Biomedical subjects

John H Healey

Publications and source records attributed to John H Healey.

48 records · Page 3Linked to original sources

PubMed2003

PMMA to stabilize bone and deliver antineoplastic and antiresorptive agents.

Antineoplastic and antiresorptive drugs added to polymethylmethacrylate cement may prevent local cancer progression and failure of reconstructive devices used to treat patients with pathologic fractures. We tested the mechanical properties of cement containing various amounts of the drugs and found that as much as 2 g of either doxorubicin or pamidronate can be added to Simplex cement and the cement retains 87% of its compressive and tensile strength after 6 months of wet storage. Approximately 1 mg pamidronate elutes from experimental pellets. One half of the drug elution occurs within the first day in experiments that combined doxorubicin and pamidronate, and within 3 days when pamidronate was the only additive. Cement containing these drugs seems to be strong enough, but its fatigue strength should be tested before using it clinically. Sufficient amounts of the tested drugs elute to have potential biologic activity.

Antineoplastic Agents↗

PubMed2003

Osteogenic and Ewing sarcomas: estimation of necrotic fraction during induction chemotherapy with dynamic contrast-enhanced MR imaging.

Dynamic contrast material-enhanced magnetic resonance (MR) images of primary osteogenic sarcoma (n = 19) and Ewing sarcoma (n = 10) were reviewed in 29 patients undergoing induction chemotherapy before surgery. Histogram distributions containing the initial slope and pharmacokinetic model parameters from individual voxels within each tumor were fitted for each patient. The histogram analysis of initial slope from the tumor correlated well with percentage necrosis as determined at pathologic examination (r = 0.60, P <.001), as did a two-compartment pharmacokinetic model (r = 0.64, P <.001). Both methods predicted tumors with clinically important degrees of necrosis (ie, > or =90%) in a large majority of cases. The ability to determine response to induction chemotherapy by means of noninvasive monitoring of necrotic fraction with perfusion MR imaging methods may provide useful prognostic information and help surgical planning.

Adolescent↗

PubMed2003

Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples.

High-dose methotrexate is a standard component of therapy for high-grade osteosarcoma. Its effectiveness may be limited by intrinsic and acquired resistance. Decreased reduced folate carrier (RFC) expression has been shown in approximately half of osteosarcomas at diagnosis. Mutations and polymorphisms in the RFC gene have been reported in various cell lines. The purpose of this study was to investigate sequence alterations in the RFC gene in osteosarcoma tumor samples. The entire coding region of the RFC gene in samples from 162 osteosarcoma patients was screened by DNA single-stranded conformational polymorphism, followed by direct sequencing of any region with altered mobility. A previously identified polymorphism at cDNA position number 174 of RFC exon 2 was observed. Sixty-one samples (37.6%) were heterozygous with both A/G at this position (His(27)/Arg(27)), 52 samples (32.2%) were homozygous with G (Arg(27)), and 49 samples (30.2%) were homozygous with A (His(27)). Fifteen (9.2%) samples were identified with other RFC sequence variants in exon 2, none of which have been reported. The sequence variants in exon 2 included a G to A substitution at cDNA position 231, a G to A substitution at cDNA position 155, a C to T substitution at cDNA position 114, and a T to C substitution at cDNA position 104, resulting in a serine to asparagine substitution at amino acid 46, a glutamate to lysine substitution at amino acid 21, an alanine to valine substitution at amino acid 7, and a serine to proline substitution at amino acid 4, respectively. A deletion of A at cDNA position 126 resulting in a frameshift was also observed. Some of these variants were observed in multiple samples. Eight samples had altered single-stranded conformational polymorphism patterns in exon 3 that were associated with nucleotide changes that altered the amino acid sequence. All of these RFC sequence variants appeared to be heterozygous. Heterozygous C/T and homozygous C also were observed at RFC cDNA position 790 in exon 3, which does not alter the amino acid coding sequence. This study shows that RFC sequence alterations are frequent in samples from osteosarcoma patients. Additional studies are under way to determine the clinical significance of these sequence alterations and their effect on methotrexate transport and resistance.

Amino Acid Sequence↗

PubMed2003

mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma.

