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Biomedical subjects

T E Witzig

Publications and source records attributed to T E Witzig.

At least 55 records · Page 3Linked to original sources
PubMed1999

Immunophenotypic analysis of peripheral blood and bone marrow in the staging of B-cell malignant lymphoma.

This study evaluated the contributing roles of flow cytometric immunophenotyping of blood and bone marrow and immunohistochemical paraffin section staining of bone marrow biopsies in the staging of B-cell malignant lymphoma. Flow immunophenotyping was performed on a marrow specimen in 175 cases; a corresponding blood specimen was also immunophenotyped in 135 of these cases. Morphologic marrow involvement by lymphoma was found in 59 cases; flow immunophenotyping identified 54 cases with a monoclonal B-cell process: morphology-positive/flow-positive (n = 49), morphology-positive/flow-negative (n = 10), morphology-negative/flow-positive (n = 5), and morphology-negative/flow-negative (n = 111). The 10 morphology-positive/flow-negative cases included 5 follicular and 5 large-cell lymphomas with minimal marrow involvement. All 5 morphology-negative/flow-positive cases were from patients with large-cell lymphomas and bulky clinical disease. Because the blood contained the same B-cell clone in 2 of 2 morphology-negative/flow-positive cases studied, blood contamination of marrow may account for these findings. Blood flow cytometric immunophenotyping studies were positive in 32 cases; 30 had marrow involvement by morphology and were from patients with follicular, mantle cell, lymphoplasmacytic, small lymphocytic, or marginal zone lymphomas. From our results, we conclude that (1) bone marrow flow cytometric immunophenotyping is not a cost-effective replacement for good morphologic evaluation in lymphoma staging and that (2) a positive peripheral blood flow cytometric immunophenotyping study when performed in low-grade lymphomas correlates with marrow involvement.

Adult↗
PubMed1999

Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.

BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P =.02) and time to recurrence (P =.01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P =.02) and time to recurrence (P =.004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P =.006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P =.003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P =. 002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P =.002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.

Adult↗
PubMed1999

Prognostic relevance of monosomy at the 13q14 locus detected by fluorescence in situ hybridization in B-cell chronic lymphocytic leukemia.

Deletion of the chromosome band 13q14, which contains the putative deleted in B-cell malignancy (DBM) gene, and trisomy 12 have been demonstrated by fluorescence in situ hybridization (FISH) techniques in malignant B-cells from patients with B cell chronic lymphocytic leukemia (B-CLL). However, the prognostic relevance of 13q14 abnormalities as detected by FISH is unknown. We prospectively studied malignant blood cells from 54 consecutive, untreated B-CLL patients using FISH probes to the RB1 locus and DBM (markers D13S25 and D13S319) for band 13q14, as well as probes to chromosome 12. The cells from all cases were CD5+ CD20+, expressed clonally restricted surface immunoglobulin light chain, and had typical features for B-CLL on careful blood smear morphologic evaluation. Patients were followed for a mean of 3.9 years and treatment-free survival (TFS) was used in the prognostic factor analysis. Twenty-four (44%) patients were observed to have monosomy of the RB1 locus and 26 (48%) monosomy of D13S25 and D13S319. The 26 patients who had a deletion at at least one of these loci had a 48.4 month (mo) median TFS vs 31.1 mo for those without evidence of deletion at any 13q14 locus (p = 0.07). The seven patients found to have trisomy 12 had a median TFS of 6.9 mo vs 39.3 mo for those diploid for chromosome 12 (p < 0.01). When these seven patients with trisomy 12 were excluded from the analysis, patients who had a deletion at 13q14 tended to have a longer median TFS (50.1 vs 36.2 mos), but this was not statistically significant (p = 0.2). This study confirms the prevalence of 13q14 deletions in B-CLL and suggests that patients with this abnormality have a better TFS than those with trisomy 12.

Adult↗
PubMed1999

Osseous Hodgkin disease.

