The objective of this study was to test a low dose of (25 mg weekly) of the mammalian target of rapamycin kinase inhibitor temsirolimus for patients with relapsed mantle cell lymphoma (MCL).
Patients ...with relapsed or refractory MCL were eligible to receive temsirolimus 25 mg intravenously every week as a single agent. Patients who had a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission and then were observed without maintenance.
Of 29 enrolled patients, 28 were evaluable for toxicity, and 27 were evaluable for efficacy. The median age was 69 years (range, 51-85 years), 86% of patients had stage IV disease, and 71% had > or = 2 extranodal sites. Patients had received a median of 4 prior therapies (range, 1-9 prior therapies), and 50% were refractory to the last treatment. The overall confirmed response rate was 41% (11 of 27 patients; 90% confidence interval CI, 22%-61%) with 1 complete response (3.7%) and 10 partial responses (37%). The median time to progression in all eligible patients was 6 months (95% CI, 3-11 months), and the median duration of response for the 11 responders was 6 months (range, 1-26 months). Hematologic toxicities were the most common, with 50% (14 of 28 patients) grade 3 and 4% (1 of 28 patients) grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reduction.
Single-agent temsirolimus at a dose of 25 mg weekly is an effective new agent for the treatment of MCL. The 25-mg dose level retained the antitumor activity of the 250-mg dose with less myelosuppression. Further studies of temsirolimus in combination with other active drugs for MCL and other lymphoid malignancies are warranted.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Blood cytokine elevations have been associated with non-Hodgkin's lymphoma (NHL) such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Although other types of NHL have been ...studied, to our knowledge, cytokine deregulation in mantle cell lymphoma (MCL) has not been comprehensively studied. In this study, we studied cytokine levels in untreated and relapsed MCL patients using a multiplex assay to determine the role of dysregulated cytokines in these patients and study any prognostic relevance that could be drawn from their effect on relapse and survival.
Samples from two data sets of MCL patients were used for this study. The first dataset was pre-treatment serum samples from newly-diagnosed patients with MCL (n=88) from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. The second dataset included pre-treatment plasma samples from relapsed MCL patients (n=20) treated on the MC0048G clinical trial studying the effect of everolimus in lymphoma patients. In addition, unrelated controls from a case-control study of lymphoma were included (n=15 serum, n=24 plasma). Thirty cytokines were assessed using a multiplex ELISA. Differences between cytokines in cases and controls were assessed using Wilcoxon rank-sum tests; associations between cytokines and event-free survival were assessed using Kaplan-Meier curves and Cox proportional hazards models. In the newly diagnosed MCL patients, IL-10 (p<0.0001), IL-1RA (p=0.001), IL-6 (p= 0.04), sIL-2Rα (p=0.005), and MIG (p=0.002) were elevated compared to normal controls. The only significantly elevated cytokine in the recurrent MCL cases compared to controls was sIL-2Rα (p= 0.0006). High levels (above median) of sIL-2Rα levels were associated with inferior event-free-survival (EFS) in both newly diagnosed (HR=2.61 (95% CI: 1.41-4.81, p= 0.0022) and relapsed MCL (HR=2.90, 95% CI: 1.08-7.80, p=0.035) patients; this remained significant after adjusting for MIPI (p=0.01 and 0.03, respectively). Moreover, in the relapsed MCL group eotaxin (p< 0.0001), IL-12 (p< 0.0001), and MCP-1 (p= 0.0002) were suppressed compared to normal controls. We hypothesized that STAT3 (pSTAT3) in MCL cells might be the possible cause behind IL-12 suppression. Indeed, 12/13 MCL samples from IL-12-suppressed relapsed MCL patients were pSTAT3+. When studying the association between cytokine levels and clinical characteristics in both untreated and relapsed MCL groups, sIL-2R was significantly associated with the MIPI score in both untreated (p<0.0001) and relapsed (p=0.007) MCL groups; and with performance status (p=0.005), lymphoma stage (p=0.004), and B symptoms (p=0.006) in the newly diagnosed MCL group. Display omitted
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Our study shows that cytokines are deregulated in both untreated and relapsed MCL patients. It emphasizes on the importance of sIL-2R in its association with negative clinical parameters and worse prognosis in MCL. These findings gives the rational for using sIL-2R along with MIPI and other parameters in predicting prognosis and further to monitor response in MCL. Furthermore, we showed that IL-12 is suppressed in relapsed MCL group and that pSTAT3 expression is a possible mechanism behind this suppression. Further studies are needed to investigate the effect of drugs that suppress pSTAT3 expression in IL-12 suppressed MCLs and disease progression in relapsed MCL patients.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Observational studies suggest a proportion of patients with lymph node metastases will benefit from lymph node dissection (LND) at the time of nephrectomy for clear cell renal ...cell carcinoma (RCC). Objective Our aim was to report the performance of five previously identified high-risk pathologic features assessed by intraoperative examination on prediction of lymph node metastases and propose a template for LND based on locations of lymph node involvement. Design, setting, and participants The study included a historical cohort of consecutive patients from a single institution who received LND in conjunction with nephrectomy for high-risk clear cell RCC between 2002 and 2006. Interventions All patients underwent nephrectomy and LND. Measurements Patients were considered high risk for nodal metastasis if two or more of the following features were identified during intraoperative pathologic assessment of the primary tumor: nuclear grade 3 or 4, sarcomatoid component, tumor size ≥10 cm, tumor stage pT3 or pT4, or coagulative tumor necrosis. Based on these features, LND was performed at the time of nephrectomy, and the numbers and sites of regional lymph node metastasis were