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Biomedical subjects

Thomas E Witzig

Publications and source records attributed to Thomas E Witzig.

At least 55 records · Page 3Linked to original sources
PubMed2005

Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group.

PURPOSE: Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). PATIENTS AND METHODS: Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided. RESULTS: Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. CONCLUSION: Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Adult↗
PubMed2005

Proteomic analysis of mantle-cell lymphoma by protein microarray.

Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19(+) purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.

Aged↗
PubMed2005

PS-341-mediated selective targeting of multiple myeloma cells by synergistic increase in ionizing radiation-induced apoptosis.

OBJECTIVE: Multiple myeloma remains incurable with current therapy. The proteosome inhibitor, PS-341, has shown objective clinical responses in relapsed refractory myeloma patients. We investigated the potential of enhancing the radiosensitivity of myeloma cells by combining with PS-341; the underlying mechanisms were delineated. MATERIALS AND METHODS: Clonogenic assays were used to evaluate cell survival after exposure to PS-341, ionizing radiation (IR), or PS-341 followed by IR. Apoptosis was studied by annexin V-propidium iodide staining and caspase activation. Cell-cycle phase distribution of cells was determined. Nuclear factor-kappaB (NF-kappaB) activity was monitored by enzyme-linked immunosorbent assay and Western blotting. The expression of death receptor Fas/APO-1/CD95 was analyzed by flow cytometry. The consequential caspase-8 activation was detected by Western blotting. RESULTS: In clonogenic assays, sequential exposure to nontoxic doses of PS-341 (10 nM) and IR (6 Gy) resulted in synergistic inhibition of proliferation of myeloma cells by modulating the apoptotic sensitivity of these cells. Biochemically, sublethal dose of IR led to potent induction of NF-kappaB activity, and this response was significantly inhibited by pretreatment with PS-341, or by the NF-kappaB inhibitory peptide SN-50. Enhanced Fas expression was seen in myeloma cells exposed sequentially to PS-341 and IR. Finally, PS-341 sensitized primary myeloma (CD138+ve) cells to IR but had little effect on CD138-ve bone marrow cells from myeloma patients. CONCLUSION: These data indicate that PS-341 can sensitize myeloma cells to IR by both intrinsic and extrinsic apoptotic pathways. The study indicates improved therapeutic benefits in treatment of multiple myeloma by combining PS-341 with conventional radiotherapy.

Antineoplastic Agents↗
PubMed2005

Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-Cell non-Hodgkin's lymphoma.

AIM: Yttrium-90 ((90)Y) ibritumomab tiuxetan (Zevalin) radioimmunotherapy is an effective treatment for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL), with overall response rates ranging from 74% to 82%. This retrospective analysis was conducted to determine the number of patients achieving long-term durable responses with (90)Y ibritumomab tiuxetan treatment. MATERIALS AND METHODS: The medical records of patients (n = 211) with relapsed, refractory, or transformed indolent CD20+ B-cell NHL who were treated with 90Y ibritumomab tiuxetan were reviewed. Time to progression (TTP) of > or =12 months was noted in 78 patients (37%), who were identified as long-term responders and were further characterized. RESULTS: Median age of the long-term responders was 58 years (range, 24-80 years) with 44% over 60 years, and 55% were male. Notably, 59% of patients had received > or =2 prior regimens, 33% had received > or =3 prior regimens, and 37% had failed to respond to immediate prior therapy. Median response duration was 28.1 months (range, 10.5-80.3+ months). Median TTP was 29.3 months (range, 12.1-81.5+ months). In patients with ongoing response, median TTP was 53.9 months (range, 49-82+ months). CONCLUSIONS: (90)Y ibritumomab tiuxetan produces durable long-term responses in patients with relapsed/refractory B-cell NHL. Failure to respond to prior therapy does not preclude achieving a long-term response with 90Y ibritumomab tiuxetan.

Adult↗
PubMed2005

Combination therapy with thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma not undergoing upfront autologous stem cell transplantation: a phase II trial.