BACKGROUND: Hodgkin disease rarely presents as an osseous lesion, and the majority of patients are found at staging to have concurrent disease in lymph nodes. Many cases of osseous Hodgkin disease have been misdiagnosed on initial biopsy. METHODS: All cases of Hodgkin disease diagnosed by open bone biopsy at the Mayo Clinic were identified. These included patients with primary osseous tumors, those presenting with multiple sites of involvement (with osseous lesions), and those with recurrence in bone. Recut sections were subjected to immunohistochemical stains to confirm the diagnosis. Clinical data and follow-up information were obtained from patients' charts. RESULTS: Twenty-five patients (15 males and 10 females with an average age of 37 years) with osseous Hodgkin disease were identified during the years 1927-1996. Three patients had solitary, osseous tumors and two had primary, multifocal, osseous Hodgkin disease without involvement of nonosseous sites. Twelve patients who presented with lesions in osseous sites also had nonosseous tumors detected at staging, and 8 patients had recurrent Hodgkin disease that presented in bone. The majority of patients with primary and recurrent tumors presented only with bone pain; >50% of patients with concurrent osseous and nonosseous disease also had B-type symptoms. Nearly all lesions were in the axial and proximal appendicular skeleton. Radiographic features included osteosclerotic, osteolytic, and mixed lytic/sclerotic patterns. Cortical destruction, periosteal new bone formation, and soft tissue masses were present in 50% of cases. The histologic diagnosis of osseous Hodgkin disease occasionally was problematic; osteomyelitis was the most frequent misdiagnosis. Immunohistochemical stains revealed expression of CD15 and CD30 in neoplastic cells (which were negative for CD45 and B-cell and T-cell antigens) in all but two cases. Involved lymph nodes typically exhibited nodular sclerosis Hodgkin disease. Three patients with primary solitary osseous Hodgkin disease received radiation treatment only; at last follow-up 2 patients were alive at 22 months and 10 years, respectively. Patients with concurrent osseous and nonosseous tumors exhibited a 60% overall survival rate, but at last follow-up all 4 patients diagnosed after 1986 still were alive; those with Hodgkin disease that recurred as osseous lesions had a 60% survival rate at 8 years, but only 1 of the 5 patients diagnosed since 1984 had died of disease. CONCLUSIONS: Osseous Hodgkin disease typically presents with bone pain, and the majority of patients have concurrent nonosseous lesions detected at staging. Radiographic features of osseous Hodgkin disease vary but indicate an aggressive malignant process. The histologic diagnosis may be problematic; immunohistochemical stains aid in establishing the diagnosis of Hodgkin disease in bone. Survival of patients with osseous Hodgkin disease has been found to be good for the last 10 years.

Adult↗
PubMed1999

Long-term survival (10 years or more) in 30 patients with primary amyloidosis.

The median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 x 10(9)/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.

Adult↗
PubMed1999

Phase II trial of high-dose dexamethasone for previously treated immunoglobulin light-chain amyloidosis.

Immunoglobulin light-chain amyloidosis (AL) is a rare disorder characterized by production of a monoclonal light chain. This insoluble light chain, or a fragment thereof, deposits in tissues as amyloid and results in disruption of organ function and, ultimately, in death. Although melphalan and prednisone are beneficial in approximately 30% of patients with the disease, many patients fail to respond, and the median survival with this disease remains < 2 years. There is a need for new agents for those patients who fail to respond to melphalan-based chemotherapy. A study was undertaken of high-dose dexamethasone in the treatment of 19 patients with AL because of reports of its benefits in previously untreated patients with amyloidosis and its known activity in the management of multiple myeloma, which has many characteristics in common with AL. In this cohort, 3 of 19 patients showed an objective organ response of the disease. The median survival of the entire group was 11.2 months. We conclude that high-dose dexamethasone therapy is of occasional benefit in patients previously treated for amyloidosis. Combining dexamethasone with other therapies may increase the response rate.

Aged↗
PubMed1999

Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis.

Primary systemic amyloidosis is the disorder that results from the deposition of insoluble immunoglobulin light chain fragments. Patients seen within 30 days of diagnosis have a median survival of 13 months. Patients treated with melphalan and prednisone have a median survival of 17 months. There is a need for new therapies. A prospective study was undertaken of high-dose dexamethasone in the treatment of 25 patients with previously untreated primary systemic amyloidosis. Treatment was similar to that given to patients with multiple myeloma. In this cohort, three patients showed objective regression with organ-specific improvement of the disease. The median survival of the entire group was 13.8 months. High-dose dexamethasone is of occasional benefit in patients with amyloidosis but does not appear to be superior to melphalan and prednisone chemotherapy.

Adult↗
PubMed1999

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone.

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.

Adult↗
PubMed1999

The role of adhesion receptors in the pathogenesis of multiple myeloma.

There is now an improved understanding of the types of adhesion receptors present on normal and malignant plasma cells. This knowledge has been helpful in identifying plasma cells and in beginning to understand the pathogenesis of myeloma. Future research is needed to delineate the signaling pathways used by the plasma cell after the adhesion receptor binds to its ligands. This information should help in designing more effective therapy for this fatal disease.

Biomarkers↗
PubMed1999

Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma.

