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Biomedical subjects

Robert E Goldsby

Publications and source records attributed to Robert E Goldsby.

14 recordsLinked to original sources
PubMed2007

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma.

BACKGROUND: Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion. PROCEDURE: We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial. RESULTS: Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home. CONCLUSIONS: Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity.

Administration, Oral↗
PubMed2006

Survival after recurrence of osteosarcoma: a 20-year experience at a single institution.

BACKGROUND: Approximately one-third of patients with osteosarcoma who have a complete response to their initial treatment can be expected to relapse. It is important to define what host, tumor, or treatment characteristics determine outcome after relapse. We present findings in 59 patients treated at our institution from 1974 to 1996 who have relapsed one or more times after their initial response. METHODS: Host and tumor characteristics at diagnosis and relapse, therapeutic interventions and survival outcomes were determined from examination of medical records and a follow-up questionnaire. RESULTS: Of the 59 patients, 37 initially presented with localized disease of the extremity, 11 with localized non-extremity disease, and 11 with metastatic disease. This report focuses on those with localized disease of the extremity. For these patients, median time from original diagnosis to first recurrence was 14 months. Median survival after first recurrence was 31 months. The median post initial relapse survival was the same for patients whose first relapse occurred before or after 14 months from original diagnosis. Seventeen of 29 patients with systemic metastasis at first recurrence had complete removal of their disease and had a median post-op survival of 2.5 years, while the remaining 12 patients with no surgery, had a median survival of 2 years. Of the 37 patients who presented with primary disease only in the extremities and relapsed: 31 died (2 more than 6 years from first recurrence) and 6 are alive from 6 to 24 years from first recurrence (5 without disease and 1 with disease). Three of the five disease-free survivors had three or more relapses. CONCLUSION: With a long follow-up time, we found 15% of patients with relapsed osteosarcoma who originally presented with localized disease in the extremity are alive with no evidence of disease at 10 years from first recurrence (Kaplan-Meier estimate). Even patients with multiple relapses may have long-term disease-free survival after salvage therapy. Chemotherapy and time to first recurrence were unrelated to survival after relapse in this study. Complete surgical removal of metastatic disease may be important for long-term survival.

Adolescent↗
PubMed2006

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

3-Iodobenzylguanidine↗
PubMed2006

Surviving childhood cancer: the impact on life.

With modern therapies, most children diagnosed with cancer are expected to reach adulthood. Therefore, there are large and ever-increasing numbers of children and young adults in our population who are survivors of childhood cancer. Many of the therapies responsible for improved cancer survival rates can also damage normal cells and tissues. As more children survive cancer, the physical and emotional costs of enduring cancer therapy become increasingly important. Although most childhood cancer survivors are now expected to survive, they remain at risk for relapse, second malignant neoplasms, organ dysfunction, and a negative psychologic impact. Individual risk is quite variable and is dependent on multiple factors including the type and site of cancer, the therapy utilized, and the individual's constitution. The risks are likely to change as we learn more about the specific long-term effects of cancer therapy, develop more refined and targeted therapies, and develop and apply more effective preventative strategies or therapeutic interventions. Guidelines for long-term follow-up have been established and are available to help facilitate appropriate monitoring of and care for potential late effects.

Antineoplastic Agents↗
PubMed2005

Ewing sarcoma as a second malignant neoplasm after acute lymphoblastic leukemia.

Second malignant neoplasms (SMNs) are being increasingly recognized. This report describes a case of a 7-year-old girl with a history of acute lymphoblastic leukemia (ALL) who presented with a mass in her humerus that was diagnosed as Ewing sarcoma. Second malignant neoplasms are relatively rare in survivors of ALL treated without radiation. Even more unusual is the development of Ewing sarcoma as the SMN.

Bone Neoplasms↗
PubMed2005

Oncologic approaches to pediatric limb preservation.

Preservation of limb function in the pediatric oncology patient is uniquely challenging. Treatment must be strictly prioritized in terms of the patient's life, the limb, its function, length equalization, and cosmetic appearance. At the same time, social, socioeconomic, and cultural factors must be understood and respected to achieve the most advantageous outcome for both the patient and family. Given these considerations, as well as the relative rarity of many oncologic diagnoses and the myriad of presentation scenarios, drafting generalized treatment recommendations is difficult. Instead, orthopaedic intervention in the care of children and young adults with oncologic conditions must be individualized, with the broad goal being optimization of limb function rather than rigid advocacy of limb salvage.

Amputation, Surgical↗
PubMed2004

Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors.

PURPOSE: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. EXPERIMENTAL DESIGN: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m(2)/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m(2)/day (n = 6) or 15 mg/m(2)/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. RESULTS: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m(2)/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing's sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O(6)-methylguanine-DNA methyltransferase expression in tumor tissue. CONCLUSIONS: The MTD using this schedule was temozolomide (100 mg/m(2)/day) and irinotecan (10 mg/m(2)/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.

Adolescent↗
PubMed2004

Neuroblastoma: evolving therapies for a disease with many faces.

Neuroblastoma is the most common extra-cranial solid tumor in children and has a heterogeneous clinical presentation and course. Clinical and biologic features of this disease have been used to develop risk-based therapy. Patients with low-risk disease can be treated with surgery alone. Patients with intermediate-risk features have an excellent prognosis after treatment with surgery and a relatively short course of standard dose chemotherapy. Unfortunately, most children with neuroblastoma present with advanced disease. More than 60% of patients with high-risk features will succumb to their disease despite intensive therapy including a myeloablative consolidation. Research efforts to understand the biologic basis of neuroblastoma and to identify new, more effective therapies are essential to improve the outcome for these children.

