Adenomatous polyposis coli I1307K mutation in Jewish patients with different ethnicity: prevalence and phenotype

BACKGROUND: A new mutation, I1307K, recently was reported in the adenomatous polyposis coli (APC) gene. This mutation was found to be predominant in Ashkenazi Jews, creating a hypermutable area and predisposing the development of carcinoma. The objective of the current study was to estimate the prevalence of this mutation in several of the ethnic groups that comprise the Israeli population and to elucidate the clinical features of the mutation carriers with colorectal carcinoma (CRC). METHODS: A total of 111 consecutive CRC patients were evaluated and their medical history and clinical data recorded. The general population (298 Ashkenazim and 189 Yemenites) also was tested for the presence of this mutation. Mutation screening was performed using both the polymerase chain reaction-based amplification refractory mutation system and a commercial APC kit. RESULTS: Of the total of 111 CRC patients, 15 (13.5%) carried the I1307K mutation and 26 of 487 subjects from the general population (5.3%) carried the I1307K mutation (P = 0.004). Among the 71 Ashkenazi CRC patients there were 12 carriers (16.9%) whereas 17 of the 298 Ashkenazi Jewish general population (5.7%) carried the mutation (P = 0.004). Of the 4 CRC patients of Yemenite origin, 3 carried the mutation and 9 carriers were found among 189 subjects in the general Yemenite population (4.7%) (P = 0.0007). None of the 34 Sepharadic or 2 Arab CRC patients carried the APC I1307K allele. Late age at diagnosis (64.6 years +/- 10.0, which is similar to that of the noncarriers), mostly right-sided tumors, and moderate to good differentiation constituted the phenotype of the mutation carriers. CONCLUSIONS: The authors believe the findings of the current study broaden the known spectrum of ethnic groups in which the APC I1307K mutation is prevalent. The phenotype of the mutation carrier CRC patients does not conform to the expected familial pattern of germline mutations. The phenotype and the differential incidence rate of CRC among APC I1307K carriers of various ethnic groups suggest low penetrance.     

Gelatinous transformation of bone marrow in chronic myeloid leukemia during treatment with imatinib mesylate: a disease or a drug effect?

Gelatinous marrow transformation (GMT) is an unusual pathological manifestation of progressive malignant diseases and severe malnutrition states. GMT has been associated with various accelerated hematological malignancies, but has never been described in patients with chronic myelogenous leukemia (CML) treated with imatinib mesylate (IM), a novel tyrosine kinase inhibitor. Herein we report 2 patients with stable chronic phase CML who developed GMT during the course of treatment with IM. A comprehensive review of the relevant published data, several possible mechanisms and therapeutic alternatives are suggested.     

Risk factors for,and reversibility of,peripheral neuropathy associated with bortezomib–melphalan–prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study

Objectives: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib‐associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high‐dose therapy who received bortezomib plus melphalan–prednisone. Methods: Patients received nine 6‐wk cycles of VMP (bortezomib 1.3 mg/m², days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m², days 1–4, cycles 1–9; and prednisone 60 mg/m², days 1–4, cycles 1–9). Results: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥3 (<1% grade 4). The PN incidence was dose‐related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m². Median time to PN onset was 2.3 months. Bortezomib‐associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non‐responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P = 0.0065], grade ≥2 PN (HR 2.205, P = 0.0032), and grade ≥3 PN (HR 2.438, P = 0.023); age, pre‐existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN. Conclusions: Rates of bortezomib‐induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases. (Clinicaltrials.gov identifier: NCT00111319).     

Secular trends in the epidemiology of major infectious diseases among Israeli soldiers

BACKGROUND: Army personnel, albeit in general young and healthy, are at greater risk for infectious morbidity owing to higher crowding, compromised hygienic conditions, and exposure to new geographic and climatic factors. We describe the changing trends in the incidence of major infectious diseases of public health importance in the Israeli military: hepatitis A, measles, meningococcal disease, and diarrheal diseases. METHODS: Departments of Epidemiology and Medical Statistics of the Israel Defense Forces Medical Corps monitor the incidence of infectious diseases within the military. Notifiable diseases are predefined and their reporting is mandatory. RESULTS: The incidence of hepatitis has declined significantly since the introduction of prophylaxis with immune serum globulin in the 1970s, and complete control of outbreaks has been achieved. Outbreaks of diarrheal diseases have decreased, probably as a result of intensive control measures begun in the last decade. However, sporadic diarrheal morbidity continues to rise. The vaccination of recruits against Neisseria meningitidis was begun in 1994, following an increase in cases caused by serogroup C bacteria. So far, the program has proved efficacious in reducing morbidity. Measles morbidity in the military was much higher than in the civilian sector over the years. It has become negligible since 1995, when the first cohorts with 2 vaccination doses began their service. CONCLUSION: Despite improvements in personal and environmental health measures, immunization remains the most efficient means for preventing infectious diseases in the military.     

