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Thomas E Witzig

Publications and source records attributed to Thomas E Witzig.

At least 37 records · Page 2Linked to original sources
PubMed2006

Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients.

BACKGROUND & AIMS: Genomic instability in colon cancers is a consequence of chromosomal instability characterized by aneuploidy or defective DNA mismatch repair (MMR) indicated by microsatellite instability (MSI). Given that high-frequency MSI (MSI-H) and diploidy are correlated, we determined whether they are independent prognostic variables. METHODS: Astler-Coller stage B2 and C colon cancers (N = 528) from patients treated in 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for hMLH1, hMSH2, and p53 proteins was performed. DNA ploidy was analyzed by flow cytometry. Associations with disease-free and overall survival were determined. RESULTS: MSI-H was detected in 95 tumors (18%), and 70 (74%) of these were diploid. Tumors showing MSI-H (hazard ratio, 0.65; 95% confidence interval, 0.44-0.96; P = .023) or loss of MMR proteins (P = .024) were associated with better overall survival. Improved disease-free and overall survival were found for diploid versus aneuploid/tetraploid tumors (overall survival: hazard ratio, 0.59; 95% confidence interval, 0.43-0.79; P = .0003). In the subgroups of MSI-H and microsatellite stable (MSS)/low-frequency MSI (MSI-L) tumors, diploidy was associated with better survival. The prognostic impact of ploidy was similar in stage B2 and C tumors. Ploidy did not predict the benefit of 5-fluorouracil-based treatment. When ploidy, MSI, and MMR proteins were analyzed in the same multivariate model, only ploidy remained significant. CONCLUSIONS: DNA ploidy and MSI-H status were independent prognostic variables, yet ploidy was the strongest marker. Diploidy was associated with better survival in MSI-H and in MSS/MSI-L patient subgroups.

Adaptor Proteins, Signal Transducing↗
PubMed2006

A phase II trial of imatinib in patients with refractory/relapsed myeloma.

Although imatinib was designed to specifically inhibit the bcr-abl gene product, it inhibits other receptor tyrosine kinases including c-kit. As pre-clinical data, 126 patients with plasma cell disorders and 19 controls were evaluated for c-kit expression. Patients were eligible for the treatment trial if they had relapsed/refractory myeloma. The primary end-point of the study was response. Of the 145 studied before the trial, c-kit expression was present on the bone marrow plasma cells of control (11%), AL amyloid (53%), MGUS (47%), SMM (67%) and MM (42%) patients. Twenty-three MM patients were enrolled on the therapeutic trial (imatinib 400 mg daily) and 52% had positive c-kit staining. There were no responses. The median duration of treatment was 48 days (range: 12-349). Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imatinib is not an active agent in patients with relapsed or refractory multiple myeloma.

Aged↗
PubMed2006

Treatment with yttrium 90 ibritumomab tiuxetan at early relapse is safe and effective in patients with previously treated B-cell non-Hodgkin's lymphoma.

Yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin), a radiolabeled monoclonal antibody against the CD20 antigen, is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), including patients with rituximab-refractory follicular NHL. Data on 211 patients treated in four clinical trials were analysed to compare the efficacy and safety of (90)Y ibritumomab tiuxetan when it was used after the first relapse of NHL and when it was used after two or more prior therapies. Sixty-three patients (30%) were treated with (90)Y ibritumomab tiuxetan after their first relapse and 148 (70%) after two or more prior therapies. Demographics, disease characteristics and the frequency of adverse events were similar in all groups, with the exception of a higher rate of marrow involvement in first-relapse patients than in patients with two or more prior therapies (57% vs. 39%; P < 0.05). The complete response rate [confirmed (CR) and unconfirmed (Cru)] was higher in first-relapse patients (49% vs. 28%; P < 0.01), and the median time to progression (TTP) was longer (12.6 vs. 7.9 months; P < 0.05). In patients with follicular NHL, the differences were even more pronounced (CR/CRu: 51% vs. 28%; P < 0.01; TTP: 15.4 vs. 9.2 months; P < 0.05). (90)Y ibritumomab tiuxetan has substantial clinical benefits as a second-line therapy, especially in patients with follicular NHL. The quality of disease remissions obtained when (90)Y ibritumomab tiuxetan is administered after first relapse appears to be comparable with that observed with most chemotherapy regimens in first-relapse patients.

Adult↗
PubMed2006

The International Prognostic Index predicts outcome after histological transformation of low-grade non-Hodgkin lymphoma.

