Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation

André Tichelli1, Christoph Bucher1, Alicia Rovó1, Georg Stussi1, Martin Stern1, Michael Paulussen2, Jörg Halter1, Sandrine Meyer-Monard1, Dominik Heim1, Dimitrios A. Tsakiris1, Barbara Biedermann3, Jakob R. Passweg1, and Alois Gratwohl1

1 Division of Hematology, University Hospital, Basel; 2 University Children's Hospital (UKBB), Pediatric Hematology/Oncology, Basel; 3 Department of Research, University Hospital, Basel, Switzerland

We assessed incidence and risk factors of cardiovascular events in 265 patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) between 1980 and 2000 and who survived at least 2 years. Results were compared with a cohort of 145 patients treated during the same period with autologous HSCT. The median age of patients with allogeneic HSCT at last follow-up was 39 years, and median follow-up was 9 years. Eighteen (6.8%) patients after allogeneic and 3 (2.1%) patients after autologous HSCT experienced an arterial event. The cumulative incidence of first arterial event after allogeneic HSCT was 22.1% (95% CI, 12.0-40.9) at 25 years. The cumulative incidence 15 years after allogeneic HSCT was 7.5% as compared with 2.3% after autologous HSCT. Adjusting for age, risk of an arterial event was significantly higher after allogeneic HSCT (RR 6.92; P =.009). In multivariate analysis, allogeneic HSCT (RR: 14.5; P =.003), and at least 2 of 4 cardiovascular risk factors (hypertension, dyslipidemia, diabetes, obesity) (RR: 12.4; P =.02) were associated with a higher incidence of arterial events after HSCT. Thus, long-term survivors after allogeneic HSCT are at high risk for premature arterial vascular disease. HSCT might favor the emergence of established risk factors, such as hypertension, diabetes, and dyslipidemia.

New proteasome inhibitor research: Carfilzomib

Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma

Deborah J. Kuhn, Qing Chen, Peter M. Voorhees, John S. Strader, Kevin D. Shenk, Congcong M. Sun, Susan D. Demo, Mark K. Bennett, Fijs W. B. van Leeuwen, Asher A. Chanan-Khan, and Robert Z. Orlowski

The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.

Blood, 1 November 2007, Vol. 110, No. 9, pp. 3281-3290.

New US cancer statistics

According to a new report by the National Institutes Of Health, the overall decline in cancer deaths nearly doubled from 2002 through 2004. Now, almost 70 percent of cancer patients live five years past their diagnosis.

Doctors said cancer deaths are actually falling a bit faster than they expected.

Deaths from colorectal cancer are down for both men and women. The No. 1 killer in both sexes, lung cancer, is decreasing in men but still rising in women, although at a slower rate than in the past.

"We're seeing the impact of early detection, better treatment, better care all around," Dr. Brenda Edwards of the National Cancer Institute said.

The rate of people being diagnosed with cancer has been stable since 1995. However, there are certain kinds that are not letting up. In men, Myeloma, kidney and liver cancers have been rising. In women, lymphoma, melanoma and thyroid cancer continue to increase.