Biomedical subjects

Anil Tulpule

Publications and source records attributed to Anil Tulpule.

13 recordsLinked to original sources

PubMed2006

Quality-of-life and health benefits of early treatment of mild anemia: a randomized trial of epoetin alfa in patients receiving chemotherapy for hematologic malignancies.

BACKGROUND: Chemotherapy-related anemia is prevalent among patients with hematologic malignancies. A randomized, open-label, multicenter trial of early versus late epoetin alfa in this population was conducted, focusing on quality of life (QOL). METHODS: Patients with non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma and baseline hemoglobin of 10 to 12 g/dL who were scheduled for > or = 4 months of myelosuppressive chemotherapy were randomized to receive < or = 16 weeks of epoetin alfa at a dose of 40,000 U once weekly immediately (early) or to wait and only receive epoetin alfa if hemoglobin decreased to < 9 g/dL (late). Those patients with a hemoglobin level > 12 g/dL after 3 chemotherapy cycles were not randomized. The primary endpoint was a mean change in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) total. RESULTS: In all, 269 patients with a hemoglobin level < or = 12 g/dL were randomized. The mean total FACT-An increased 3.84 (95% confidence interval [95% CI], 0.21-7.46) in early patients and decreased 4.37 (95% CI, -7.99 to -0.74) in late patients (P = .003). Early patients had significantly (P < .05) higher mean scores for total FACT-General; FACT-General physical and functional well-being subscales, total anemia scale, and fatigue subscale; and daily activity, energy, and important activity Linear Analog Scale Assessment scales, as well as reduced bedrest days and restricted activity days. The mean hemoglobin increased 1.2 g/dL (95% CI, 0.98-1.46) in early patients but decreased 0.2 g/dL (95% CI, -0.32-0.12) in late patients (P < .0001). Adverse events were similar between groups (with fatigue being the most prevalent); clinically relevant thromboembolic events were more common in early patients. CONCLUSIONS: Treating mild anemia immediately with epoetin alfa during chemotherapy for hematologic malignancy significantly improved QOL, productivity, and hemoglobin compared with delaying treatment until the hemoglobin level decreases to < 9.0 g/dL.

Adult↗

PubMed2006

Phase I study of antisense oligonucleotide against vascular endothelial growth factor: decrease in plasma vascular endothelial growth factor with potential clinical efficacy.

PURPOSE: Vascular endothelial growth factor antisense (VEGF-AS) is an antisense oligonucleotide that targets VEGF, inhibiting angiogenesis and tumor cell proliferation. This study established the safety, biologic effects, and pharmacokinetics of VEGF-AS in 51 patients with advanced malignancies. METHODS: VEGF-AS was administered as a 2-hour infusion daily for 5 consecutive days for only one cycle on the first four dose levels, and then administered daily for 5 days every other week for up to 4 months on subsequent levels. Pharmacokinetics, tumor response, and the effect on plasma VEGF levels were determined. RESULTS: The maximum-tolerated dose was 200 mg/m2. Dose-limiting toxicities included grade 4 fever, and pulmonary embolism in one patient each at 250 mg/m2. Mild anemia, fever, fatigue, and gastrointestinal complaints were the most common adverse events. VEGF-AS t(1/2beta) (beta-phase terminal half-life of drug concentration) was 2.25 hours (range, 1.97 to 2.95 hours). Mean plasma VEGF-A (P = .002) and VEGF-C (P = .01) levels decreased 24 hours postinfusion, with a trend towards greater decreases at higher dose levels. At the maximum-tolerated dose, five of six patients demonstrated reductions in plasma VEGF. Clinical responses included complete remission in one patient with AIDS-Kaposi's sarcoma, a mixed but dramatic response in one patient with cutaneous T-cell lymphoma, and prolongation of progression-free survival compared with that obtained on the immediate prior regimen in six patients (12%) with renal cell, bronchoalveolar, small cell lung, thyroid, and ovarian carcinomas, and chondrosarcoma, respectively. CONCLUSION: VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.

Adult↗

PubMed2006

Phase I/II trial of nonpegylated liposomal doxorubicin, cyclophosphamide, vincristine, and prednisone in the treatment of newly diagnosed aggressive non-Hodgkin's lymphoma.

