Soft-tissue images. Melanosis coli.
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Adenoma↗
Biomedical subjects
J Mehta
Publications and source records attributed to J Mehta.
Antitumor activity of thalidomide in refractory multiple myeloma.
BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.
Angiogenesis Inhibitors↗
Age is not a prognostic variable with autotransplants for multiple myeloma.
Multiple myeloma (MM) typically afflicts elderly patients with a median age of 65 years. However, while recently shown to provide superior outcome to standard treatment, high-dose therapy (HDT) has usually been limited to patients up to 65 years. Among 550 patients with MM and a minimum follow-up of 18 months, 49 aged >/=65 years were identified (median age, 67; range, 65 to 76 years). Their outcome was compared with 49 younger pair mates (median, 52; range, 37 to 64 years) selected among the remaining 501 younger patients (<65 years) matched for five previously recognized critical prognostic factors (cytogenetics, beta2-microglobulin, C-reactive protein, albumin, creatinine). Nearly one half had been treated for more than 1 year with standard therapy and about one third had refractory MM. All patients received high-dose melphalan-based therapy; 76% of the younger and 65% of the older group completed a second transplant (P =.3). Sufficient peripheral blood stem cells to support two HDT cycles (CD34 > 5 x 10(6)/kg) were available in 83% of younger and 73% of older patients (P =.2). After HDT, hematopoietic recovery to critical levels of granulocytes (>500/microL) and of platelets (>50,000/microL) proceeded at comparable rates among younger and older subjects with both first and second HDT. The frequency of extramedullary toxicities was comparable. Treatment-related mortality with the first HDT cycle was 2% in younger and 8% among older subjects, whereas no mortality was encountered with the second transplant procedure. Comparing younger/older subjects, median durations of event-free and overall survival were 2.8/1.5 years (P =.2) and 4.8/3.3 years (P =.4). Multivariate analysis showed pretransplant cytogenetics and beta2-microglobulin levels as critical prognostic features for both event-free and overall survival, whereas age was insignificant for both endpoints (P =.2/.8). Thus, age is not a biologically adverse parameter for patients with MM receiving high-dose melphalan-based therapy with peripheral blood stem cell support and, hence, should not constitute an exclusion criterion for participation in what appears to be superior therapy for symptomatic MM.
Adult↗
Total therapy with tandem transplants for newly diagnosed multiple myeloma.
Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.
Adult↗
Comparison of the growth patterns and morphological characteristics of mechanically and enzymatically isolated fallopian tube epithelial cells.
This study set out to compare the growth patterns and morphological characteristics of human fallopian tube epithelial cells isolated: (1) mechanically; and (2) enzymatically. Cells were cultured in medium supplemented with fetal bovine serum and antibiotics and their epithelial nature was established by immunocytochemistry for cytokeratins. Primary cultures were polygonal in shape with centrally located nuclei, irrespective of the isolation method. Cells isolated enzymatically exhibited a higher growth rate, but the survival rate was poor after more than 2-3 passages. Mechanical isolation gave a lower yield of cells, but had a higher survival rate when sub-cultured, even beyond 8 passages. Thus, mechanically isolated cells might be useful for longer term cultures, whereas enzymatically isolated cells are best only for short-term work.
Adult↗
Impact of previous high-dose therapy on outcome after allografting for multiple myeloma.
We describe a single centre experience of 33 patients allografted for multiple myeloma, of which 28 received matched sibling marrow, one haploidentical family donor marrow and four matched but unrelated donor marrow. Median follow-up after transplant is 27 months, and 13 patients are currently alive. One out of four patients with an unrelated donor survives and 12 out of 28 (42.8%) with matched sibling donors. Four patients were unevaluable because of early death (<day 21), and one patient experienced graft failure. The probability of overall survival is 35.7 % at 3 years. The probability of disease-free survival is 39% at 3 years, and the probability of treatment-related mortality is 54% at 1 year. Acute GVHD developed in 26 (78.8%) patients and was responsible for six deaths. Twenty-four patients (72.7%) developed renal dysfunction and 22 (66.7%) developed hepatic dysfunction. Seventeen patients (51.5%) died of transplant-related problems in the first 150 days, and one at 6 months. Among the 13 survivors, none has experienced disease progression at a median follow-up of 27 months (range 3-65 months). We conclude that since allogeneic bone marrow transplantation is the only potentially curative option in myeloma, it should be offered to younger patients early in the course of their disease, when procedure-related morbidity and mortality are likely to be at their lowest.