Biomarkers, Tumor↗
PubMed2003

Ig gene somatic hypermutation in mice defective for DNA polymerase delta proofreading.

This study is an investigation of the possible role of DNA polymerase (pol) delta with an inactivated exonuclease (exo) in somatic hypermutation (SHM). Analysis of endogenous heavy chain transcripts revealed no difference in mutation frequency and pattern between exo(-/-), exo(+/-) and exo(+/+) mice. The lack of an effect of the pol delta exo mutation on SHM could be due to: (i) normally pol delta is used in SHM, but the exo is prevented from proofreading, (ii) normally pol delta is used, but the decrease in fidelity of the exo(-) pol does not increase hypermutation frequency enough to be detected, and (iii) pol delta is not used in SHM. Based on the finding in the exo(-/-) mice and the current understanding of the process of SHM, it is concluded that pol delta is not normally involved in creating the mutations. The majority of the mutated sequences obtained in this study, including many from the exo(-/-) mice, were from genes which had switched to a gamma heavy chain class. Thus, the pol delta proofreading activity is not required for class switch recombination (CSR). Genealogical trees observed with multiple mutated sequences of various Ig classes show that CSR and SHM occur intermingled during expansion of a cell clone, raising the possibility that they may occur at the same time.

Animals↗
PubMed2003

Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification.

The purpose of this study was to investigate whether Her-2/neu expression at diagnosis of osteosarcoma could provide biologic and prognostic information that predicts the risk of pulmonary metastases and outcome. Human epidermal growth factor (Her-2/neu) expression in 25 initial pretreatment osteosarcoma biopsies and 12 posttreatment pulmonary metastatic osteosarcoma resection specimens was assessed by standard immunohistochemical techniques on formalin-fixed paraffin-embedded tissue. As a screening analysis to determine if gene amplification may be a mechanism for increased Her-2/neu expression, FISH analysis was conducted on seven Her-2/neu immunostain-positive samples and five Her-2/neu immunostain-negative samples. Cytoplasmic Her-2/neu reactivity was identified in 11/25 (44%) of primary tumors and in 7/12 (58%) resection specimens from pulmonary metastases. Cytoplasmic Her-2/neu expression was associated with shorter overall metastasis-free survival. Her-2/neu gene amplification was identified by FISH analysis in six of the seven immunostain-positive samples but was also identified in two of the five immunostain-negative samples. Her-2/neu expression in patients with osteosarcoma is associated with an increased risk of metastasis and may define a subset of patients with a more aggressive tumor phenotype. Her-2/neu gene amplification may provide a mechanism for Her-2/neu overexpression in certain cases of osteosarcoma. Whether Her-2/neu expression influences outcome needs to be examined further in a prospective fashion. The hope is that Her-2/neu expression will identify patients who may benefit from the addition of directed biologic therapy.

Adolescent↗
PubMed2003

Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer.

OBJECTIVES: Recombinant tissue plasminogen activator, alteplase, began to be commonly used to restore the patency of occluded central venous catheters (CVCs) as urokinase production was halted in the late 1990s. However, alteplase often requires an extended dwell time to restore patency to occluded CVCs. In adults, reteplase, a newer thrombolytic agent, has been reported to restore patency to CVCs in 30 minutes. The authors prospectively evaluated the safety and efficacy of reteplase in restoring patency to occluded CVCs in children with cancer. METHODS: This was a dose escalation trial. The dose of reteplase was initiated at 0.1 units and increased by increments of 0.1 units to a maximum dose of 0.4 units. Each dose was tested on at least three participants. Time to patency after reteplase administration was recorded by nurses caring for the patients. Attempts to access the line occurred every 15 minutes for 1 hour. CVCs that remained occluded after 1 hour were treated with alteplase. RESULTS: Reteplase was administered to 15 clotted CVCs. Twelve of the 15 were cleared with an average dwell time of 38 minutes. The time to patency did not appear to correlate with the dose. No adverse events were reported. CONCLUSIONS: Reteplase can restore patency to occluded CVCs in a pediatric population. Reteplase appears to have comparable efficacy with alteplase, but reteplase may require shorter dwell times. A prospective, randomized, clinical trial is warranted to determine whether reteplase is as effective as alteplase in restoring patency to occluded CVCs.

Adolescent↗
PubMed2002

High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading.

Mutations are a hallmark of cancer. Normal cells minimize spontaneous mutations through the combined actions of polymerase base selectivity, 3' --> 5' exonucleolytic proofreading, mismatch correction, and DNA damage repair. To determine the consequences of defective proofreading in mammals, we created mice with a point mutation (D400A) in the proofreading domain of DNA polymerase delta (poldelta, encoded by the Pold1 gene). We show that this mutation inactivates the 3' --> 5' exonuclease of poldelta and causes a mutator and cancer phenotype in a recessive manner. By 18 months of age, 94% of homozygous Pold1(D400A/D400A) mice developed cancer and died (median survival = 10 months). In contrast, only 3-4% of Pold1(+/D400A) and Pold1(+/+) mice developed cancer in this time frame. Of the 66 tumors arising in 49 Pold1(D400A/D400A) mice, 40 were epithelial in origin (carcinomas), 24 were mesenchymal (lymphomas and sarcomas), and two were composite (teratomas); one-third of these animals developed tumors in more than one tissue. Skin squamous cell carcinoma was the most common tumor type, occurring in 60% of all Pold1(D400A/D400A) mice and in 90% of those surviving beyond 8 months of age. These data show that poldelta proofreading suppresses spontaneous tumor development and strongly suggest that unrepaired DNA polymerase errors contribute to carcinogenesis. Mice deficient in poldelta proofreading provide a tractable model to study mechanisms of epithelial tumorigenesis initiated by a mutator phenotype.

Amino Acid Sequence↗