Abacavir and lamivudine exposures during pregnancy and non-defect adverse pregnancy outcomes: data from the antiretroviral pregnancy registry.

BACKGROUND: The antiretroviral (ARV) pregnancy registry, an international voluntary registry, provides information on teratogenicity and non-defect adverse pregnancy outcomes. METHODS: We analyzed ARV pregnancy registry prospective singleton pregnancies, estimating frequencies of and risk for nondefect adverse outcomes among HIV-infected women. Prenatal exposures to abacavir (ABC)-containing regimens vs. non-ABC ARV regimens, and lamivudine (3TC)-containing regimens vs. non-3TC regimens were compared. RESULTS: Of 2006 outcomes with prenatal ABC exposure, 95.6% were live births; 4.4% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had low birth weight (LBW); 11.9% were preterm births. Relative risks comparing exposure to ABC vs. non-ABC ARV regimens were spontaneous abortions 0.92 [95% confidence interval (CI): 0.66 to 1.27], induced abortions 0.84 (95% CI: 0.59 to 1.21), stillbirths 0.59 (95% CI: 0.35 to 1.00), preterm births 0.96 (95% CI: 0.84 to 1.09), and LBW 1.00 (95% CI: 0.90 to 1.13). Of 11,211 outcomes with prenatal 3TC exposure, 95.3% were live births; 4.7% were spontaneous/induced abortions and stillbirths. Of live births, 16.2% had LBW; 11.9% were preterm births. The relative risks comparing exposure to 3TC vs. non-3TC ARV regimens were spontaneous abortions 0.63 (95% CI: 0.50 to 0.80), induced abortions 0.54 (95% CI: 0.43 to 0.69), stillbirths 1.25 (95% CI: 0.86 to 1.80), preterm births 0.86 (95% CI: 0.77 to 0.95), and LBW 1.02 (95% CI: 0.93 to 1.12). CONCLUSIONS: ABC-containing and non-ABC ARV regimens have similar risks for non-birth defect adverse pregnancy outcomes. 3TC-containing regimens have lower risk for spontaneous abortions, induced abortions, and preterm births compared with non-3TC ARV regimens, whereas both regimens had similar prevalence and risks for stillbirths and LBW.

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.

Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma.

BACKGROUND: Metastatic melanoma carries a poor prognosis, with a median survival of 7-9 months. Surgical resection of metastatic disease has been advocated to improve survival. Immunotherapy after metastasectomy may further improve the outcome for high-risk resected disease. METHODS: Charts from patients treated on institutional vaccine trials were analyzed. Patients with American Joint Committee on Cancer (AJCC) Stage IV melanoma who underwent surgical resection of metastatic sites followed by treatment on a peptide vaccine trial were eligible for this study. Survival was calculated from the date of enrollment on the clinical trial. RESULTS: Forty-one patients met inclusion criteria. The median age was 56.5 years, with approximately equal numbers of men and women. The ECOG performance status was 0 in all patients. Approximately 46% of patients underwent resection of visceral metastases before vaccine. The median follow-up was 5.6 years. The median overall survival was 3.8 years. CONCLUSIONS: In selected patients with AJCC Stage IV melanoma, resection of metastatic disease followed by vaccine therapy can result in long-term survival.

Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma.

PURPOSE: To determine the combined effects of p53, p21, and pRb alterations in predicting the progression of bladder transitional cell carcinoma. PATIENTS AND METHODS: p53, p21, and pRb expression was examined immunohistochemically on archival radical cystectomy samples from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinoma (TCC; lymph node-negative, 117 patients; lymph node-positive, 47 patients). Median follow-up was 8.6 years. Based on percentage of nuclear reactivity, p53 was considered as wild-type (0% to 10%) or altered (>10%); p21 was scored as wild-type (>10%) or altered (<10%); and pRb status was considered wild-type (1% to 50%) or altered (0% or >50%). RESULTS: As individual determinants, the p53, p21, and pRb status were independent predictors of time to recurrence (P<.001, P<.001, and P<.001, respectively), and overall survival (P<.001, P=.002, and P=.001, respectively). By examining these determinants in combination, patients were categorized as group I (no alteration in any determinant, 47 patients), group II (any one determinant altered, 51 patients), group III (any two determinants altered, 42 patients), and group IV (all three determinants altered, 24 patients). The 5-year recurrence rates in these groups were 23%, 32%, 57%, and 93%, respectively (log-rank P<.001), and the 5-year survival rates were 70%, 58%, 33%, and 8%, respectively (log-rank P<.001). After stratifying by stage, the number of altered proteins remained significantly associated with time to recurrence and overall survival. CONCLUSION: This study suggests that alterations in p53, p21, and pRb act in cooperative or synergistic ways to promote bladder cancer progression. Examining these determinants in combination provides additional information above the use of a single determinant alone.

A phase I trial of SD-9427 (progenipoietin) with a multipeptide vaccine for resected metastatic melanoma.