Adult↗
Reimmunization after blood or marrow stem cell transplantation.
Protective immunity to diseases preventable by routine vaccination is lost over time following allogeneic and autologous blood and marrow transplantation. Adoptive transfer of immunity from donors to recipients after allogeneic transplantation is not sufficient to prevent this decline. Systematic reimmunization is necessary at appropriate time intervals following transplantation to re-establish immunity. Response to vaccination depends upon the type of transplant, the source of cells, the immune status of the patient, and the vaccine being used. While inactivated or subunit vaccines are safe in all transplant recipients, live vaccines are generally contraindicated. Reimmunization practices vary widely amongst transplant centers. This comprehensive review summarizes published data on post-transplant vaccination, and based upon these, suggests guidelines which may be used as a framework for development of reimmunization protocols.
Antibodies, Viral↗
Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD).
Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4-35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1-12). The median total serum bilirubin level was 116 mmol/l (range 63-194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in nonresponders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.
Adult↗
Long-term outcome of adult acute leukemia patients who are alive and well 2 years after autologous blood or marrow transplantation.
We studied the long-term outcome of 87 adults with acute leukemia (age 15-59 years at transplant, median 27; 44 myeloid, 42 lymphoblastic, one biphenotypic) who were alive in continuous remission 2 years after a marrow (n = 74) or blood stem cell (n = 13) autograft. Nine relapsed 25-50 months (median 38) after transplantation. Five relapses were straightforward with no karyotypic or morphologic evolution of the original disease. Four recurrences were unusual, with development of myelodysplasia (n = 3) or myeloproliferative disease (n = 1). Five patients died of relapsed disease and four are still alive. Two patients died of complications related to the transplant, and one of ischemic heart disease. Seventy-nine patients (91%) are alive in remission 24-149 months (median 67) after transplantation (75 in continuous remission and four after further therapy) with Karnofsky scores of 80-100% (median 100%). The 8-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 89%, 3% and 12%. Eleven (12%) survivors had creatinine levels of >110 micromol/l (one more than double), and 14 (16%) had bilirubin levels of >17 mmol/l (one more than double) at the last follow-up. None of the following factors was found to be predictive for survival, non-relapse death, or relapse from the 2-year mark in multivariate analysis: age, sex, type of leukemia, disease stage, diagnosis, conditioning, origin of cells, and nucleated cell dose. We conclude that adult patients with acute leukemia who are alive and well 2 years following an autograft have a high probability of being cured, and the incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.
Acute Disease↗
Collection of peripheral blood stem cells after a preceding autograft: unfavorable effect of prior interferon-alpha therapy.
Eighty-eight previously autografted (78 transplanted twice and 10 once) myeloma patients who had no cryopreserved stem cells available for possible future use received G-CSF for mobilization of stem cells. One-fourth of the patients had progressive disease at the time of apheresis. All patients had received 200 mg/m2 melphalan for the first transplant. The interval between the preceding transplant and the harvest was 5-68 months (median 29). A total of 0.46-9.16 (median 3.03) x 10(6) CD34+ cells/kg were collected. More than 2 x 10(6)/kg CD34+ cells were collected in 76% of the patients, and > or = 5 x 10(6)/kg in 14%. On multivariate analysis, patients with platelet counts of > or = 200 x 10(9)/l (P < 0.0001), those who had not received any myelosuppressive chemotherapy between the last transplant and the collection (P = 0.02), and those who had received interferon-alpha for < or = 6 months (P = 0.03) had better collections. Eleven of 12 patients autografted with these cells had prompt neutrophil recovery (median 10 days to 0.5 x 10(9)/l) but recovery to 50 x 10(9)/l platelets was delayed or incomplete in 11 of 12. We conclude that it is possible to harvest peripheral blood stem cells with G-CSF stimulation in patients who have been autografted previously. Limited data suggest that platelet recovery may be suboptimal when these cells are used. These findings have practical implications for patients with malignant diseases in remission after autografting who may be candidates for future salvage therapy but have no stem cells stored, and for patients with chronic myeloid leukemia who are on long-term interferon-alpha therapy to attain cytogenetic remission for eventual collection of normal stem cells.
Adult↗
Patients with multiple myeloma may safely undergo autologous transplantation despite ongoing RSV infection and no ribavirin therapy.