Transplantation after high-dose chemotherapy prolongs survival in patients with multiple myeloma compared with standard therapy. It is unclear whether the optimal timing of transplantation is immediately after induction chemotherapy or whether stem cells may be cryopreserved for transplantation at subsequent progression or relapse. In this study, stem cells were collected within 6 months of diagnosis, followed by transplantation only at progression of myeloma. One hundred and eighteen patients with multiple myeloma had stem cells collected and cryopreserved. Eleven had transplants early in the disease after they demonstrated failure to respond to primary therapy. The remaining 107 were eligible for transplants when there was evidence of progressive disease. Of the 118 patients, 67 had transplants, nine died of progressive disease before transplantation, and 42 remain alive in plateau phase. The median survival of the group is 58.5 months; 67 are alive. Serum beta2-microglobulin, bone marrow labeling index (S phase), and hemoglobin level predicted overall survival (P < 0.006, P < 0.001, and P < 0.01, respectively). We conclude that early cryopreservation of blood stem cells followed by transplantation at progression is a feasible approach to therapy in patients with myeloma. The underlying biology of the disease has a greater impact on survival than the timing of transplantation. A prospective randomized trial is required to answer definitively the question of the optimal timing of blood cell transplantation.

Adult↗
PubMed1999

Beta2-microglobulin and bone marrow plasma cell involvement predict complete responders among patients undergoing blood cell transplantation for myeloma.

We studied the prognostic value of clinical and laboratory variables, measured before blood cell transplantation, in predicting complete response among patients undergoing autologous blood cell transplantation for relapsed or primary refractory myeloma. Sixty-seven patients who underwent transplantation for relapsed or primary refractory myeloma were studied. The overall response rate was 90%, and the complete response rate was 33%. Low beta2-microglobulin (< or =2.7 mg/l) was associated with a significantly better complete response rate compared with high levels (54 vs 19%, P = 0.002). Similarly, the complete response rate was 39% when the bone marrow plasma cell percentage was low (<40%) and 21% with greater involvement (P = 0.04). Complete response rate was 50% when beta2-microglobulin and bone marrow plasma cell percentage were low, 36% if either was high, and 12% when both were high (P = 0.01). Median survival measured from initial diagnosis of myeloma was 51 months. Overall survival after transplantation was better among responders who achieved complete response than those who did not: median survival, 24 vs 11 months, P = 0.04 (log-rank) and 0.009 (Gehan-Wilcoxon). Attainment of a complete response independently predicted better survival in a multivariate analysis. beta2-Microglobulin and bone marrow plasma cell percentage predict complete responders among patients undergoing transplantation for myeloma.

Adult↗
PubMed1999

Autologous stem cell transplantation for relapsed and primary refractory myeloma.

The aim of this study was to evaluate the effectiveness of autologous stem cell transplantation for patients with relapsed or primary chemotherapy-refractory myeloma. Seventy-five patients, 50 men and 25 women, ages 33-68 years (median, 53 years), who underwent transplantation for relapsed or primary refractory myeloma were studied. Patients underwent transplantation 5-88 months (median, 23 months) after diagnosis of myeloma. The time to transplantation was significantly shorter in patients with refractory disease than for those with relapsed myeloma (median, 8 and 32 months, respectively; P < 0.001). Patients with primary refractory myeloma had a significantly lower plasma cell labeling index than those with relapsed disease (P = 0.008). There were no differences in overall and complete response rates between patients with primary refractory and relapsed disease. The median survival of the entire cohort from diagnosis was 53 months. Overall survival from transplantation among patients with relapsed myeloma receiving therapy, relapsed myeloma off therapy, and primary refractory myeloma was significantly different (P = 0.04), with median times of 12, 21 and 30 months, respectively. Progression-free survival also was different (P < 0.001), with median times of 7, 13, and 26 months, respectively. We conclude that overall and progression-free survival in patients with primary refractory myeloma appear better than in patients with relapsed disease and need further study.

Adult↗
PubMed1999

Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma.

Although most of the initial studies in angiogenesis were done on solid tumors, there is now data suggesting the importance of angiogenesis in hematologic malignancies. We estimated bone marrow microvessel density before autologous stem cell transplantation and at the time of response in 13 patients with myeloma (seven complete and six partial responders) using an immunohistochemical stain for factor VIII-related antigen (von Willebrand factor). Baseline microvessel density was significantly different between bone marrow samples from patients with myeloma and morphologically normal, staging marrows from patients with limited stage Hodgkin's disease, mean (+/- s.d.) 294 (+/-115)/mm2 vs 93 (+/-26/mm2, respectively, P = 0.001. After transplantation, microvessel density continued to be high in myeloma samples compared to samples from control patients with limited stage Hodgkin's disease, mean (+/- s.d.) 230 (+/-68)/mm2, P = 0.003. There was no difference in microvessel density at the time of complete or partial response compared to values prior to transplantation. This report confirms that increased angiogenesis is found in myeloma bone marrow prior to transplantation, and suggests that increased angiogenesis persists even after complete response.