BACKGROUND: The toxicity and efficacy of nonpegylated liposomal doxorubicin (TLC D-99) when substituted for conventional doxorubicin in the CHOP (doxorubicin/cyclophosphamide/vincristine/prednisone) regimen were evaluated in the treatment of newly diagnosed patients with aggressive non-Hodgkin's lymphoma. Liposomal doxorubicin at doses of 40 mg/m2, 50 mg/m2, 60 mg/m2, and 80 mg/m2 was given with fixed doses of cyclophosphamide, vincristine, and prednisone. Chemotherapy cycles were repeated every 21 days. PATIENTS AND METHODS: Forty-seven patients with a median age of 55 years (range, 25-83 years) were studied. RESULTS: No dose-limiting toxicities were observed at any level. Reversible grade 3/4 neutropenia was the most common toxicity (95.8%). Most nonhematologic side effects were grade 1/2 in severity. Complete remissions were documented in 31 of 46 evaluable patients (67.4%) and partial remissions in 7 (15.2%), for an overall major response rate of 82.6%. The median duration of complete remission is > or = 27.7 months (range, 2.4 months to > or = 59.8 months). An exploratory objective was to correlate multidrug resistance-1 (MDR-1) expression with outcome. Immunohistochemistry for MDR-1-related p-glycoprotein was assessed in lymphoma tissues from 27 patients. Of the 27 lymphoma tissues studied, 8 (30%) were MDR-1 positive at diagnosis. The complete response rate was 63% in MDR-1-positive lymphomas and 74% in the MDR-1-negative cases (P = 0.66). CONCLUSION: Nonpegylated liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is an active regimen for patients with newly diagnosed, aggressive non-Hodgkin's lymphoma. The regimen is relatively well tolerated, with hematologic suppression as the major toxicity. Liposomal encapsulation might evade resistance caused by MDR-1 expression.

Adult↗

PubMed2005

Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy.

PURPOSE: To compare the prognostic factors for survival and the validity of the International Prognostic Index (IPI) in patients with HIV-related diffuse large-cell lymphoma (HIV-DLCL) treated with curative intent in the pre-highly active antiretroviral therapy (HAART) era versus the HAART era. PATIENTS AND METHODS: We retrospectively reviewed 192 patients with HIV-DLCL diagnosed from 1982 to 2003. Pre-HAART era included 120 patients who did not receive HAART, whereas the HAART era included 72 patients diagnosed after January 1997 who received HAART. RESULTS: There were no statistically significant differences in terms of either lymphoma or HIV-related characteristics in the two time periods. The complete response rate improved from 32% in the pre-HAART to 57% in the HAART era (P = .0006), and median survival time improved from 8.3 to 43.2 months (P = .0005). In groups with low-, low-intermediate-, and high-intermediate-risk IPI disease, 3-year overall survival rates were 20%, 22%, and 5% in the pre-HAART era and 64%, 64%, and 50% in the HAART era, respectively. On multivariate analysis, factors independently associated with decreased survival in both periods were increasing IPI scores and failure to attain complete remission, whereas CD4 less than 100 cells/microL predicted shorter survival in only the pre-HAART era. CONCLUSION: Prognostic factors and overall survival of patients with HIV-DLCC have changed. Clinical outcomes in patients with HIV-DLCL are now approaching the outcomes of patients with de novo lymphoma.

Adult↗

PubMed2005

AIDS-related Burkitt's lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy.

PURPOSE: To compare outcomes of patients with HIV-Burkitt's lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre-highly active antiretroviral therapy (HAART) versus HAART eras. PATIENTS AND METHODS: Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART. RESULTS: There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm(3) independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era. CONCLUSION: Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.

Adult↗

PubMed2005

Multidrug resistance in AIDS-related lymphoma.

PURPOSE OF REVIEW: AIDS-related lymphoma has a decreased response rate and poorer prognosis to standard chemotherapy when compared with lymphoma in the non-HIV population. In addition to the known HIV-related and lymphoma-related poor prognostic factors, this review discusses another factor, MDR-1 expression and its impact on response to therapy in patients with AIDS-related lymphoma. RECENT FINDINGS: There is an increased incidence of de-novo MDR-1 expression in AIDS-related lymphoma compared with lymphoma in the non-HIV settings. MDR-1 expression in AIDS-related lymphoma is associated with poor response to conventional combination chemotherapy. Liposomal encapsulation of doxorubicin when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) seems to overcome P-glycoprotein-mediated drug resistance in AIDS-related lymphoma. SUMMARY: The overexpression of MDR-1 gene product P-glycoprotein is an adverse prognostic factor in AIDS-related lymphoma. Treatment with liposomal encapsulated doxorubicin seems to overcome the P-glycoprotein-related drug resistance. This and other strategies to modulate MDR-1 should be further explored in order to improve success rates in the treatment of AIDS-related lymphoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS Malignancy Consortium and IM862 Study Team.