Respiratory syncytial virus (RSV) has been reported as a cause of death among autologous peripheral blood stem cell (ASCT) and marrow recipients and recommendations for therapy with aerosolized ribavirin plus intravenous immunoglobulin (IVIG) made. This therapy is expensive, may be toxic, and causes a significant disruption of patient care. The purpose of this study was to evaluate the morbidity and mortality of RSV infections in patients with multiple myeloma undergoing ASCT without ribavirin therapy. During the months of February-April 1997, 10 consecutive patients (median age 57 years, seven males) with advanced and heavily pretreated myeloma underwent ASCT while having active RSV upper respiratory tract infection. After melphalan (200 mg/m2), all patients became neutropenic (<1000 cells/mm3) for a median of 7 days. Ribavirin was not given to any patient. No patient developed lower respiratory tract infection, required transfer to intensive care or died at a median follow-up of 8 months. One patient developed tracheobronchitis requiring oxygenation by nasal cannula. No delay in the treatment of the underlying myeloma was incurred. RSV infection may not necessarily be a contraindication for ASCT or an indication for therapy with aerosolized ribavirin. Additional studies are needed to confirm our preliminary findings.
Aged↗
High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia.
Standard doses of alkylating agents or purine analogues effect response rates of up to 50% in Waldenström's macroglobulinaemia (WM); however, complete responses are infrequent and there are no cures. We have evaluated the feasibility, safety and efficacy of high-dose chemotherapy with peripheral blood stem cell support in six patients aged 45-69 years (median 51.5) with WM; four patients relapsed after prior therapy inclusive of purine analogues and two patients proceeded with transplant after minimal therapy. Four patients mobilized adequate numbers of stem cells; however, two patients with more extensive fludarabine therapy failed to mobilize and required a second attempt at stem cell collection. Five patients were treated with melphalan 200 mg/m2, including one patient who received tandem transplants and one patient who received melphalan 140 mg/m2 with added total body irradiation (TBI). There was no treatment-related mortality and non-haematological toxicities were manageable. Engraftment was prompt except in one patient with extensive prior use of fludarabine. All the six patients achieved at least partial response (PR), including one who achieved complete response (CR). Five patients are alive and four are event-free at 52+, 15+, 12+ and 2+ months post transplant. This pilot study suggests safety and efficacy of high-dose therapy in WM and suggests that the peripheral blood stem cells should preferably be procured prior to extensive use of purine analogues.
Aged↗
Lipid preparations of amphotericin for the treatment of fungal infections.
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Amphotericin B↗
Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system.
Because the presence of IgG paraprotein in the blood is clear cut, it makes IgG myeloma a more circumscribed disease than myeloma as a whole in which to study treatment efficacy, particularly relating to complete remission (CR). Between May 1989 and December 1997, 177 consecutive patients with IgG myeloma who were <75 years old were seen, of whom 153 entered a sequential therapy (ST) programme of initial courses of C-VAMP infusional chemotherapy (IC), high-dose treatment (with or without stem cell rescue) (119 patients) and maintenance interferon (87 patients). 74/153 (48.4%) patients entered CR. Median overall survival (OS) and event-free survival (EFS) were 4.9 and 2.1 years, respectively. Multivariate analysis at presentation showed OS was significantly prolonged for beta2M <2.7 mg/l and age 8.5 g/dl predicted for longer EFS. For CR patients, age <median 51 years, absence of Bence-Jones proteinuria (BJP), male sex and white blood cells (WBC) <7 x 109/l predicted for a longer OS. Longer length of first CR was predicted by absence of BJP at presentation (P = 0.03) and fewer than five courses of IC (P = 0.02) to attain CR. We have therefore been able to refine the use of ST in IgG myeloma, redefine CR as a 'macro' endpoint, and propose a new staging system for IgG myelomas. Analysis of 41 comparable IgA patients showed IgG to be a distinct entity.
Adult↗
Vitamins C and E prolong time to arterial thrombosis in rats.
