Interim analysis of the use of the anti-idiotype breast cancer vaccine 11D10 (TriAb) in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer.

The anti-idiotype monoclonal antibody breast cancer vaccine 11D10 (TriAb) was administered before and after autologous stem cell transplantation (ASCT) in 45 patients with metastatic breast cancer whose disease was responsive to conventional chemotherapy. Evidence of a positive anti-anti-idiotype antibody (Ab3) humoral response was noted at a median of 1.76 months post-ASCT (range, before ASCT-6 months) with this strategy. Maximal Ab3 levels and idiotype-specific T-cell proliferative responses were observed at a median of 3 and 4 months, respectively, after ASCT. The achievement of rapid immune responses after ASCT, during a known period of decreased immunoresponsiveness, opens the possibility of an additional antitumor effect at a time when the tumor burden is relatively small. Moreover, in this interim analysis, patients with the most vigorous humoral and cellular immune responses had a significant improvement in progression-free survival. Further follow-up and evaluation of this approach is warranted.

Use of the anti-idiotype antibody vaccine TriAb after autologous stem cell transplantation in patients with metastatic breast cancer.

Between April 1997 and March 1998 we evaluated the immune response and outcome in 11 chemosensitive patients who were treated with the anti-idiotype antibody vaccine TriAb after recovery from intensive therapy and autologous stem cell transplant (ASCT). Triab was commenced after recovery from the acute effects of ASCT; a minimum interval of 1 month was required from completion of consolidation radiotherapy, if given. Nine patients (82%) manifest anti-anti-idiotype antibody (Ab3) responses post ASCT. The maximal Ab3 response was seen after a median of 10 doses (range 5-20), which corresponded to a median of 14 months (range 5-19) post ASCT. Evidence of a T cell proliferative response was seen in eight patients; the response was modest in most of these. At a median follow-up of 24 months (range 22-33) after ASCT, four patients are alive without evidence of disease progression. All four of these patients were in the subgroup with more vigorous immune responses. Subsequent efforts have been directed toward the achievement of higher levels of immune responses more rapidly post ASCT. Bone Marrow Transplantation (2000) 26, 729-735.

Blood tacrolimus concentrations in bone marrow transplant patients undergoing plasmapheresis.

Microangiopathic hemolytic anemia (MAHA) is a well-described complication of stem cell transplantation. Plasmapheresis is one modality utilized as therapy for patients who develop this complication. However, plasmapheresis may alter whole blood levels of certain medications and its effect on tacrolimus in bone marrow transplant patients is unknown. Because tacrolimus has a narrow therapeutic range, the effect of plasmapheresis on whole blood concentrations would be important to know. We report three allogeneic BMT patients who were receiving tacrolimus as acute GVHD therapy while undergoing plasmapheresis for MAHA. Tacrolimus levels seemed unaffected by plasmapheresis in these patients.

G-CSF Primed Autologous Marrow Harvest and Transplantation in Cytapheresis "Mobilization Failure" Patients: A Descriptive Analysis; Bone Marrow Transplantation.

Fifteen cancer patients, deemed blood HSC "mobilization failures" due to CD34 + cell yields of < 0.5 x 10(6) /kg from two consecutive daily cytaphereses, underwent G-CSF primed autologous bone marrow harvest in an attempt to obtain adequate hematopoietic support for subsequent autotransplantation. CD34 + cell yields from the primed marrow harvest were variable; however, some patients had > 5-fold increases in CD34 + cell yields in the marrow compared to cytapheresis, and 4 patients had CD34 + cell yields of > 1.0 (i.e., 1.2, 1.44, 1.61 and 2.45) x 10(6) /kg from the primed marrow harvest. None of the five patients previously exposed to stem cell toxins or fludarabine achieved > 0.85 x 10(6) /kg CD34 + cells with the primed marrow harvest. A significant difference was noted between G-CSF primed blood and marrow for CD34 + cells but not for GM-CFU ( p = 0.011 and p = 0.135, respectively, paired t-test). All evaluable patients engrafted; a median ANC > 0.5 x 10(9) /L recovery was achieved on D + 12 (range + 9 to + 17) in 12 of 13 evaluable patients - one died on D + 9 without recovery. The last day of platelet transfusion occurred at a median D + 13 (range + 8 to > + 66); only one patient remained platelet transfusion-dependent beyond D + 34. As anticipated, patients with higher numbers of CD34 + cells transplanted had somewhat more rapid recoveries. Although stem cell damage is obviously a key factor in mobilization failure patients, these findings raise the possibility that poor mobilization, at least in some patients, results from a mechanism other than, or in addition to, simple stem cell damage. Moreover, they raise the issue of the minimum number of marrow CD34 + - or more arguably other - cells needed for adequate short- and long-term reconstitution. The role of G-CSF in this situation, especially regarding dose and/or schedule, is intriguing but remains to be clarified. G-CSF primed marrow harvest is a potential option in certain poor mobilizers but, as fully expected, is frequently inadequate. Whether such is preferable to "steady-state" marrow harvest, continued or repeated G-CSF primed cytapheresis (with or without chemotherapy), or primed marrow with G-CSF in other schedules - or with other cytokines - is unclear and will be the subject of further study.

