Citations

PurposeMantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.Patients and MethodsPatients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.ResultsThirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.ConclusionsSingle-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.

ABSTRACT Niemann‐Pick disease type C (NPC) is a genetic disorder in which patient cells exhibit lysosomal accumulation of cholesterol and sphingolipids (SLs) caused by defects in either NPC1 or NPC2 proteins. We previously demonstrated that NPC1 human skin fibroblasts overexpressing endosomal Rab proteins (Rab7 or Rab9) showed a correction in the storage disease phenotype. In the current study, we used protein transduction to further investigate Rab9‐mediated reduction of stored lipids in NPC cells. Recombinant human Rab9 fused with the herpes simplex virus VP22 protein fragment was overexpressed, purified, and added to culture medium to induce protein transduction. When VP22‐Rab9 was transduced into NPC1 fibroblasts, nearly all cells showed significant reduction in cellular free cholesterol levels, with no cytotoxicity up to 5 µM. A fraction of the VP22‐Rab9 that was transduced into the cells was shown to bind to rab GDP dissociation inhibitor, suggesting that this pool of VP22‐Rab9 had become prenylated. The reduction in cellular free cholesterol was associated with correction of abnormal intracellular trafficking of BODIPY‐lactosylceramide and an increase of sterols in the culture media. The clearance of lysosomal free cholesterol was also associated with a decrease in LDL‐receptor levels. In addition, we demonstrated reduction of intracellular cholesterol by VP22‐Rab9 transduction in NPC2 fibroblasts and in cultured mouse NPC1 neurons. These observations provide important new information about the correction of membrane traffic in NPC cells by Rab9 overexpression and may lead to new therapeutic approaches for treatment of this disease.

Abstract We detected circulating plasma cells (PCs) by flow cytometry in 302 patients with newly diagnosed multiple myeloma (MM) by gating on CD38+CD45- cells. The number of circulating PCs per 50 000 mononuclear cells was reported. In 80 (27%) patients, no circulating PC were seen; 106 (35%) patients had 1 to 10 and 115 (38%) patients had more than 10 circulating PCs. Median overall survival for the 302 patients was 47 months. Patients with 10 or fewer circulating PCs had a median survival of 58.7 months, whereas patients with more than 10 circulating PCs had a median survival of 37.3 months (P = .001). On multivariate analysis, the prognostic value of circulating PCs was independent of β2-microglobulin, albumin, and C-reactive protein. There was only a weak correlation between tumor mass and circulating PCs, suggesting that the appearance of circulating PCs may be a reflection of tumor biology. We conclude that the number of circulating PCs measured by flow cytometry in patients with newly diagnosed MM is an independent predictor of survival.

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47–68 years of age, including 36 ε4 homozygotes, 46 heterozygotes, and 78 ε4 noncarriers who were individually matched for their gender, age, and educational level, we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk.

Purpose To prospectively assess the impact of treatment with cisplatin alone or in combination with topotecan (CT) on quality of life (QOL) in patients with advanced or recurrent cervical cancer, and to explore the prognostic value of baseline QOL scores. Patients and Methods Patients entered on Gynecologic Oncology Group (GOG) Protocol 179 were expected to complete QOL assessments at four time points using Functional Assessment of Cancer Therapy–General (FACT-G), Cervix subscale (Cx subscale), FACT/GOG–Neurotoxicity subscale (NTX subscale), Brief Pain Inventory (BPI), and UNISCALE (UNI). Adjusting for patient age, baseline scores, and effects of time, we longitudinally examined treatment effect on QOL during and after chemotherapy. Results Among patients randomly allocated to receive cisplatin (n = 146) or CT (n = 147), there were no statistically significant differences in QOL up to 9 months after randomization despite more hematologic toxicity in the combination arm. QOL assessments were completed at rates of 98%, 85%, 68%, and 59%, respectively, for the four time points, with similar rates and reasons for nonparticipation between regimens. Baseline FACT-G (P = .0016) and BPI (P = .0001) scores were significantly associated with patient age; older patients had better QOL and less pain. Baseline UNI was positively correlated with FACT-G (r = 0.66; P < .001) and Cx subscale (r = 0.29; P < .001), and negatively related to BPI (r = −0.41; P < .0001). Baseline FACT-Cx (FACT-G + Cx subscale) was associated with survival. Conclusion Despite increased toxicity, CT did not significantly reduce patient QOL when compared with cisplatin alone. Patient-reported QOL measures may be an important prognostic tool in advanced cervix cancer.

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.

An instrument has been developed to acquire polarized attenuated total internal reflection (ATIR) mid-IR spectra of supported monomolecular films in situ at the lipid/water (L/W) interface. The monolayer film is applied to the treated surface of a trapezoidal germanium crystal as it is immersed into the subphase of a specially designed Langmuir-Blodgett trough. This approach offers several advantages over the study of monolayer films at the air/water (A/W) interface by external reflection techniques, including (1) an improved signal throughput and multiple reflections, both contributing to an improved signal-to-noise (S/N) ratio; (2) versatility with respect to the chemical nature of the surface; and (3) the ability to use standard spectral subtraction methods to compensate for absorption of the aqueous subphase. The enhanced sensitivity of this approach facilitates the study of in situ interactions of peptides with fully hydrated lipid membrane surfaces.