PURPOSE: IM862 is a synthetic dipeptide (L-glutamine L-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day. PATIENTS AND METHODS: Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo. RESULTS: Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012). CONCLUSION: Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.

AIDS-Related Opportunistic Infections↗

PubMed2004

Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium.

Kaposi sarcoma (KS) is an angioproliferative tumor derived from endothelial cells in which tumor cells form aberrant vascular structures. Ephrin B2 and ephrin B4 (EphB4) are artery- and vein-specific proteins, respectively, with critical roles in vessel maturation. We investigated whether the disorganized KS vasculature was due to unbalanced expression of ephrin B2 and EphB4. Secondly, we wished to determine if human herpesvirus type 8 (HHV-8), the viral agent associated with KS, regulates ephrin B2 and EphB4. An arterial phenotype was observed in KS tissue and cell lines, as shown by abundant expression of ephrin B2 with little or no EphB4. Infection of venous endothelial cells with HHV-8 resulted in a phenotype switch from EphB4 to ephrin B2, similar to that seen with vascular endothelial growth factor (VEGF). The HHV-8 effect on ephrin B2 expression was reproduced with the HHV-8-specific viral G-protein-coupled receptor. We also showed that ephrin B2 expression is required for KS cell viability by knock down with siRNA. KS is the first example of a human tumor with a predominantly arterial phenotype. This predominance can be attributed to expression of HHV-8 proteins and their downstream effects. Ephrin B2 is thus an important novel factor in KS biology and a potential target for therapy.

Arteries↗

PubMed2004

Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma: results of therapy and correlates of response.

PURPOSE: To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS: Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m(2) was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS: Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm(3) (range, 19/mm(3) to 791/mm(3)). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P =.027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. CONCLUSION: Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Treatment of AIDS related non-Hodgkin's lymphoma with combination mitoguazone dihydrochloride and low dose CHOP chemotherapy: results of a phase II study.

PURPOSE: To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). METHODS: Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle. RESULTS: Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. CONCLUSIONS: Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.

Adult↗

PubMed2002

Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma.

BACKGROUND: Treatment options are limited for patients with advanced acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (AIDS-KS) whose disease has progressed after receiving therapy with liposomal anthracyclines or combination chemotherapy with doxorubicin (Adriamycin), bleomycin, and vincristine (ABV). This study was performed to assess the safety and efficacy of a novel dose and schedule of paclitaxel in patients with AIDS-KS who failed to respond to previous systemic chemotherapy. METHODS: This was an open-label, multicenter Phase II study. Eligible patients had advanced AIDS-KS consisting of at least 25 mucocutaneous lesions, visceral disease, or lymphedema, and had failed to respond to at least one previous systemic chemotherapy regimen. Patients were treated with paclitaxel at a dose of 100 mg/m(2) given intravenously over 3 hours, every 2 weeks. Primary efficacy end points were tumor response, time to progression, time to treatment failure, and survival. Quality of life and adverse events were evaluated using the Symptom Distress Scale (SDS) and the World Health Organization Toxicity Criteria, respectively. RESULTS: One hundred and seven male patients with advanced AIDS-KS were enrolled from nine participating sites. The median entry CD4+ lymphocyte count was 41/mm(3) (range 0-1139). Previous treatment regimens included ABV in 52, liposomal daunorubicin in 49, and liposomal doxorubicin in 40 patients. Forty-one patients (38%) received two or more previous chemotherapy regimens. Protease inhibitor use during the study was reported by 82 (77%) patients overall; 47 patients (44%) were receiving a protease inhibitor before study entry. Complete or partial response was documented in 60 patients (56%). The median duration of response was 8.9 months. Major response rate was similar when comparing patients not on a protease inhibitor at the time of response (59%) with patients on a protease inhibitor at time of response (54%). However, protease inhibitor use had a significant impact on survival (P = 0.04). Grade 4 neutropenia was reported in 35% of patients; other life-threatening side effects were uncommon. Significant improvements were seen in the total quality of life scores measured by the SDS, including significant improvement in KS-related symptoms such as facial disease, tumor-associated edema, and pulmonary involvement. CONCLUSION: Paclitaxel given every 2 weeks induces major tumor regression in the majority of patients with advanced KS who failed to respond to previous systemic chemotherapy. Paclitaxel is associated with significant improvement in quality of life with acceptable toxicity and should be considered as an effective treatment option for patients with advanced KS.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Characteristics of indolent non-Hodgkin lymphoma in patients with type 1 human immunodeficiency virus infection.