Expression of VEGF-C, VEGF-D and their receptor VEGFR-3 in diffuse large B-cell lymphomas

Lymphangiogenesis-the new growth of lymphatic vessels is an important route for the metastatic spread of human cancer. The receptor tyrosine kinase VEGFR-3 is expressed predominantly on lymphatic endothelium, and activation by its ligands VEGF-C and VEGF-D induces lymhpangiogenesis. VEGF-C, VEGF-D and VEGFR-3 have been found to play an important role in the lymphangiogenesis of several cancers. The present study investigated the expression of these factors by immunohistochemical staining of diagnosis specimens from 38 patients with diffuse large B-cell lymphoma (DLBCL). VEGF-C, VEGF-D and VEGFR-3 were expressed in both lymphoma cells and endothelial cells of blood and lymphatic tissue in all but one patient (who was negative for VEGF-D in lymphoma). There was a significant correlation in the intensity of staining between VEGF-C and -D in lymphoma and blood vessels (P < 0.001), and between the intensity of staining of VEGF-D and the patient International Prognostic Index score (P = 0.049) and borderline significance with overall survival (P = 0.051). Mean microvessel count was 58 (range 23-120), and it increased in association with high-intensity VEGF-C staining in lymphoma cells. Our findings indicate the importance of lymphangiogenic factors in the pathogenesis of DLBCL and suggest a potential therapeutic role for antilymphangiogenesis agents.     

Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase

Background:

Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allowing SC delivery of drug volumes that might not otherwise be feasible.

Methods:

Clinical trials assessing coformulation of rituximab or trastuzumab with rHuPH20 for SC administration were reviewed.

Results:

Phase I trials of rituximab SC maintenance therapy in patients with follicular lymphoma and trastuzumab SC in healthy volunteers and patients with early breast cancer have demonstrated substantially shorter administration times and comparable tolerability and pharmacokinetics compared with IV formulations. Rituximab SC 1400-mg and trastuzumab SC 600-mg doses were identified for further study. Phase III clinical data for rituximab SC 1400 mg have shown comparable efficacy to rituximab IV, and initial clinical data suggest comparable efficacy of trastuzumab SC 600 mg and the IV formulation.

Conclusion:

Coformulation with rHuPH20 may enable effective, well-tolerated, cost-effective, and convenient SC administration of rituximab and trastuzumab. Additional studies are ongoing.     

5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome - a systematic review and meta-analysis

Hypomethylating agents have recently been shown to improve the outcome of patients with myelodysplastic syndrome. A meta-analysis and systematic review was carried out of randomized controlled trials comparing treatment with hypomethylating agents to conventional care, i.e., best supportive care or chemotherapy, in patients with myelodysplastic syndrome. The outcomes assessed were overall survival, time to transformation or death, overall response rate and toxicity. Hazard ratios with 95% confidence intervals were estimated and pooled for time-to-event data. For dichotomous data, relative risks were estimated and pooled. Four trials including 952 patients examined the effect of 5-azacitidine and decitabine. Treatment with hypomethylating agents significantly improved overall survival (hazard ratio 0.72, 95% confidence interval 0.60–0.85, three trials) and time to transformation or death (hazard ratio 0.69, 95% confidence interval 0.58–0.82, four trials). In a subgroup analysis per type of drug, these benefits could be shown for 5-azacitidine but not for decitabine. Both agents favorably influenced response rates. A higher rate of grade 3/4 adverse events was observed with their use. Since 5-azacitidine prolongs overall survival and time to transformation or death it should be highly considered in the treatment of patients with high-risk myelodysplastic syndrome. Further studies are needed to establish the exact role of decitabine compared to 5-azacitidine in these patients.