Adenovirus infections in hematopoietic stem cell transplant recipients.

We report a 12% incidence of adenovirus infections among 532 recipients of hematopoietic stem cell transplant (HSCT) from January 1986 through March 1997. The median time from day of stem cell infusion to first positive culture was 41 days. Recipients of allogeneic stem cells, as opposed to autologous stem cell recipients, were more likely to have a culture positive for adenovirus (16% vs. 3%; P<.0001). Pediatric patients were also more likely than adults to have a positive culture (23% vs. 9%; P<.0001). Among stem cell recipients with partially matched related donors, pediatric recipients appear to be at significantly greater risk for infection than adult recipients (P<.001). Positive cultures were associated with evidence of invasion in 64% of cases (41 of 64). A multiple logistic regression analysis showed that isolating adenovirus from more than 1 site correlated with greater risk for invasive infections (P=.002). Invasive infections were associated with poorer chance of survival.

Expression of p53, bcl-2, E-cadherin, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis.

The objectives of this study were to: (a) characterize the immunohistochemical expression of p53, bcl-2, E-cadherin (EC), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in brain metastases; (b) compare immunohistochemical (IHC) expression of brain metastases with their primary tumors; and (c) assess the prognostic value of expression of these markers. Tumors from 35 patients with brain metastasis were studied for IHC expression of p53, bcl-2, EC, MMP-9, and TIMP-1. In 17 cases, primary tumors were also available for study. In brain metastases, p53 was positive in 91% of cases and intermediate in 9%, MMP-9 was positive in all cases, TIMP-1 was intermediate in 6% and negative in 94% of cases, EC expression was positive in 86% of cases and intermediate in 14%, and bcl-2 was variable. All primary tumors were positive for p53 and MMP-9, 3% were intermediate for TIMP-1 and 97% were negative, 65% were positive for EC and 35% were intermediate, whereas bcl-2 expression was variable. Neither p53, bcl-2, TIMP-1, or EC staining correlated with overall survival or survival with brain metastases. No assessment of survival differences could be made for MMP-9 because of its overexpression in all tissues. This study found that MMP-9 and p53 were markedly overexpressed in primary tumors and matched brain metastasis, TIMP-1 expression was negative in the majority of specimens, whereas EC expression was maintained in both primary tumors and brain metastases and bcl-2 expression was variable. This study suggests that the functional balance of MMP-9 and TIMP-1 is shifted toward extracellular matrix degradation in brain metastases and that deregulation of cell cycle control by p53 also exists in brain metastases. The high expression of EC may indicate the importance of adherence at late stages of metastasis but requires further study.

Granulocyte-colony stimulating factor (G-CSF)-primed, delayed marrow harvests as a source of hematopoietic stem and progenitor cells for allogeneic transplantation.

We evaluated the ability of G-CSF to increase the number of hematopoietic stem cells obtained by "delayed" BM harvest for allogeneic transplantation. Five normal donors received G-CSF @ 10 mcg/kg/day x 5 followed by repeat PB and BM assays at day 6 and 16, and BM harvest at day 16. Stem cells were not increased in the BM at day 16. Five patients underwent BMT and engrafted at +10 to +19 days. While the tested strategy offers no intrinsic advantages, its potential cannot be evaluated fully without alternative timing and/or additional, "early acting" growth factors.

Spinal cord compression due to extramedullary hematopoiesis in beta-thalassemia intermedia.

BACKGROUND: Extramedullary hematopoiesis (EMH) occurs in many disorders, including thalassemias and other hemoglobinopathies, and commonly presents in the spleen and liver. We present a case of spinal cord compression in a patient with beta-thalassemia intermedia, and review the literature and available treatment options. PATIENT AND METHODS: A 35-year-old black female with beta-thalassemia intermedia presented with a 3-week history of back pain and lower extremity weakness. Neurologic examination was consistent with spinal cord compression, and gadolinium enhanced magnetic resonance imaging (MRI) confirmed this diagnosis. She was given intravenous steroids and radiotherapy was begun in 200 cGy fractions to a total dose of 2000 cGy. RESULTS: At the completion of radiotherapy the patient was ambulatory with mild residual weakness. MRI scans 16 months later showed smaller, but persistent masses, and she remains asymptomatic 5 years from her diagnosis. CONCLUSION: Recognition of spinal cord EMH requires prompt physical examination and MRI for accurate diagnosis. EMH can be managed with radiation, surgery, transfusions, or a combination of these therapies. Radiation in conservative doses of (750-3500 cGy) is non-invasive, avoids the surgical risks of potentially severe hemorrhage and incomplete resection, and has a high complete remission rate in the majority of patients. Relapse rates are moderate (37.5%), but retreatment provides excellent chance for second remission.