Adult↗
PubMed1999

Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders.

The proliferative rate of malignant plasma cells, as measured by the plasma cell labelling index (PCLI), is an important prognostic factor in multiple myeloma (MM); however, the PCLI alone is probably Inadequate to describe tumour growth because it ignores the idea that myeloma cells may have a reduced rate of apoptosis. The aims of this study were to develop a flow cytometric method to measure the apoptosis index of fresh marrow plasma cells and develop a plasma cell growth index (PCGI) that related both proliferation and apoptosis to disease activity. Marrow aspirates were obtained from 91 patients with plasma cell disorders and the plasma cells in apoptosis were identified by either 7-amino actinomycin-D (7-AAD) or annexin V-FITC three-colour flow cytometry. The median plasma cell apoptotic index (PCAI) for patients with monoclonal gammopathy of undetermined significance (MGUS), smouldering or indolent myeloma (SMM/IMM), and new multiple myeloma (MM) was 5.2, 3.4 and 2.4, respectively (P=0.03, MGUS v MM). The median PCLI for these same patient groups was 0.0, 0.2 and 0.6, respectively (P<0.001, MGUS v MM). The paired PCLI and PCAI for each sample were used to derive the PCGI=2 + [PCLI-(O.1)(PCAI)]. The median PCGI for patients with inactive disease (MGUS, SMM/IMM or amyloidosis) was 1.8 compared to 2.4 for those with active disease (new or relapsed MM) (P<0.001). These results suggest that a decrease in the PCAI may be a factor in the progression from MGUS to SMM to overt MM.

Apoptosis↗
PubMed1999

Clinical significance of the translocation (11;14)(q13;q32) in multiple myeloma.

The most common chromosomal translocation in multiple myeloma (MM) is t(11;14)(q13;q32). Here, we describe the clinical characteristics of patients with MM who have this translocation. We have identified 24 patients at our institution who had t(11;14)(q13;q32) as determined by standard cytogenetic analysis (CC). Seven patients had the translocation detected at the time of original diagnosis and 17 at the time of relapse. Median survival in all patients after original diagnosis was 43 months; median survival after the translocation was detected was 11.9 months. Four patients had a clinical diagnosis of plasma cell leukemia. Most patients had an elevated beta2-microglobulin (13/20 had >4 microg/ml). The bone marrow (BM) labeling index (LI) of patients, at the time of translocation detection, was elevated in most (median 1.4%, 17/23 patients had BMLI > or = 1%). Of the 24 patients, 19 (79%) died of disease progression and 5 (21%) were alive with disease at last follow-up. Lytic lesions, bone pain, or compression fractures eventually developed in all patients. Patients with MM who have t(11;14)(q13;q32) detected by standard cytogenetics seem to have an aggressive clinical course.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously untreated B-cell chronic lymphocytic leukemia.

The objective was to determine the safety and efficacy of adding a maximally tolerated dose of 2-chlorodeoxyadenosine (2-CdA) to standard chlorambucil (CLB) therapy in previously untreated B-cell chronic lymphocytic leukemia (CLL). Thirty patients with CLL (median age, 64 years) received two courses of 2-CdA given intravenously (2 mg/m2 daily for 7 days) added to biweekly administration of CLB at 30 mg/m2 given orally. The diagnosis of CLL, treatment indications, and response criteria were according to the National Cancer Institute established guidelines. Sixteen patients (53%) had advanced-stage disease, and four (13%) had trisomy 12 abnormality. The overall remission rate was 80%, including 20% complete remission (CR), 30% nodular partial remission (nPR), and 30% partial remission (PR). Minimal residual disease was detected phenotypically in two of five patients with CR and in eight of nine with nPR. Overall, CR, nPR, and PR rates were not influenced significantly by the presence of cytogenetic abnormalities or advanced clinical stage. With a median follow-up of 33 months, 58% of patients who had a response had relapse. Median time to progression in all 30 patients was 30 months, and time to progression and progression-free survival were not significantly different for the different response groups, clinical stages, or cytogenetic groups. Severe neutropenia and thrombocytopenia occurred in 33% and 7% of patients, respectively. Only two patients had documented bacterial infections, and four had herpetic infections. Concurrent combination chemotherapy with abbreviated doses of 2-CdA and standard-dose CLB is feasible and safe in previously untreated CLL. Antitumor activity may be superior to that of CLB alone given in conventional doses. Whether a different schedule of combining these two agents would result in improved outcome is being investigated.

Antineoplastic Combined Chemotherapy Protocols↗