recorded for each patient. Results and limitations Of the 169 high-risk patients, 64 (38%) had lymph node metastases. All patients with nodal metastases had nodal involvement within the primary lymphatic sites of each kidney prior to involvement of the nodes overlying the contralateral great vessel. A limitation of the study is the lack of a standardized LND performed throughout the study period. Conclusions Pathologic features of renal tumors are associated with the risk of regional lymph node metastases and lymph node metastases that appear to progress though the primary lymphatic drainage of each kidney. Based on these findings we recommend that when performing LND the lymph nodes from the ipsilateral great vessel and the interaortocaval region be removed from the crus of the diaphragm to the common iliac artery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose In 2010 the American Joint Committee on Cancer updated the renal cell carcinoma TNM classification. Without independent validation of the new classification its predictive ability for cancer ...specific survival and generalizability remains unknown. In this setting we determined the predictive ability of the 2010 TNM classification compared to that of the 2002 classification. Materials and Methods Using the nephrectomy registry at our institution we retrospectively reviewed the records of 3,996 patients with unilateral or bilateral synchronous renal cell carcinoma treated with radical nephrectomy or nephron sparing surgery between 1970 and 2006. Cancer specific survival was estimated using the Kaplan-Meier method and predictive ability was evaluated using the concordance index. Results There were 1,165 deaths (29.1%) from renal cell carcinoma a median of 1.9 years after surgery compared to a median followup of 7.4 years for survivors. The estimated 10-year cancer specific survival rate was 96%, 80%, 66%, 55%, 36%, 26%, 25% and 12% for patients with 2010 primary tumor classifications of pT1a, pT1b, pT2a, pT2b, pT3a, pT3b, pT3c and pT4, respectively (p <0.001). The multivariate concordance index for the 2002 and 2010 TNM classifications was 0.848 and 0.850, respectively. Conclusions The new 2010 classification remains a robust predictor of cancer specific survival compared to the 2002 classification by dividing pT2 lesions into pT2a and pT2b, reclassifying ipsilateral adrenal involvement as pT4, reclassifying renal vein involvement as pT3a and simplifying nodal involvement as pN0 vs pN1. However, the 2010 TNM classification showed only modest improvement in predictive ability compared to the 2002 classification.
A new high‐throughput computational strategy was established that improves genomic data mining from MS experiments. The MS/MS data were analyzed by the SEQUEST search algorithm and a combination of ...de novo amino acid sequencing in conjunction with an error‐tolerant database search tool, operating on a 256 processor computer cluster. The error‐tolerant search tool, previously established as GenomicPeptideFinder (GPF), enables detection of intron‐split and/or alternatively spliced peptides from MS/MS data when deduced from genomic DNA. Isolated thylakoid membranes from the eukaryotic green alga Chlamydomonas reinhardtii were separated by 1‐D SDS gel electrophoresis, protein bands were excised from the gel, digested in‐gel with trypsin and analyzed by coupling nano‐flow LC with MS/MS. The concerted action of SEQUEST and GPF allowed identification of 2622 distinct peptides. In total 448 peptides were identified by GPF analysis alone, including 98 intron‐split peptides, resulting in the identification of novel proteins, improved annotation of gene models, and evidence of alternative splicing.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives To evaluate the impact of the category of unclassified renal cell carcinoma (URCC) on survival following nephrectomy. Methods Patients with clear cell RCC (ccRCC, n = 3048) and URCC (n = ...38) were identified. Patients with URCC were matched 4:1 with ccRCC patients based on year of surgery, symptoms at presentation, tumor size, stage, regional lymph node involvement, metastases, grade, coagulative tumor necrosis, and sarcomatoid differentiation. Survival was estimated using the Kaplan–Meier method and compared between ccRCC and URCC patients using log-rank tests. Results Patients with URCC were more likely to have regional lymph node involvement ( P <.001), higher grade ( P <.001), tumor necrosis ( P <.001), and sarcomatoid differentiation ( P <.001) as compared to patients with ccRCC. Overall survival was not significantly different between URCC and ccRCC patients in either the unmatched ( P = .337) or matched ( P = .345) cohorts. Cancer-specific survival was significantly worse for URCC patients compared with unmatched ccRCC patients ( P = .020). However, this difference was not statistically significant when the URCC patients were compared with the matched cohort ( P = .688). Distant metastases-free survival was somewhat worse for M0 URCC patients compared with unmatched M0 ccRCC patients ( P = .063), but not in the matched cohort ( P = .788). Conclusions Although URCC is more likely to present with advanced clinicopathologic features compared with ccRCC, no statistically significant differences in outcome were noted after adjusting for these features in a matched analysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We present a new approach that allows the identification of intron-split peptides from mass spectrometric data in genomic databases. Our algorithm uses small regions of peptide sequence information ...which are automatically deduced from de novo amino acid sequence predictions together with the molecular mass information of the precursor ion. The sequence predictions are based on selected collision-induced mass spectrometric fragmentation spectra. Fragments of the predicted amino acid sequence are aligned with each of the six frames of the translated genome and the precursor mass information is used to assemble the corresponding tryptic peptides using the sequence as a matrix. Hereby, intron-split peptides can be gathered and in turn verified by mass spectrometric data interpretation tools such as Sequest.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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