BACKGROUND AND OBJECTIVES: Thalidomide plus dexamethasone (Thal/Dex) has emerged as an effective alternative to vincristine, doxorubicin and dexamethasone as a pre-transplant induction therapy for newly diagnosed multiple myeloma. However, many patients treated initially with Thal/Dex do not proceed to autologous stem cell transplantation (ASCT) and the time to progression and other outcome measures with Thal/Dex as primary therapy for multiple myeloma are not known. We present the first data on the outcome of patients with newly diagnosed multiple myeloma treated with Thal/Dex who did not undergo upfront ASCT. DESIGN AND METHODS: We identified 21 patients with newly diagnosed multiple myeloma treated with Thal/Dex on a phase II clinical trial who did not undergo ASCT due to age, comorbidity or the patient's refusal. Patients received thalidomide at a dose of 200 mg/day orally and dexamethasone 40 mg daily on days 1-4, 9-12, 17-20 (odd months) and days 1-4 (even months). Cycles were repeated every 28 days. RESULTS: The median age was 66 years (range 36-78). The median duration of follow-up was 21 months (range 1-52). One (5%) patient achieved a complete response, and 9 (43%) had a partial response, so the overall response rate was 48%. Of the remaining patients, 7 (33.3%) had stable disease, one patient did not respond, and three died while on therapy prior to response assessment. The median overall survival and time to progression were 21 months and 18 months, respectively. INTERPRETATION AND CONCLUSIONS: The median time to disease progression in patients with multiple myeloma who receive initial therapy with Thal/Dex and who do not undergo ASCT is 18 months.

Adult↗
PubMed2004

Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.

PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006). CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.

Adult↗
PubMed2004

Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis.

PURPOSE: Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL. PATIENTS AND METHODS: Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 microg/L, and cTnI < 0.1 microg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively. RESULTS: Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively. CONCLUSION: Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.

Adult↗
PubMed2004

Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome.

BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.

Adult↗
PubMed2004

Thalidomid: current role in the treatment of non-plasma cell malignancies.

Thalidomide, initially introduced as a sedative, was withdrawn from the market in the early 1960s after it was found to be a teratogen. However, it later found use as an investigational agent in the treatment of erythema nodosum leprosum, oral ulcers, graft versus host disease, and wasting associated with the human immunodeficiency syndrome. Its antiangiogenic properties were recognized in the early 1990s during a period where the importance of angiogenesis became increasingly apparent as a critical step in the in the proliferation and spread of malignant neoplasms. This led to the evaluation of thalidomide as an antiangiogenic agent in the treatment of several cancers. Thalidomide has already become part of standard therapy for the treatment of patients with relapsed and refractory multiple myeloma. It has also been found to have varying degree of benefit in various other malignancies. Although more clinical trials are needed, Kaposi' s sarcoma and myelofibrosis represent other malignancies in which thalidomide has already demonstrated promising activity. The mechanism of action of thalidomide in cancer is still unclear, but do appear to be mediated by several other mechanisms in addition to its anti-angiogenic properties. This article reviews the current status of thalidomide for the treatment of non-plasma-cell malignancies.

Angiogenesis Inhibitors↗
PubMed2004

High-dose intravenous methotrexate followed by autologous stem cell transplantation as a potentially effective therapy for neurolymphomatosis.

BACKGROUND: Neurolymphomatosis (NL) is a rare neurologic manifestation of systemic lymphoma characterized by lymphomatous infiltration of the peripheral nervous system. The diagnosis of NL is difficult and requires a multidisciplinary approach for obtaining an adequate biopsy specimen of the suspected nerve. The prognosis of patients with NL has been poor because adequate penetration of chemotherapy into the nervous system is difficult. METHODS: The authors presented the case of a 37-year-old man who was treated for Ann Arbor Stage IVB diffuse large B-cell lymphoma. The patient developed disease recurrence in the sciatic nerve without systemic involvement. RESULTS: The patient achieved a clinical response after receipt of high-dose intravenous methotrexate followed by high-dose chemotherapy and autologous stem cell transplant. CONCLUSIONS: The authors reported this case to highlight the effectiveness of this regimen in a rare and fatal disorder. In the current study they also reviewed the literature regarding the diagnosis, prognosis, and treatment of NL.

Adult↗
PubMed2004

Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression.

