Citations

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

AbstractOBJECTIVE:Olfaction is often sacrificed to gain access to the cranial base in anterior craniofacial surgery. We describe the long-term results of olfactory function in patients who underwent anterior craniofacial surgery and a cribriform plate osteotomy to preserve olfaction.METHODS:Between 1992 and 2004, 28 patients underwent 29 cribriform plate osteotomies in an attempt to preserve olfaction during anterior craniofacial surgery performed through modified extended transbasal approaches. Patients' charts and office notes were reviewed retrospectively. Formal olfactory testing was available in 5 patients, but most data were based on patients' subjective reports of olfaction. Olfactory preservation was defined by the subjective ability to detect fumes such as coffee, chocolate, roses, and orange juice regardless of the intensity of the sensation. Follow-up was based on phone calls to patients.RESULTS:Four patients were lost to follow-up and excluded. Therefore, follow-up was available in 24 patients after 25 procedures. On the basis of patients' subjective reports, olfaction was spared in 22 patients after 23 procedures (92%) and was confirmed objectively in the five patients formally tested. After surgery, only two patients were anosmic.CONCLUSION:Olfaction can be preserved in selected patients undergoing anterior craniofacial surgery. At least 1 cm of nasal mucosa should remain attached to the cribriform plate, which can be achieved by including the nasal bone in the osteotomy of the orbital bar. A medial orbital canthopexy is therefore necessary after these procedures.

Purpose On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens. Patients and Methods Eligible patients were randomly allocated to receive cisplatin 50 mg/m2 every 3 weeks (CPT); cisplatin 50 mg/m2 day 1 plus topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m2 days 1, 15, and 22, vinblastine 3 mg/m2 days 2, 15, and 22, doxorubicin 30 mg/m2 day 2, and cisplatin 70 mg/m2 day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately. Results The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. Conclusion This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.

AbstractSuccessful therapy for pituitary apoplexy depends on prompt recognition of the clinical syndrome, accurate anatomic evaluation of the lesion with the CT scan, intensive steroid replacement therapy, and effective transphenoidal decompression of the tumor. Successful long‐term management of patients who have suffered pituitary apoplexy requires recognition by the complex interrelationships of the pituitary with adrenal, thyroid, gonadal, pancreatic, and gut physiology. Such patients often require multiple medications for replacement therapy. Surgical treatment is often supplemented with radiation therapy, and prolactin‐ and growth hormone‐secreting adenomas may require long‐term management with bromocriptine. Careful follow‐up evaluations and appropriate post‐surgical therapy enable most of these patients to live normal lives.

Purpose To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL). Patients and Methods A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries. Results We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (≤ 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively. Conclusion This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.

ABSTRACT Transforming growth factor‐β (TGF‐β) is the single most important cytokine promoting renal fibrogenesis. p21‐activated kinase‐2 (PAK2) and activa‐ tion of abelson nonreceptor tyrosine kinase (c‐abl) have been shown recently to be smad‐independent, fibro‐ blast‐specific targets downstream of the activated TGF‐β receptor. In the current study we show that in cultured NRK49F‐renal fibroblasts (but not in tubular or mesangial cells) TGF‐β similarly activates PAK2 as well as c‐abl and induces cell proliferation. Inhibition of the c‐abl kinase with imatinib mesylate prevents increased proliferation after TGF‐β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a dis‐ ease model of TGF‐β‐driven renal fibrogenesis. In obstructed kidneys, PAK2 and c‐abl activity were in‐ creased but only c‐abl activation was blocked by ima‐ tinib. Treatment with imatinib did not prevent renal interstitial infiltration of macrophages or phosphoryla‐ tion and nuclear translocation of smad2/3 in ob‐ structed kidneys. In contrast, imatinib substantially inhibited an increase in the number of interstitial fibroblasts and myofibroblasts and reduced the expres‐ sion and interstitial accumulation of collagen type III, collagen type IV and fibronectin. These findings indi‐ cate that TGF‐β‐induced activation of the nonreceptor c‐abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF‐β‐ dependent renal fibrogenesis. Inhibition of c‐abl activ‐ ity with imatinib mesylate ameliorates experimental renal fibrosis in rats.—Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non‐ Smad TGF‐β pathway and reduces renal fibrogenesis in vivo. FASEB J. 19, 1‐11 (2005)

AbstractB-cell chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. We evaluated the ability of the investigational antileukemic agent adaphostin to induce apoptosis in CLL B cells and synergize with fludarabine in vitro. Analysis by annexin V/propidium iodide (PI) staining revealed that the concentration of adaphostin required to induce 50% cell death (IC50) at 24 hours was 4.2 μM (range, 1.10-11.25 μM; median, 4.25 μM; n = 29) for CLL isolates and more than 10 μM for B and T cells from healthy donors. Immunoblots demonstrated adaphostin induced poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage and cleavage of caspase-3 substrates, suggesting that adaphostin induces apoptosis. Adaphostin increased the level of reactive oxygen species (ROS) within CLL B cells, and the antioxidant N-acetylcysteine blocked both adaphostin-induced ROS generation and apoptosis. Adaphostin also caused a decrease in the level of the antiapoptotic protein Bcl-2. When adaphostin was combined with fludarabine (F-ARA-AMP), a synergistic effect on cell death was observed in all 10 CLL samples. These findings not only indicate that adaphostin induces apoptosis selectively in CLL B cells through a mechanism that involves ROS generation but also demonstrate its ability to augment the effects of fludarabine. Further preclinical development of adaphostin as a novel agent for the treatment of CLL appears warranted.