Previous studies have shown that decreased expression of the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR) are associated with intrinsic and acquired methotrexate resistance, respectively, in osteosarcoma (OS). It has also been shown in colorectal cancer that E2F-1 expression correlates with thymidylate synthase (TS) and, to a lesser extent, DHFR expression. To begin to investigate the regulation of DHFR and RFC expression in OS samples, mRNA expression of E2F-1 and E2F-4 were measured in OS tumor samples and related to DHFR, RFC, and TS mRNA expression. Using fluorescent quantitative real-time PCR, 112 human OS patient samples were investigated for potential E2F-1/E2F-4:DHFR, E2F-1/E2F-4:RFC, and E2F-1/E2F-4:TS correlations. The expression ranges for each gene are as follows: DHFR, 0.02-33.13 (median = 0.20); RFC, 0.02-229.13 (median = 1.91); TS, 0.01-9.99 (median = 0.15); E2F-1, 0.05-69.07 (median = 0.52); and E2F-4, 0.24-52.35 (median = 1.45). Spearman correlation coefficients (r(s)) for E2F-1:DHFR, E2F-1:RFC, E2F-1:TS, E2F-4:DHFR, E2F-4:RFC, and E2F-4:TS were calculated to be 0.53, 0.63, 0.60, 0.41, 0.58, and 0.33, respectively (P < 0.001). On the basis of this data, moderate correlations exist between E2F-1/E2F-4 and DHFR, RFC, and TS. These results suggest E2F-1/E2F-4 may play a role in the regulation of RFC expression, which has not been reported previously. The E2F transcription factors are also related to DHFR and TS expression in OS samples, suggesting a possible involvement in methotrexate resistance. Although E2F mRNA levels correlate with DHFR, RFC, and TS mRNA expression, additional experiments are necessary to determine the direct effects of these transcription factors and identify other proteins that may influence this relationship.

Adolescent↗

PubMed2002

Second malignant neoplasms in long-term survivors of osteosarcoma: Memorial Sloan-Kettering Cancer Center Experience.

BACKGROUND: The authors investigated the incidence and relative risk of secondary malignant neoplasms in long-term survivors of osteosarcoma. METHODS: A comprehensive list of 509 patients with primary osteosarcoma treated at our institution between February 1973 and March 2000 was identified. All study patients received chemotherapy and/or surgery on one of six different protocols (T4, 5, 7, 10, 12, and CCG-7921/POG-9351). Chemotherapy was scheduled for up to 40 weeks with some variations in the actual treatment period and consisted of various combinations of the following agents: high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin, and ifosfamide. RESULTS: Secondary malignant neoplasms (SMN) occurred in 14 of 509 patients. Only one had pulmonary metastasis at diagnosis and subsequent multiple recurrences that required thoracotomies and further modification of the chemotherapy regimen. The median age at diagnosis for osteosarcoma was 16.6 years (range, 3.1-74.4 years). The median follow-up was 5.2 years (range, 0.1-25.0 years). The time interval from diagnosis of the primary osteosarcoma to the development of SMN was 1.3-13.1 years (median, 5.5; 95% confidence interval [CI], 3.6-9.6). The most common SMN occurred in the central nervous system (n = 4): anaplastic glioma, meningioma, high-grade glioma, and maxillary astrocytoma. There were two cases of acute myeloid leukemia and one case each of myelodysplastic syndrome, non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, breast carcinoma, and mucoepidermoid carcinoma. The overall 5 and 10-year cumulative incidences of SMNs were 1.4% +/- 1.1% and 3.1% +/- 1.8%. The standardized incidence ratio was 4.6 (95% CI, 2.53-7.78, P = 0.00001) for the cohort and 3.64 (95% CI, 1.82-6.52, P = 0.0007) when patients with a history of retinoblastoma or Rothmund-Thomson syndrome were excluded. CONCLUSIONS: The overall incidence of secondary malignancies in long-term survivors of osteosarcoma was significantly higher than the expected incidence of cancer in the general population. However, the standardized incidence ratios were much lower than those reported for Hodgkin disease and retinoblastoma. Although additional follow-up is warranted, the successes of current treatment regimens consisting of intensive, high-dose chemotherapy in combination with topoisomerase II inhibitors outweigh the risks.

