Comorbidities, not age, impact outcomes in autologous stem cell transplant for relapsed non-Hodgkin lymphoma.

High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation is a widely applied treatment for advanced non-Hodgkin lymphoma (NHL), but few studies have analyzed the tolerability and outcomes in older patients compared with younger patients treated in a homogeneous manner. We retrospectively reviewed 152 consecutive patients who underwent autologous stem cell transplantation (ASCT) following BEAM conditioning (carmustine, etoposide, cytarabine, and melphalan) for NHL from January 2000 through August 2004 at our institution. We compared 59 patients age > or =60 years and 93 patients age <60 years. Supportive care was identical for all patients. The frequency of comorbidities was similar between both groups. CD34+ cell doses, days to neutrophil recovery, and days to platelet count >20,000/mm3 were similar in younger and older patients, although days to platelet count >50,000/mm3 were longer in the older patients (median 30.0 days versus 22.5 days, P = .01). Patients over the age of 60 were more likely to develop grade III/IV mucositis than their younger counterparts (37.7% versus17.4%, P = .0063). Otherwise, the frequency of other grade III/IV toxicities were similar between younger and older patients. Treatment-related mortality (TRM) was similar between older and younger patients (8.5% versus 5.4%, P = .45). Although age was not associated with TRM, the Charlson Comorbidity Index Score was significantly correlated with TRM (P = .03). Median disease-free survival was similar between older and younger patients (21.8 months versus 29.9 months, P = .93), as was overall survival (OS) (47.7 months versus 62.5 months, P = .20). After controlling for age, the Charlson Comorbidity Index Score influenced OS [P = .013]. Overall, our cohort of patients with NHL over the age of 60 who underwent ASCT following BEAM conditioning experienced toxicities and survival similar to their younger counterparts. Comorbidities significantly influenced TRM and OS in this retrospective cohort. Future study should focus on improving tolerability of conditioning and careful prospective evaluation of comorbidities and their association with outcomes.

Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

Bortezomib inhibits osteoclast activity in patients with multiple myeloma.

BACKGROUND: The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-kappaB. Although NF-kappaB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. PATIENTS AND METHODS: We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. RESULTS: During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. CONCLUSION: The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.

Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease.

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.