Histological transformation of low-grade non-Hodgkin lymphoma (NHL) to diffuse large cell NHL is well recognized and is associated with a poor prognosis. We sought to determine the overall outcome and the factors that affect survival in patients with histological transformation of low-grade NHL. Between November 1979 and September 2000, 93 patients who developed transformed lymphoma were identified. The median time to transformation was 4.2 years from the original diagnosis. The median age at transformation was 63 years. Seventy-eight percent had stage III or IV disease. Fifty-seven percent had extranodal involvement, including bone marrow; 33% had an elevated lactate dehydrogenase. The International Prognostic Index (IPI) at transformation was termed the transformation IPI (tIPI); 29% had a tIPI of 0-1, 59% had a tIPI of 2-3 and 8% had a tIPI of 4-5. At a median follow-up of 15 months from histological transformation, 20 of 93 patients (22%) were alive. The median survival from transformation was 15 months (4 months to 19.7 years). On univariate analysis, the following factors at the time of histological transformation were associated with an improved survival: low tIPI (P = 0.009), time to transformation > 4 years (P = 0.02), age < or = 60 years (P = 0.02) and stage I or II disease (P = 0.04). On multivariate analysis, factors that remained significant included a low tIPI (P = 0.0001) and a time to transformation > 4 years (P = 0.004). tIPI correlated with overall survival (OS); IPI 0-1, median OS 38 months; IPI 2-3, median OS 12 months; IPI 4-5, median OS 4 months. In conclusion, tIPI at the time of histological transformation is an important predictor of OS. A time to transformation > 4 years from diagnosis is associated with better OS.

Adult↗
PubMed2006

Natural history of thromboembolism in AL amyloidosis.

To determine the natural history of thromboembolism in patients with biopsy-proven AL amyloidosis, medical records of 2,132 patients evaluated at Mayo Clinic between 1975 and 2000 were reviewed. Forty patients (21 male) were found to have objectively documented thromboembolism. The median age was 65 years. Four patients had a monoclonal gammopathy of undetermined significance, 20 had an unspecified plasma cell proliferative disorder, 11 had multiple myeloma, and 1 had Waldenström macroglobulinemia. Twelve patients had cardiac amyloid, and 20 had renal amyloid. Neither the extent of the amyloid nor the type of monoclonal protein was predictive of the development of thromboembolic events. Thromboembolism preceded the diagnosis of AL amyloidosis in 11 patients, occurred at the time of diagnosis or within 1 month after diagnosis in 11 patients, and occurred 1 month or more after diagnosis in 18 patients. Twenty-nine patients (73%) had venous thrombosis and 11 (28%) had arterial thrombosis. Eight patients (20%) died within 1 month after the thrombotic event, and 18 (45%) died within 1 year. The development of thrombosis in patients with AL amyloidosis appears to predict significant mortality within the first month and year after the event.

Aged↗
PubMed2006

Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia.

We sought to define prognostic factors for survival in Waldenstrom macroglobulinaemia (WM). Of 585 patients diagnosed with WM and seen at Mayo Clinic between 1960 and 2001, 337 symptomatic patients met the inclusion criteria and were analysed for overall and disease-specific survival. The median survival from the time of diagnosis was 6.4 years. The median disease-specific survival was 11.2 years. Univariate analysis for overall survival identified the following adverse prognostic factors: age >65 years (P < 0.001), organomegaly (P < 0.001), elevated beta2-microglobulin (<0.001), anaemia (Hb < 10.0 g/dl) (P = 0.01), leucopenia (<4.0 x 10(9)/l) (P = 0.03), thrombocytopenia (<150 x 10(9)/l) (P = 0.01), serum albumin <40 g/l (P = 0.001), and quantitative IgM < 0.4 g/l (P = 0.04). On multivariate analysis, age >65 years and organomegaly were associated with poor prognosis. A prognostic model was built based on these two variables. Patients at high risk (1-2 risk factors, median survival 4.2 years) experienced worse survival than patients at low risk (0 risk factors, median survival 10.6 years), P < 0.001. The prognostic model was validated in 204 patients who were not included in the analysis cohort. Beta2-microglobulin > or =4 mg/l was associated with a threefold increase in the risk of death when added to the prognostic model. We describe a simple prognostic model for overall survival for newly diagnosed patients with WM.

Adult↗
PubMed2006

Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma.

Bisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is Increasingly recognized as a serious complication of long-term bisphosphonate therapy. Issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the Interest of patient safety and will be reexamined as new data emerge regarding risks and benefits.

Bone Density Conservation Agents↗
PubMed2006

Radioimmunotherapy for B-cell non-Hodgkin lymphoma.

Radioimmunotherapy is an established and effective treatment in B-cell non-Hodgkin lymphoma (NHL). Currently, two radioimmunoconjugates (RICs) are approved for clinical use in the United States, ibritumomab tiuxetan and tositumomab. Both agents target the CD20 antigen on B-cell lymphoma cells. Although there are differences between these two agents, such as different murine monoclonal antibodies, radioisotopes, and dosimetry techniques, they share similar toxicity and efficacy profiles. These anti-CD20 RICs are active in patients who are refractory to single-agent rituximab, documenting the added value of the conjugated radioisotope. This review focuses on the current use of these agents in the treatment of previously untreated indolent NHL and relapsed/refractory and transformed NHL.

Antibodies, Monoclonal↗
PubMed2005

Flow cytometric detection of circulating myeloma cells before transplantation in patients with multiple myeloma: a simple risk stratification system.