We compared the angiogenic potential of bone marrow plasma and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and their receptors on plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (NMM). Cytokine and cytokine-receptor expression was studied by bone marrow immunohistochemistry, quantitative reverse transcription-polymerase chain reaction (RT-PCR) on sorted plasma cells, and quantitative Western blot analysis. Bone marrow angiogenic potential was studied using a human in vitro angiogenesis assay. The expression levels of VEGF, bFGF, and their receptors were similar among MGUS, SMM, and NMM. Sixty-one percent of NMM samples stimulated angiogenesis in the in vitro angiogenesis assay compared with SMM (0%) and MGUS (7%) (P <.001). Importantly, 63% of MGUS samples inhibited angiogenesis compared with SMM (43%) and NMM (4%) (P <.001). The inhibitory activity was heat stable, not overcome by the addition of VEGF, and corresponded to a molecular weight below 10 kd by size-exclusion chromatography. Our results suggest that increasing angiogenesis from MGUS to NMM is, at least in part, explained by increasing tumor burden rather than increased expression of VEGF/bFGF by individual plasma cells. The active inhibition of angiogenesis in MGUS is lost with progression, and the angiogenic switch from MGUS to NMM may involve a loss of inhibitory activity.

Bone Marrow↗
PubMed2004

Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study.

PURPOSE: Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. PATIENTS AND METHODS: Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). RESULTS: Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P <.05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P <.01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. CONCLUSION: This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

Adult↗
PubMed2004

Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.

Primary systemic amyloidosis (AL) is a fatal plasma cell disorder. Pilot data suggest survival is better in patients undergoing peripheral blood stem cell transplantation (PBSCT), but the selection process makes the apparent benefit suspect. We have reported that circulating cardiac biomarkers are the best predictors of survival outside of the transplantation setting. We now test whether cardiac troponins (cTnT and cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are prognostic in transplant recipients. In 98 patients with AL undergoing PBSCT, serum cardiac biomarkers were measured (cTnT, 98 patients; cTnI, 65 patients; and NT-proBNP, 63 patients). Elevated levels of cTnT, cTnI, and NT-proBNP were present in 14%, 43%, and 48% of patients, respectively. At 20 months median follow-up, median survival has not been reached for patients with values below the thresholds; in patients with values above the thresholds, median survival is 26.1 months, 66.1 months, and 66.1 months, respectively. Our previously reported risk systems incorporating these markers were also prognostic, notably the cTnT/NT-proBNP staging. Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT.

Adult↗
PubMed2004

Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study.

Primary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 micromol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.

Adult↗
PubMed2004

Cell proliferation of myeloma plasma cells: comparison of the blood and marrow compartments.

The plasma cell labeling Index (PCLI), a measure of marrow plasma cells in S phase of the cell cycle, provides a good estimate of the proliferative capacity of the malignant clonal plasma cells. Multiple studies have also demonstrated its prognostic value in multiple myeloma (MM). Clonal plasma cells have been demonstrated in the peripheral blood of patients with multiple myeloma. The labeling index of these circulating cells can also be determined by a method similar to that employed for marrow plasma cells. The goal of this study was to compare the proliferation kinetics of plasma cells in the marrow to that in the circulation. The PCLI was estimated on peripheral blood (PBLI) and bone marrow aspirates (BMLI) using a slide-based bromodeoxyuridine (BrdU) immunofluorescence microscopy technique. One hundred seventeen patients who had simultaneous estimation of the PBLI and BMLI and who had > or =90% of the blood cIg+ cells identified as monoclonal plasma cells were studied. The PBLI was generally lower than the BMLI (median difference 0.4) and correlated with the BMLI (rho = 0.491, P < 0.0001). Twenty-seven patients with PBLI higher than BMLI had a poorer prognosis, with median survival of 2 months from the time of the labeling index determination, compared to 12 months for the remaining 90 patients (P = 0.01). Myeloma plasma cells circulating in the peripheral blood are capable of proliferation, albeit at a slower rate compared to those in the marrow. These differences reflect a more favorable microenvironment in the marrow likely resulting from the differences in the cytokine levels and supporting stromal cells in the marrow.

Adult↗
PubMed2004

Initial increase in the cryoglobulin level after rituximab therapy for type II cryoglobulinemia secondary to Waldenström macroglobulinemia does not indicate failure of response.

Type II (mixed) cryoglobulinemia is a systemic vasculitis that may affect many organs, including the skin, leading to ulcerations secondary to immune complex deposition. We report a patient who presented with a large necrotic ulcerative lesion on the right ankle secondary to type II cryoglobulinemic vasculitis due to Waldenström macroglobulinemia that was resistant to multiple modalities of therapy. Amputation to prevent further necrosis and infections was almost performed. Treatment with rituximab was initiated and the patient had a dramatic response. This case report highlights the effectiveness and prompt response to rituximab when used in patients with small vessel vasculitis and skin ulceration. We describe a rise in the cryoglobulin level that may occur initially after rituximab therapy.

Aged↗