluated according to the modified Sydney classification. Histological grading of eNOS expression and microvessel density as estimated by CD34 expression were determined by immunohistochemistry (degree 0-3) and correlated with H. pylori infection and histological degree of gastritis. RESULTS: Twelve patients were H. pylori-positive and 18 patients were H. pylori-negative. The two groups were matched for age (P=0.139), sex (P=0.342) and similar degree of gastritis. Intensity of eNOS and CD34 expression in the corpus and antrum were significantly correlated (P<0.001). eNOS expression was correlated with H. pylori infection in the mucosa of the body and antrum (P=0.013 and 0.037, respectively) but not with gastric inflammation and activity (P=0.848 and 0.871, respectively, for the corpus and P=0.565 and 0.793, respectively, for the antrum). H. pylori-positive patients showed higher expression of CD34-positive blood vessels in the mucosa of the antrum (P=0.048). CD34 expression was correlated with gastric inflammation and activity (P=0.03 and 0.044, respectively) in the mucosa of the antrum of H. pylori-positive patients. CONCLUSION: H. pylori infection upregulates eNOS, and induces angiogenesis, contributing to H. pylori-associated pathophysiology in gastric mucosa.     

Inflammatory markers and plaque morphology: an optical coherence tomography study

Background

OCT with its unique image resolution is the ideal method to detect culprit lesion characteristics in different clinical presentations. The identification of inflammatory markers related to plaque characteristics may be of clinical importance.

Methods

Thirty-two patients with acute coronary syndromes (ACS) and fourteen patients with stable angina pectoris (SAP) were enrolled in this study. Culprit lesion morphology was assessed by optical coherence tomography (OCT) in patients with ACS and SAP. The possible relations between serum levels of high sensitivity-C reactive protein (hs-CRP) and interleukin-18 (IL-18) with plaque characteristics were investigated in those patients.

Results

Plaque rupture and thin-cap fibroatheroma (TCFA) were detected more frequently in ACS patients compared with SAP patients, (78.6% vs. 14.3%, p < 0.001, 92.9% vs. 14.3%, p < 0.001, respectively). Higher levels of serum hs-CRP and IL-18 were found in patients with plaque rupture vs. those with no plaque rupture (median value: 19.2 mg/L vs. 1.6 mg/L, p < 0.001 and 219.5 pg/ml vs. 127.5 pg/ml, p = 0.001 respectively), and TCFA vs. those without TCFA (median value: 15.2 mg/L vs. 1.6 mg/L, p = 0.004 and 209.0 pg/ml vs.153.2 pg/ml, p = 0.03 respectively). Serum hs-CRP was the only independent predictor of plaque rupture (p = 0.02, odds ratio 1.1, 95% confidence interval 1.0 to 1.2). A cut-off value of hs-CRP > 4.5 mg/L could detect ruptured plaque with a sensitivity of 91.7% and a specificity of 77.8%.

Conclusions

OCT detected plaque rupture and TCFA more frequent in ACS patients compared with SAP. Elevated hs-CRP and IL-18 were positively related to plaque instability and rupture.     

Metachronous early gastric adenocarcinoma presenting coinstantaneously with complete remission of stage IV gastric MALT lymphoma

Adenocarcinoma and lymphoma represent the two most common malignant tumours of the stomach, with both neoplasms being associated with infection by Helicobacter pylori. However, the presence of lymphoma and adenocarcinoma in the same patient is a rare entity with synchronous neoplasms being more common than metachronous types. We report a case of stage IV gastric MALT lymphoma of the gastric angle with infiltration of the bone marrow successfully treated with chemotherapy and the occurrence of metachronous early gastric adenocarcinoma of the fundus presenting 1 year after the diagnosis of the lymphoma.     

Association of susceptible genotypes to periodontal disease with the clinical outcome and tooth survival after non-surgical periodontal therapy: A systematic review and meta-analysis

Background

The real clinical utility of genetic testing is the prognostic value of genetic factors in the clinical outcome of periodontal treatment and the tooth survival. A meta-analysis was undertaken to estimate the effect of a susceptible genotype to periodontitis on the clinical outcomes of non-surgical periodontal therapy and the tooth survival.

Material and Methods

A systematic search of MEDLINE-Pubmed, Cochrane Library and Scopus was performed. Additionally, a hand search was done in three journals. No specific language restriction was applied. Two reviewers screened independently titles and abstracts or full text copies. Quality assessment of all the included studies was held.

Results

Initial screening of electronic databases resulted in 283 articles. Ten studies met the inclusion criteria, nine of them examined the clinical outcome, while the other one investigated the tooth survival in susceptible individuals after non-surgical periodontal therapy. Eight of included studies were selected for the meta-analysis. IL-1 positive genotypes increase the risk of tooth loss, while no association found between the bleeding on probing (BOP), clinical attachment loss (CAL) and plaque index (PI) with the genotype status. Probing pocket depth (PPD) reduction in the first three months and in long-term results found to have a significant association with the genotype.

Conclusions

There is no difference in the clinical measurements after non-surgical periodontal treatment, apart from PPD. More publications are needed to identify a cause-effect relationship. Key words:Periodontal disease, periodontitis, periodontal therapy, clinical outcome, tooth loss, susceptibility, polymorphism, genotype, meta-analysis, systematic review.