Impact of oncogenes in tumor angiogenesis: Mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells

Targeted disruption of the single mutant K-ras allele in two human colorectal carcinoma cell lines (DLD-1 and HCT-116) leads to loss of tumorigenic competence in nude mice with retention of ability to grow indefinitely in monolayer culture. Because expression of the mutant K-ras oncogene in these cell lines is associated with marked up-regulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), we sought to determine whether this potent angiogenesis inducer plays a role in K-ras-dependent tumorigenic competence. Transfection of a VEGF₁₂₁ antisense expression vector into DLD-1 and HCT-116 cells resulted in suppression of VEGF/VPF production by a factor of 3- to 4-fold. The VEGF/VPF-deficient sublines, unlike the parental population or vector controls, were profoundly suppressed in their ability to form tumors in nude mice for as long as 6 months after cell injection. In contrast, in vitro growth of these sublines was unaffected, thus demonstrating the critical importance of VEGF/VPF as an angiogenic factor for HCT-116 and DLD-1 cells. Transfection of a full-length VEGF₁₂₁ cDNA into two nontumorigenic mutant K-ras knockout sublines resulted in a weak but detectable restoration of tumorigenic ability in vivo in a subset of the transfectants, with no consistent change in growth properties in vitro. The findings indicate that mutant ras-oncogene-dependent VEGF/VPF expression is necessary, but not sufficient, for progressive tumor growth in vivo and highlight the relative contribution of oncogenes, such as mutant K-ras, to the process of tumor angiogenesis.     

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.     

Is application of electrocardiographic exercise test always usefull in the diagnosis of coronary artery disease? Advantages and limitations of this method

To determine the diagnostic value of the electrocardiographic exercise testing (EET) in 551 patients with chest pain regarded as definite or probable stable angina pectoris (CAD), results of performed EET were compared with coronary angiography. All patients underwent exercise testing according to the Bruce protocol. The criterion for a positive exercise ST-segment response was > or = 1 mm of horizontal or down sloping depression 80 msec after J-point. The indications for cardiac catheterization in each patient were determined at the discretion of the attending physician. Clinically important coronary artery disease was defined as > 50 per cent narrowing of the diameter of at least one major vessel or > or = 50 per cent of the left main coronary artery. RESULTS: The sensitivity and specificity of EET for detection of CAD were for the entire group, in women and men respectively: 93%, 91%, 94% and 21%, 16%, 27%. CONCLUSION: 1. Indications for EET should be based on prior probability of coronary artery disease. 2. Application of higher than conventional ST depression criteria (> or = 2 mm) lowers sensitivity but increases specificity of EET. 3. Variables determining false positive results are as follows: age, sex (female), low probability of CAD, ST-segment depression in leads: II, III, aVF and mitral valve prolapse. 4. Variables determining false negative results are as follows: high probability of CAD, sex (male) and one vessel disease.     

Are Women with Severely Symptomatic Brugada Syndrome Different from Men?

Introduction: Spontaneous type‐1 ECG has been recognized as a risk factor for sudden cardiac death (SCD) in Brugada syndrome (BrS), but studied populations predominantly consisted of men. We sought to investigate whether a spontaneous type‐1 ECG pattern was also associated in women with severely symptomatic BrS. Other known risk factors were also examined for gender specificity. Methods: Patients with severely symptomatic BrS, defined as resuscitated SCD and/or appropriate implantable cardioverter‐defibrillator (ICD) shock, were included from 11 European centers. Clinical data, investigation of family history, 12‐lead ECG, and results of electrophysiological study (EPS) were collected. The average follow‐up was 4 ± 3 years. Results: Fifty‐eight patients fulfilled the inclusion criteria (mean age 47 ± 11 years, 8 women). Thirty‐six men (72%) but only two women (25%) had a spontaneous type‐1 ECG at baseline (P = 0.02). Maximal ST elevation before or after drug challenge was 3.7 ± 1.3 mm in men versus 2.4 ± 0.7 mm in women (P = 0.007). The proportion of patients with a family history of SCD or an SCN5A mutation was not significantly different between both groups. Of those patients with high‐risk BrS who underwent EPS, 76%(12/25) of men and 50%(2/4) of women had a positive study. Conclusion: In contrast to men, most women with BrS and resuscitated SCD or appropriate ICD shock do not have a spontaneous type‐1 ECG pattern. In addition, the degree of ST elevation is less pronounced in women than men. While women represent a lower‐risk group overall, risk factors established from a predominantly male population may not be helpful in identifying high‐risk females.     

Is the BRAFV600E mutation useful as a predictor of preoperative risk in papillary thyroid cancer?

ObjectiveRecent studies have shown that a BRAF^V600E reflects poor prognosis, mainly in Western countries. However, some clinicians in Japan have suggested that the BRAF^V600E mutation is not associated with a poor prognosis. Therefore, we investigated a relationship between BRAF^V600E mutation and clinicopathologic factors.MethodsFrom September 2008 to December 2009, we performed routine analysis of the BRAF^V600E mutation using thyroid cancer tissue from 424 patients who underwent thyroidectomy with cervical lymph node dissection.ResultsThe BRAF^V600E mutation was found in 335 of 424 cases (79%) and was higher in classic papillary thyroid carcinoma (PTC) (79.7%) than in the follicular variant of PTC (62.5%) (P = .019). On univariate analysis, the BRAF^V600E mutation was associated with extrathyroidal extension (P = .009) and variants of PTC (P = .019), but a high-risk Metastasis, Patient Age, Completeness of resection, local Invasion and Tumor Size (MACIS) score (≥ 6) (P = .146) and lymph node metastasis (P = .628) were not significantly associated with the BRAF^V600E mutation. Multivariate analysis showed that extrathyroidal extension is independently associated with the BRAF^V600E mutation (relative ratio: 2.466; 95% confidence interval, 1.213–5.011; P < .013).ConclusionIt is not clear that the BRAF^V600E mutation is useful for prediction of poor prognosis of PTC.