Prospective Phase II Study of Neoadjuvant Therapy with Cisplatin, 5-Fluorouracil, and Bevacizumab for Locally Advanced Resectable Esophageal Cancer

Background: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. Patients and Methods: In this prospective phase II study, 22 patients with adenocarcinoma and 6 with squamous cell carcinoma received 2 4-day cycles of bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m(2) infusion on day 1 followed by 5-FU 1,000 mg/m(2) as a 96-h continuous infusion on days 1-4, separated by a 3-week interval. Results: The response rate was 39%, the R0 resection rate was 43%, and the median overall survival (OS) was 17 months. The regimen was well tolerated, with the most common severe toxicities being venous thromboembolism (10%), nausea, and gastrointestinal bleeding (7% each). In 37 patients previously treated with cisplatin and 5-FU alone at our institution and thus serving as historical controls, the response rate was 30%, the R0 resection rate was 44%, and the median OS was 23 months. There was no statistically significant difference between the 2 groups of patients. Conclusion: Adding bevacizumab to cisplatin and 5-FU neoadjuvant chemotherapy was active and well tolerated but did not seem to improve the resection rate or OS compared with prior regimens, including the historical controls at our institution.     

Infectious inflammation of the CNS involves activation of mitogen-activated protein kinase and AKT proteins in CSF in humans

Abstract The mitogen-activated protein kinases (MAPKs) and the AKT are interacting proteins that serve as transmitters of numerous extracellular signals to their intracellular targets, thereby regulating many cellular processes, such as proliferation, differentiation, development or stress responses. Whereas a large amount of information about the MAPKs/AKT participation in biological processes is available, less is known about their role in human diseases. We postulated that the MAPKs/AKT could be involved in inflammatory processes of the central nervous system (CNS) in humans and we investigated the CSF of 12 patients with viral infection of the CNS for the presence of the distinct components of these cascades. The cerebrospinal fluid (CSF) of 18 individuals who underwent a lumbar puncture for diagnostic purposes served as controls. Six patients with inflammatory disease of the CNS revealed the presence of activated ERK. In five patients p38MAPK was detected, in three in its activated form. The activity of AKT could be demonstrated in four patients. JNK was not found. None of the control patients showed the presence of MAPK enzymes. The mean CSF cellularity was higher in MAPK-positive than in MAPKnegative patients. There was no difference in mean age or gender between the patients and controls, or between the MAPK- and AKT-positive or -negative patients. Our work demonstrates that the MAPK and AKT cascades might participate in inflammatory processes of the CNS. As selective inhibitors of the MAPKs are available, their application in the future might reduce an inappropriate inflammatory response and thus limit brain damage in severe cases of meningoencephalitis.     

Effectiveness of reloading to overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction

Whether increasing doses of clopidogrel can overcome nonresponsiveness was evaluated. Clopidogrel nonresponsiveness was found in up to 25% of treated patients and was associated with worse prognosis in patients with acute coronary syndrome and patients undergoing coronary intervention. Adenosine diphosphate (ADP)-induced platelet aggregation was prospectively determined on day 4 of acute myocardial infarction in 200 consecutive patients, who received clopidogrel 300 mg as a loading dose and 75 mg/day thereafter. Thirty patients (15%) had ADP-induced platelet aggregation >or=80% using light transmittance aggregometry and were considered clopidogrel nonresponders. Nonresponders were reloaded with clopidogrel 600 mg, followed by 150 mg/day for 4 weeks. A 75-mg/day dose was resumed thereafter. ADP-induced platelet aggregation was reassessed 4 hours after reloading and biweekly for 10 weeks. Flow cytometry was used to determine platelet P-selectin expression and fibrinogen binding before and 4 hours after reloading. ADP-induced platelet aggregation significantly decreased 4 hours after reloading (from 83 +/- 6% to 56 +/- 14%; p <0.01). The decrease in platelet aggregation was maintained throughout the 4-week doubled maintenance dose. After resuming a maintenance dose of 75 mg/day, ADP-induced platelet aggregation returned to 66 +/- 12% (p <0.001), and 5 patients (17%) had ADP-induced platelet aggregation >or=80%. Flow cytometry showed a significant decrease in P-selectin expression (from 37 +/- 16% to 26 +/- 13%; p <0.01) and fibrinogen binding (from 84 +/- 7% to 70 +/- 13%; p <0.01) in ADP-stimulated platelets 4 hours after reloading. In conclusion, clopidogrel reloading and increased maintenance dose may overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction.     

Natural frequencies and the representation of risk

To the Editor: The findings reported by Olsen and Gøtzschelin a recent paper in The Lancet have re-sparked a heated controversyconcerning the merits (or lack thereof) of mammography screening[1]. The dispute is not confined to the medical realm, but haspolitical, economical, and ethical ramifications as well.     

Surgery in postmenopausal women — the value of transvaginal sonography

Summary Transvaginal sonography is a recent addition to the diagnostic techniques available for the evaluation of the female pelvis. Transvaginal sonography is performed with a high-frequency transducer placed in the vagina where it is in close anatomic proximity to the pelvic structures. The procedure overcomes difficulties in imaging obese patients, those with a large amount of bowel gas, and those with inadequate bladder filling. Our experience in over 200 cases of postmenopausal women is the subject of this review. This technique has been employed to detect ovarian and adnexal abnormalities, endometrial changes (hyperplasia and endometrial carcinoma), myometrial invasion, fibroids, adnexal torsion and free fluid in the rectouterine fossa. The results suggest that transvaginal sonography has considerable advantages in the evaluation of pelvic structures in postmenopausal women prior to planned surgical exploration.     

Lynch Syndrome in high risk Ashkenazi Jews in Israel

Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68 %) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73 %) of these families carried one of the 3 ‘Ashkenazi’ founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6 %) were large deletions. Only 20/51 (39 %) families were Amsterdam Criteria positive; 42 (82 %) were positive for the Bethesda guidelines and 9 (18 %) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73 % families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.     

Outcome of Right Colectomy for Cancer in Octogenarians

Background  Colorectal cancer is one of the commonest malignancies in the elderly and, as such, is a major cause of morbidity and mortality. There is no consensus yet if age itself is a risk factor for adverse outcome after colectomy. The aims of the study were to evaluate the impact of age on operative results of right colectomy for cancer and to define factors that influence the postoperative mortality in octogenarians. Methods  Data of all patients who underwent right colectomy for colon cancer between January 2001 and December 2006 were collected retrospectively. Patients were divided into two groups: those who were 80 years and older and those who were less than 80 years old. Analysis included patients’ demographics, comorbidities, American Society of Anesthesiologists class, functional status, mode of presentation, stage of disease, length of hospital stay, postoperative morbidity, and mortality. Results  A total of 124 consecutive patients with right colon cancer were operated. Control group included 84 patients less than 80 year old. Study group included 40 patients 80 years or older. In Cox multivariate regression analysis, poor functional status and emergent surgery were independent factors for postoperative mortality. Conclusions  There was no significant difference in the outcome of elective right colectomy between elderly patients and their younger counterparts. Operative mortality of emergency surgery was significantly higher in octogenarians. Emergent setting and poor functional status are major risk factors for postoperative mortality. This study was presented in part at the Biennial Meeting of the Israel Surgical Association, Jerusalem, Israel, June 6–7, 2007.