Detection of circulating myeloma cells (CMCs) by flow cytometry in patients with multiple myeloma (MM) indicates active disease. We hypothesized that detection of CMCs at the time of stem-cell collection prior to autologous stem-cell transplantation (ASCT) identifies patients at high risk of rapid progression. A cohort of patients undergoing ASCT was identified. CMCs were determined by gating on CD38+/CD45- cells using flow cytometry. The impact of CMCs on overall survival (OS) and time to progression (TTP) was evaluated in univariate and multivariate analyses. Of 246 patients undergoing ASCT, 95 had CMCs. Complete response (CR) rates after transplantation were 32% and 36% for patients with and without CMCs, respectively (P = .50). OSs were 33.2 and 58.6 months (P = .01) whereas TTPs were 14.1 and 22 months, respectively (P = .001). On multivariate analysis, CMCs remained independent of cytogenetics and disease status at time of transplantation (P = .03). CMCs and cytogenetics were combined in a new scoring system. Patients with neither, one, or both parameters had a median OS of 55, 48, and 21.5 months and a median TTP of 22, 15.4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management.

Adult↗
PubMed2005

B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia.

Waldenström macroglobulinemia (WM) is a serious and frequently fatal B-cell malignancy associated with an elevated monoclonal IgM protein in the serum. Many of the mechanisms leading to this disease are not yet known. B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells. It also regulates immunoglobulin secretion by normal B cells. To determine the relevance of BLyS in WM, we examined the role of BLyS in WM patient samples. Malignant B cells were found to bind soluble BLyS and variably express the receptors BAFF-R, TACI, and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. BLyS, alone or in combination with cytokines that induce immunoglobulin production, was found to increase IgM secretion by malignant B cells. Furthermore, BLyS was found to increase the viability and proliferation of malignant B cells from WM patients. Due to the role of BLyS in WM, strategies to inhibit BLyS may potentially have therapeutic efficacy in these patients.

B-Cell Activating Factor↗
PubMed2005

Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma.

PURPOSE: Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients. PATIENTS AND METHODS: One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology. RESULTS: BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS. CONCLUSION: BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age > or = 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.

Adolescent↗
PubMed2005

Current treatment approaches for mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell non-Hodgkin's lymphoma. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The cells are characterized as CD20+ CD5+ CD23- with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. Response to chemotherapy usually results in a tumor response but unmaintained remissions are short and the median survival is 3 to 4 years. The treatment approach to newly diagnosed patients with MCL depends on the patient's eligibility for stem cell transplantation (SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by SCT or rituximab-HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) followed by observation. The purine nucleoside analogues also have activity as single agents and with rituximab. Unfortunately none of these approaches can definitively cure patients with MCL, and new agents are needed. Recent studies in patients with relapsed MCL have shown substantial antitumor activity of single-agent bortezomib, single-agent temsirolimus, and the combination of thalidomide and rituximab. Studies integrating these novel agents earlier in the disease course or in combination with each other will hopefully produce more durable responses with less toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.

We report the results of a phase 2 trial using lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for myeloma. Thirty-four patients were enrolled. Lenalidomide was given orally 25 mg daily on days 1 to 21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1 to 4, 9 to 12, and 17 to 20 of each cycle. Objective response was defined as a decrease in serum monoclonal protein level by 50% or greater and a decrease in urine M protein level by at least 90% or to a level less than 200 mg/24 hours, confirmed by 2 consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete response (CR) and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an objective response, 2 had minor response (MR) and one had stable disease. Forty-seven percent of patients experienced grade III or higher nonhematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%), and rash (6%). Rev/Dex is a highly active regimen with manageable side effects in the treatment of newly diagnosed myeloma.

Adult↗
PubMed2005

Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma or another related plasma cell disorder (PCD) at a rate of approximately 1% per year. Identification of patients with MGUS at high risk of progression will allow development of preventive strategies. We studied the prognostic value of circulating plasma cells (PCs) in patients with MGUS to predict progression. PATIENTS AND METHODS: Patients were eligible for this retrospective analysis if they were seen at the Mayo Clinic between 1984 and 1997, were diagnosed with MGUS, and had an analysis of the peripheral blood for circulating PCs by the slide-based immunofluorescence method. Patients were observed for progression to another PCD. RESULTS: Three hundred twenty-five patients were eligible and 63 (19%) had circulating PCs. Patients with circulating PCs were twice as likely (hazard ratio, 2.1) to experience progression to another PCD (most commonly myeloma), compared with those without circulating PCs (95% CI, 1.1 to 4.3; P = .03). In patients with circulating PCs, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating PCs (P = .028). The median overall survival also was shorter for those with circulating PCs. Other factors with prognostic value were high levels of M protein and non-immunoglobulin G heavy-chain type. CONCLUSION: The presence of circulating PCs, especially when combined with other known prognostic factors such as M protein concentration and immunoglobulin isotype, identify a group of individuals with MGUS at higher risk of progression to overt multiple myeloma.

Adolescent↗
PubMed2005

Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma.

PURPOSE: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma. PATIENTS AND METHODS: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2. RESULTS: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months). CONCLUSION: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.

Adult↗
PubMed2005

Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma.

PURPOSE: Mantle 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 METHODS: Patients 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. RESULTS: Thirty-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. CONCLUSIONS: Single-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.

Adult↗
PubMed2005

Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma.

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 beta2-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.

Adult↗