To examine the modulation of arterial thrombosis by vitamins C and E, Sprague-Dawley rats were fed nonpurified diet, or diet mixed with vitamin C [100 mg/(kg body weight.d)], vitamin E [100 mg/(kg.d)] or both vitamins C and E [each 100 mg/(kg.d)], for a period of 9-19 d (mean 15 d). An occlusive aortic thrombus was created by application of a Whatman filter soaked in 1 mol/L FeCl3. Both vitamins C and E and their combination decreased platelet aggregation and delayed time to occlusive thrombus formation (P < 0.05 vs. control). Vitamins C and E decreased arterial superoxide generation (P < 0.05 vs. control). Interestingly, vitamin E also increased endogenous superoxide dismutase activity (SOD) and protein expression in aortic tissues (P < 0.05 vs. control). The combination of vitamins C and E was not superior to each vitamin alone with regard to effect on time to thrombus formation, but it was more potent with regard to platelet inhibition. The increase in endogenous antioxidant activity by vitamin E is an intriguing observation. This study shows that the antioxidant vitamins C and E have important effects on platelet aggregation, SOD activity, superoxide generation and thrombus formation.
Animals↗
Long-term outcome of adult acute leukemia patients who are alive and well two years after allogeneic bone marrow transplantation from an HLA-identical sibling.
We studied the long-term outcome of 136 adults with acute leukemia (age 15-48 years at transplant, median 28; 112 myeloid, 22 lymphoblastic, 2 undifferentiated) who were alive in continuous remission two years after allografting from HLA-identical sibling donors. Six relapsed 25-46 months (median 30) after BMT. Fourteen (10%) died of non-relapse causes (12 transplant-related and 2 unrelated) 24-140 months (median 73) after BMT; mainly due to complications of chronic GVHD (8 infections, 3 secondary malignancies). One hundred and seventeen (86%) patients are alive in remission 25-226 months (median 103) after BMT; 116 (85%) in continuous remission. Eight survivors have symptomatic chronic GVHD requiring therapy (Karnofsky scores 60-90%, median 80%). The majority of those without chronic GVHD have Karnofsky scores of 100%. The 10-year probabilities of survival, toxic death, and relapse (from the 2-year mark) are 81%, 13%, and 5%. Twenty-two (19%) survivors had creatinine levels of > 110 mumol/L (one more than double), and 11 (9%) had bilirubin levels of > 17 mmol/L (one more than double) at the last follow-up. The absence of chronic GVHD at the 2-year mark (RR 3.5, P = .004), and female sex (RR 2.9, P = .04) influenced overall survival favorably, and the absence of chronic GVHD at the 2-year mark (RR 8.1, P = .001) influenced toxic death favorably. We conclude that patients with acute leukemia who are alive and well without chronic GVHD two years following an allograft have a high probability of being cured, whereas patients with active chronic GVHD requiring immunosuppression continue to be at risk of non-relapse death. The incidence of long-term liver and kidney dysfunction measured by serum bilirubin and creatinine is low.
Acute Disease↗
Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse.
Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.
Acute Disease↗
The impact of karyotype on remission rates in adult patients with de novo acute myeloid leukemia receiving high-dose cytarabine-based induction chemotherapy.
One hundred and twenty-eight patients aged 15 years or over (median 34) with de novo acute myeloid leukemia (AML) received 2- or 3-drug induction chemotherapy comprising 5 days of daily high-dose cytarabine (2 g/m2 q12h) and etoposide (100 mg/m2), without (n=62, 1985-90, protocol BF11) or with (n=66, 1990-97, protocol BF12) daily 5 mg/m2 anthracycline (61 idarubicin, 5 mitoxantrone). Twelve patients with t(15;17) were not included. Evaluable karyotypes were obtained in 110 (86%): 30 (27%) favorable, 60 (55%) intermediate, and 20 (18%) adverse. Three patients dying during chemotherapy were inevaluable. Eighty-four (67%) patients remitted with one cycle, and the overall complete remission (CR) rate was 72%. CR rates were comparable for patients with and without evaluable karyotypes. CR rates with BF11 (64% after one cycle; 72% overall) and BF12 (70% after one cycle; 72% overall) were comparable (P=.4 and 1.0 respectively). CR rates after one cycle (86%, 61% and 55%; P=.03) as well as overall CR rates (90%, 69% and 55%; P=.02) were significantly different for patients with favorable, intermediate and adverse karyotypes respectively. In Cox analysis, the karyotype was the only factor found to influence CR independently. We conclude that the karyotype of the leukemic clone is the most important determinant of response to high-dose cytarabine-based induction chemotherapy in AML. The addition of idarubicin to high-dose cytarabine and etoposide does not appear to improve CR rates. A different treatment strategy may be needed to improve CR rates for patients with non-favorable karyotypes.
Acute Disease↗