Thyroid lymphoma: is there a role for surgery?

The role of surgery in the treatment of Stage I and II non-Hodgkin's thyroid lymphoma (NHTL) is not well defined. At our institution, we have treated seven patients (six women and one man) with NHTL during the past 6 years. Three patients (43%) had a prior history of thyroid disease, usually lymphocytic thyroiditis. Clinical symptoms included a rapidly enlarging neck mass (86%), dysphagia (71%), dyspnea (71%), and hoarseness (71%). Five patients (71%) had hypothyroidism; one patient, hyperthyroidism; and one patient, normal thyroid function. Five patients underwent fine-needle aspiration (FNA) at our institution. In three instances, FNA results were indicative of NHTL; the remaining FNA tests yielded no diagnosis. Surgical procedures were varied: incisional biopsy (n = 4), limited tumor debulking with tracheostomy (n = 2), and thyroidectomy (n = 1). Each of the seven patients was found to have large cell lymphoma. Treatment consisted of combination chemotherapy with consolidative irradiation. All tumors dramatically decreased in size soon after the initiation of therapy. One patient refused radiotherapy. All patients except one are still alive (median follow-up, 24 months). In conclusion, 1) a diagnosis of NHTL, although rare, should be considered when patients have rapidly growing goiters; 2) FNA is a useful first step in diagnosing NHTL; 3) NHTL is exquisitely sensitive to both chemotherapy and radiation; 4) surgical intervention is generally confined to incisional biopsy with occasional limited pretracheal tumor debulking; and 5) when a biopsy is obtained from a patient suspected of having NHTL, immediate processing by the pathologist is recommended so that material can be obtained for special studies as needed.

The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I.

Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.

Hereditary cancer risk notification and testing: how interested is the general population?

PURPOSE: Great interest in predictive testing for hereditary cancer syndromes has been reported. Prior research has focused on testing for specific hereditary syndromes and/or among individuals at high risk for positive carrier status. Given anticipated expansion of both the range of hereditary syndromes for which testing will be available, as well as the clinical settings in which testing will occur, assessment of interest in hereditary cancer risk testing and notification in the general public is warranted. METHODS: As part of an annual statewide telephone survey, adults' (N = 654) interest in hereditary cancer risk testing and notification was assessed. RESULTS: Interest in both risk testing (82%) and risk notification (87%) was high. Logistic regression analyses indicated that disinterest in risk notification was associated with female sex, performance of fewer health protective behaviors, and better perceptions of personal health. Disinterest in risk testing was associated with these same variables as well as older age, less concern over developing cancer, and a more extensive history of cancer in first degree relatives. CONCLUSION: In the absence of risk-reducing behaviors with demonstrable efficacy, hereditary risk testing programs may have difficulty attracting the interest of those at greatest risk for carrier status. In contrast, many individuals at low risk for positive carrier status might seek testing, perhaps as a means of seeking reassurance regarding their low hereditary risk.

Treatment of leukemia with partially matched related bone marrow transplantation.

The results of partially matched related donor (PMRD) marrow transplantation for 82 patients with leukemia are reported, including 45 who received two antigen disparate grafts. Following intensive radiochemotherapy, patients received grafts which were partially depleted of T cells by the monoclonal antibody T10B9 and complement. Actuarial probability of engraftment was 86% (95% CI = 78-93%). The median day to engraftment was similar among recipients of grafts disparate at one, two or three antigen loci. The incidence of severe (grades III and IV) acute graft-versus-host disease and extensive chronic graft-versus-host disease was 13% and 6%, respectively. The probability of disease-free survival for the entire cohort of patients is 31% at 3 years. Age < or = 30 years, early or intermediate stage disease and a graft disparate at one or two loci predicted longer disease-free survival in multivariant analysis. Moreover, 47% of patients receiving PMRD grafts disparate at two loci who had both these favorable pretransplant characteristics were alive and free of disease 3 years after transplantation. We believe that the utilization of PMRDs, especially those with two antigen disparate grafts, can extend allogeneic transplantation to additional leukemic patients lacking a histocompatible donor, with acceptable results.

Interest in learning of personal genetic risk for cancer: a general population survey.