BACKGROUND: There is recent evidence that the incidence of indolent non-Hodgkin lymphoma (NHL) appears to be increased in persons with the acquired immunodeficiency syndrome (AIDS). The current study was conducted to describe the clinical, immunologic, and pathologic characteristics of indolent B-cell lymphoma in patients infected with the human immunodeficiency virus (HIV). METHODS: The current report was a retrospective study of 10 cases of indolent NHL identified from the AIDS-Lymphoma Registry at the University of Southern California School of Medicine. These patients were compared with 336 consecutive patients with systemic intermediate/high-grade AIDS-related NHL who were diagnosed and treated at a single institution. RESULTS: The pathology of the indolent cases included follicular lymphoma (five patients), small lymphocytic lymphoma (two patients), and one case each of mucosa-associated lymphoid tissue (MALT), monocytoid B-cell, and marginal zone lymphoma. When comparing the indolent lymphomas with the intermediate/high-grade AIDS-NHL cases, no differences were observed with regard to demographic characteristics or history of prior opportunistic infection. HIV patients with indolent lymphomas were found to have a significantly higher median CD4+ lymphocyte count compared with patients with intermediate/high-grade NHL (531 /mm3 vs. 90 /mm3) (P < 0.0001). Bone marrow involvement was significantly more common in indolent NHL cases (50%) versus intermediate/high-grade NHL cases (17%) (P = 0.02). The median survival for patients with indolent NHL was significantly longer compared with patients with intermediate/high-grade NHL (66.8 months vs. 7.1 months) (P = 0.007). CONCLUSIONS: Indolent lymphomas occurring in patients infected with HIV appear to differ from intermediate/high-grade lymphomas with regard to immune status and propensity for bone marrow involvement and prolonged survival. The median survival in the group of HIV-seropositive patients with indolent NHL examined in the current study was found to be comparable to that reported in HIV-negative individuals.

Adult↗

PubMed2002

Multidrug resistance (MDR-1) expression in AIDS-related lymphomas.

P-glycoprotein is a product of the multidrug resistance (MDR-1) gene. In non-Hodgkin's lymphoma, less than 20% of untreated de novo lymphomas express MDR-1 compared with approximately 50% after failure of chemotherapy. We wished to study the expression of MDR-1 in AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Tissue biopsies from 50 patients with newly diagnosed AIDS-NHL were studied by immunohistochemical analysis using C494, a monoclonal antibody specific for the MDR-1 isoform of P-gp. MDR-1 expression was correlated with patient demographics, lymphoma characteristics, response to chemotherapy, and survival. Forty-six males and four females with a median age of 38 years (range 26-63) were studied. A prior AIDS-defining opportunistic infection was reported in 35 patients (70%). The median CD4+ lymphocyte count was 69/mm(3) (range 0-920). Thirty-two patients (63%) had received prior anti-HIV therapy, including a protease inhibitor in five (10%). Pathologic types consisted of diffuse large cell in 13 (26%), immunoblastic in 13 (26%), small non-cleaved in 22 (44%), and high grade not otherwise specified in two (4%). The majority of patients (76%) had stage III/IV disease. Pre-treatment lymphoma tissues from 33 patients (66%) stained positively for MDR-1. MDR-1 positive patients had a significantly lower complete remission rate compared to MDR-1 negative patients (33 versus 65%, P=0.042). Duration of complete response was significantly longer in MDR-1 negative patients compared with MDR-1 positive patients (not reached versus 9.9 months, P=0.003). Strategies to overcome MDR-1 expression may be important for initial treatment in patients with AIDS-NHL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