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Joseph Rosenthal

Publications and source records attributed to Joseph Rosenthal.

8 recordsLinked to original sources
PubMed2006

Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow Transplant Survivor study.

BACKGROUND: Because of treatment-related toxicity, research is increasingly being focused on long-term sequelae secondary to hematopoietic stem cell transplantation (HSCT) in survivor populations. METHODS: This study describes the incidence of auditory, sensory, motor, and visual impairments, including cataracts, among 235 individuals who were treated with HSCT during childhood or adolescence. Outcomes were compared with 705 siblings of childhood cancer survivors. Participants completed a survey with questions on posttransplant organ system impairments. Approximately half of survivors were transplanted when younger than 10 years of age. The median length of followup was 11 years. RESULTS: The cumulative incidence of cataracts was 36% at 15 years post-HSCT, although cataracts occurred only in those who received total body irradiation as an HSCT conditioning agent or head irradiation before transplant. Persistent pain was reported by 21% of survivors. Loss of hearing in one or both ears, and legal blindness in one or both eyes, each occurred after transplant in 2% of survivors. Occurrences were uncommon, but survivors were 4.3 times (95% confidence interval [CI]: 2.0-9.4) more likely to report coordination problems, 7.7 times (95% CI: 3.2-18.5) more likely to report chewing or swallowing problems, and 3.5 times (3.5; 95% CI: 1.6-7.9) more likely to report muscle weakness than those in the comparison group. Muscle weakness was strongly associated with positive history of chronic graft-versus-host disease. CONCLUSIONS: Increased risks were found for motor impairments, hearing loss, vision loss, and persistent pain among study participants. Cataracts were a frequent adverse effect, suggesting that close monitoring with appropriate intervention for preservation of vision, particularly among those who received total body irradiation, should be a primary goal in survivors of HSCT performed in childhood.

Adolescent↗
PubMed2006

Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation.

Total body irradiation (TBI) is an important part of bone marrow transplantation conditioning regimens. In TBI, dose escalation is difficult, because of associated normal organ toxicities. A method to deliver a more targeted dose of TBI preferentially to sites of greatest tumor burden is needed to reduce the dose to normal organs, reduce toxicities, and permit dose escalation. The purpose of this study was to evaluate, through a dosimetric analysis, the potential advantages and feasibility of selectively delivering targeted myeloablative doses of radiation to bone and marrow using a recently developed image-guided tomographic intensity-modulated radiation therapy delivery system (helical tomotherapy). Whole-body computed tomography datasets from 3 patients, age 5, 20, and 53 years, were used for treatment planning studies to evaluate 2 targeted TBI strategies: total marrow irradiation (TMI), in which the target region was defined as the skeletal bone, and total marrow and lymphoid irradiation (TMLI), in which the target regions were defined as bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Organ doses and dose distributions were compared with those in conventional TBI. A 1.7- to 7.5-fold reduction in median organ doses was observed with TMI and TMLI compared with conventional TBI. With this more targeted approach, a dose-volume histogram analysis predicted the potential to escalate the dose to bone (and containing marrow) up to 20 Gy, while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy. Results were similar for the adult and pediatric patients, indicating that this form of targeted TBI will be applicable to most patients regardless of frame size. TMI to 10 Gy was delivered as part of a tandem transplant regimen to the 53-year-old patient with multiple myeloma. Clinical results confirmed the treatment planning predictions. After TMI, the patient experienced the expected blood count nadir, followed by successful engraftment. Grade 2 nausea and grade 1 emesis occurred only briefly on day 2 of TMI. Skin erythema, oral mucositis, esophagitis, and enteritis were not observed. This report demonstrates the feasibility and potential dosimetric advantages of selectively delivering myeloablative doses of radiation to bone and marrow using an image-guided tomographic intensity-modulated radiation therapy delivery system. Organ doses are substantially lower than those associated with standard TBI and predict the potential to significantly reduce associated toxicities and allow for dose escalation. The results also suggest that this form of targeted TBI may have potential advantages over other forms of targeted TBI, such as radioimmunotherapy or bone-seeking radionuclide therapy. Ongoing clinical trials will define the maximum TMI and TMLI doses achievable and define the potential advantages and limitations of this new approach for patients undergoing hematopoietic stem cell transplantation.

Adult↗
PubMed2005

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy.

Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

Animals↗
PubMed2005

Performance limitations and participation restrictions among childhood cancer survivors treated with hematopoietic stem cell transplantation: the bone marrow transplant survivor study.

BACKGROUND: Hematopoietic stem cell transplantation (HCT) may result in important disease- and treatment-related late effects. This study estimated physical, emotional, and educational limitations (performance limitations) and restrictions in the ability to perform personal care or routine daily activities (physical participation restrictions) and restrictions in the ability to participate in social roles (social participation restrictions) in a cohort of cancer survivors treated with HCT during childhood. METHODS: Study participants included 235 persons who had a malignancy or hematologic disorder, were treated with HCT before the age of 21 years, and survived at least 2 years after transplantation. A comparison group was recruited and frequency matched for age, sex, and ethnicity. Medical data were abstracted, and patients or parents (if <18 years at survey completion) completed a mailed 24-page questionnaire. RESULTS: Adult survivors of childhood cancer were more likely than the comparison group to report limitations in physical (prevalence odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.7) and emotional domains (OR, 2.9; 95% CI, 1.4-5.8) and to report physical participation restrictions (OR, 3.9; 95% CI, 1.9-8.2). Adult survivors were also less likely than the comparison group to be married (OR, 0.4; 95% CI, 0.2-0.6). Child survivors were more likely than similarly aged children to have participated in special education (OR, 3.0; 95% CI, 1.5-6.0), to report physical participation restrictions (OR, 10.8; 95% CI, 2.2-53.9), and to have behaviors that indicated impaired social competence (OR, 2.0; 95% CI, 0.9-4.2). CONCLUSION: This study demonstrated that persons treated with HCT as children were at increased risk for performance limitations that restricted participation in routine daily activities and interpersonal relationships.

Activities of Daily Living↗
PubMed2005

Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease.

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n = 24) or first-line (n = 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%-100%). With a median follow-up of 24 months (range, 6-28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.

Chronic Disease↗
PubMed2004

Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas.

The treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.

Adolescent↗
PubMed2003

Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis.

Results of unrelated cord blood transplantation (UCBT) in childhood acute myeloid leukemia (AML) have not been previously reported. We analyzed 95 children receiving UCB transplants for AML (20 in first complete remission [CR1], 47 in CR2, and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 5.2 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 78% +/- 4%, acute graft-versus-host disease (GVHD) was 35% +/- 5%, and 100-day transplantation-related mortality (TRM) was 20% +/- 4%. In multivariable analysis, a collected NC dose higher than 5.2 x 107/kg was associated with a lower 100-day TRM. The 2-year CI of relapse was 29% +/- 5% and was associated with disease status. The 2-year leukemia-free survival (LFS) was 42% +/- 5% (59% +/- 11% in CR1, 50% +/- 8% in CR2, and 21% +/- 9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS compared with other patients (44% +/- 11% vs 40% +/- 8%). In CR2, LFS was not influenced by the length of CR1 (53% +/- 11% in CR1 < 9.5 months compared with 50% +/- 12% in later relapses). We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.

Acute Disease↗