BACKGROUND: Previous studies have reported high interest in genetic testing for risk for colon or breast-ovarian cancer. These studies, however, have used samples which might be atypical with regard to level of interest evident among the general U.S. population. METHODS: As part of an annual statewide telephone health survey, adults' (n = 649) interest in learning about their personal genetic predisposition for cancer was assessed. RESULTS: High levels of interest in learning about a personal genetic predisposition for cancer in general (87%) and breast cancer in particular (93%) were expressed. Logistic regression analysis indicated that lack of interest was associated with less education, minority status, and less performance of other health-protective behaviors. Only 53% of respondents reported their understanding of genetics was "good" or "excellent." CONCLUSION: While interest in learning of one's personal genetic predisposition for cancer was high, many individuals requesting testing may have a less than good understanding of genetics and the implications of test results. Furthermore, variables associated with lack of interest in learning about personal genetic risk for cancer in this study were similar to those which have been previously found to be associated with poor utilization of other cancer control activities such as breast or cervical cancer screening.

Allogeneic bone marrow transplantation with T cell-depleted partially matched related donors for advanced acute lymphoblastic leukemia in children and adults: a comparative matched cohort study.

Allogeneic BMT provides the best treatment currently available for long-term disease-free survival in patients with recurrent ALL. Historically, partially matched related donors provided the opportunity for treatment to a greater number of patients than matched related donors at the expense of decreased overall survival. In this study we compare the results in recurrent ALL patients transplanted with either HLA identical sibling bone marrow or partially matched related bone marrow. Thirty-two patients with relapsed ALL received partially matched bone marrows from a relative with one to three HLA, A, B and Dr antigen mismatches. Bone marrow was partially T cell-depleted with murine T10B9.1A-31 moAb. Sixteen patients with relapsed ALL received HLA-matched sibling bone marrows. All partially matched patients received additional GVHD prophylaxis with methylprednisolone in addition to anti-CD5 immunotoxin and/or CYA. All matched patients in addition to methylprednisolone received MTX and/or CYA. We observed no difference in disease-free survival between patients transplanted with partially matched bone marrow (median follow-up 1252 days, range 778-2035 days) vs those transplanted with HLA-matched bone marrow (median follow-up 1472 days, range 1165-2800 days; P = 0.48). Median survival for all patients is 38% (95% CI 24-52%) at 6 years. Patients transplanted in remission had a significant increase in disease-free survival when compared to those in relapse (P = 0.007). Our data suggest that partially matched BMTs from related donors are a comparable alternative to fully matched transplants in patients with ALL.

Characterization of human T-cell responses to Yersinia enterocolitica superantigen.

We reported that antigenic preparations from Yersinia enterocolitica stimulate murine T cells in a manner consistent with that of superantigens. As a consequence we examined whether Y. enterocolitica antigenic preparations stimulate human T-cell cultures. Human T cells, enriched from peripheral blood lymphocytes, were stimulated to proliferate in the presence of Y. enterocolitica cytoplasmic and membrane preparations. This activity has also been shown to be sensitive to protease treatment, indicating the presence of a protein, and when separated by ion-exchange chromatography a single peak of activity is resolved. Furthermore, this proliferation was inhibited, in a dose-dependent manner, by the presence of antibodies directed against MHC class II antigens, indicating a requirement for these molecules. When these cells were stained with a panel of V beta-specific antibodies to determine if there was an enrichment of a particular V beta-bearing T-cell subset after stimulation, results indicate a significant enrichment of T cells bearing V beta 3, V beta 12, V beta 14, and V beta 17 over controls. Taken together, these data are consistent with a Y. enterocolitica product acting as a superantigen for human T cells.

Malignant joint effusions secondary to solid tumor metastasis.

We describe the case of a patient with breast cancer who developed bilateral malignant knee effusions, and review the English language literature. Patients with solid tumors who develop malignant joint effusions are rare; 27 cases have been reported (including our patient). The knee is the predominant site of joint involvement (p < 0.001). Synovial fluid (SF) analysis often demonstrates noninflammatory bloody effusion. Synovial biopsy was positive in 11 of 16 cases in which it was performed. SF cytology was positive in one half of cases in which it was obtained. Arthritis secondary to metastasis is a poor prognostic finding. A strong clinical suspicion is necessary to make the diagnosis; SF cytology or synovial biopsy can confirm it.

Catastrophic antiphospholipid antibody syndrome presenting with multiple thromboses and sites of avascular necrosis.

We describe the case of a 25-year-old woman who presented with the antiphospholipid antibody syndrome (APS) manifesting as hemolytic anemia, thrombocytopenia, renal insufficiency, thromboses in multiple sites including skin, spleen and nasal mucosa, and multiple sites of avascular necrosis of bone. Interestingly, she also had low grade disseminated intravascular coagulation, which has been suggested to be a mechanism for avascular necrosis. We suggest that the APS may be one cause of thrombosis in avascular necrosis.