PURPOSE: The melanoma tumor antigen epitope peptides MART-1(26-35 (27L)), gp100(209-217 (210M)),and tyrosinase(368-376 (370D)) were emulsified with incomplete Freund's adjuvant and administered with SD-9427 (progenipoietin), an agonist of granulocyte colony-stimulating factor and the FLT-3 receptor, to evaluate the toxicities of and immune responses to this regimen as primary end points and time to relapse and survival as secondary end points. EXPERIMENTAL DESIGN: Fifteen patients with high-risk resected stage III and IV melanoma were enrolled. Each patient received peptides + incomplete Freund's adjuvant with SD-9427 at doses of either 10, 20, or 40 microg/kg s.c. for 3 days before and 7 days after each vaccination. Immunizations were administered every month for 6 months and then administered once 6 months later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses as well as skin testing with peptides and recall antigens was performed before and after vaccination. IFN- gamma release assay, ELISPOT, and MHC-peptide tetramer analysis were performed using peripheral blood mononuclear cells collected before and after vaccination to evaluate peptide-specific cytotoxic T-cell responses. RESULTS: Local pain and granuloma formation and fatigue of grade I or II were the most common side effects. One patient developed antibody-mediated leukopenia and transient grade III neutropenia that resolved after stopping SD-9427. Six of 12 patients tested developed a positive skin test response to one or more of the peptides. Seven of 10 patients tested demonstrated an immune response to at least one peptide when evaluated by IFN-gamma release assay and ELISPOT assay after vaccination, as did 11 of 12 patients analyzed by MHC-peptide tetramer assay. Four of 15 patients have relapsed with a median follow-up of 20 months, and 1 patient in this high-risk group has died of disease. CONCLUSIONS: SD-9427 with a multipeptide vaccine was generally well tolerated, although one patient developed reversible antibody-mediated neutropenia. These data suggest that the majority of patients with resected melanoma mount an antigen-specific immune response against a multipeptide vaccine administered with SD-9427.

Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.

PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine for resected Stage II melanoma.

BACKGROUND: Forty-eight patients with resected Stages IIA and IIB melanoma were immunized with two tumor antigen epitope peptides derived from gp100(209-217) (210M) (IMDQVPSFV) and tyrosinase(368-376) (370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive either peptides/IFA alone or with 250 microm of granulocyte-macrophage-colony-stimulating factor (GM-CSF) subcutaneously daily for 5 days to evaluate the toxicities and immune responses in either arm. Time to recurrence and survival were secondary end points. METHODS: Immunizations were administered every 2 weeks x 4, then every 4 weeks x 3, and once 8 weeks later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses and skin testing with peptides and recall reagents was performed before and after eight vaccinations. RESULTS: Local pain and granuloma formation, fever, and lethargy of Grade 1 or 2 were observed. Transient vaccine-related Grade III and no Grade IV toxicity was observed. Seventeen of the 40 patients for whom posttreatment skin tests were performed developed a positive skin test response to the gp100 peptide, but only 1 of the 40 patients developed a positive skin test response to tyrosinase. Immune responses were measured by release of interferon-gamma (IFN-gamma) in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells, by cytokine release of IFN-gamma, GM-CSF, and tumor necrosis factor-alpha in a Luminex assay, or by an antigen-specific tetramer flow cytometry assay. Thirty-four of the 39 patients for whom the ELISA data were performed demonstrated an immune response after vaccination, as did 37 of 42 patients by tetramer assay. Enzyme-linked immunosorbent assay, Luminex, and tetramer responses in the GM-CSF/peptide/IFA group were higher than in the peptide/IFA group. Epitope spreading to the MART-1/MelanA 27-35 and 26-35 (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48 patients experienced disease recurrence with a median of 24 months of follow-up and 2 patients in this intermediate to high risk group have died. CONCLUSION: These data suggest a significant number of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine. There is a trend for GM-CSF to modestly increase the immune response and support further development of GM-CSF as a vaccine adjuvant.

Segregation and linkage analysis for longitudinal measurements of a quantitative trait.

We present a method for using slopes and intercepts from a linear regression of a quantitative trait as outcomes in segregation and linkage analyses. We apply the method to the analysis of longitudinal systolic blood pressure (SBP) data from the Framingham Heart Study. A first-stage linear model was fit to each subject's SBP measurements to estimate both their slope over time and an intercept, the latter scaled to represent the mean SBP at the average observed age (53.7 years). The subject-specific intercepts and slopes were then analyzed using segregation and linkage analysis. We describe a method for using the standard errors of the first-stage intercepts and slopes as weights in the genetic analyses. For the intercepts, we found significant evidence of a Mendelian gene in segregation analysis and suggestive linkage results (with LOD scores >or= 1.5) for specific markers on chromosomes 1, 3, 5, 9, 10, and 17. For the slopes, however, the data did not support a Mendelian model, and thus no formal linkage analyses were conducted.