Adolescent↗

PubMed2002

Outcome of primary soft tissue sarcoma of the knee and elbow.

PURPOSE: Concern is frequently raised regarding the tolerance of irradiation over a joint space. The purpose of this study was to determine the outcome in terms of relapse and potential complications in patients with knee and elbow soft tissue sarcoma treated with limb-sparing surgery with or without adjuvant radiotherapy (RT). METHODS AND MATERIALS: A review of our prospective database between June 1982 and December 1999 identified 86 adult patients with primary soft tissue sarcoma arising from the knee (n = 65; 76%) or elbow (n = 21; 24%) treated with limb-sparing surgery. Tumors had high-grade histologic features in 72% and were >5 cm in 48% of patients. Adjuvant RT was given to 46 (54%) of 86 patients. The type of RT was postoperative external beam RT in 63% and brachytherapy in 37%. Of the 46 patients who received RT, 85% (n = 39) had deep, 78% (n = 36) high-grade, and 54% (n = 25) >5-cm tumors. Complications were assessed in terms of wound complications requiring repeated surgery, bone fracture, nerve damage, and joint stiffness. RESULTS: With a median follow-up of 48 months (range 4-175), the 5-year actuarial rate of local control, distant control, and overall survival was 75% (95% confidence interval [CI] 64-85%), 82% (95% CI 73-91%), and 81% (95% CI 71-91%), respectively. The 5-year local control rate for patients who received RT was 80% vs. 71% for those who did not (p = 0.3). The type of RT did not significantly influence the local control rate. Patients treated with external beam RT had a 5-year local control rate of 84% compared with 73% for those treated with brachytherapy (p = 0.4). On multivariate analysis, tumor size >5 cm retained its significance as an independent predictor of poor local control (p = 0.04; relative risk 3; 95% CI 1-6). In addition, high-grade histologic features emerged as an independent predictor of local recurrence (p = 0.02; relative risk 4; 95% CI 1-20). No statistically significant difference was found between the RT and no-RT group in terms of the 5-year actuarial rate of wound reoperation (10% vs. 3%, p = 0.1), bone fracture (3% vs. 5%, p = 0.5), or nerve damage (6% vs. 3%, p = 0.5). Joint stiffness was significantly higher in the RT group (24% vs. 0%, p = 0.001), but this stiffness was severe to moderate in only 2 patients. CONCLUSION: On the basis of the findings of this retrospective review, adjuvant RT seems to be relatively well tolerated despite the inclusion of part of the joint space in the irradiation portal. Joint stiffness was seen more frequently with adjuvant RT, but it was moderate to severe in only a small number of patients.

Adolescent↗

PubMed2002

Soft-tissue flap coverage maximizes limb salvage after allograft bone extremity reconstruction.

Limb salvage after extremity tumor ablation may include the use of allograft bone. The primary complication of this method is infection of the allograft, which can lead to limb loss in up to 50 percent of cases. The purpose of this study is to evaluate the efficacy of primary muscle flap coverage in the setting of allograft bone limb salvage surgery. This study is a prospective review of all patients with flap coverage of extremity allografts over the 10-year period 1991 to 2001. There were 20 patients (11 male and nine female patients) with an average age of 28 years (range, 6 to 72 years). Flap coverage was primary in 16 patients and delayed in four. Delayed coverage was performed for failed wounds that did not have a primary soft-tissue flap. Pathologic findings included osteosarcoma in nine patients, Ewing sarcoma in five patients, malignant fibrohistiocytoma in two patients, chondrosarcoma in two patients, synovial sarcoma in one patient, and leiomyosarcoma in one patient. Allograft reconstruction was performed for the upper extremity in 12 patients and for the lower extremity in eight patients. Flap reconstruction was accomplished with 20 pedicle flaps in 17 patients (latissimus dorsi, 12; gastrocnemius, four; soleus, three; and fasciocutaneous flap, one) and four free flaps (rectus abdominis, three; latissimus dorsi, one) in four patients. All pedicled flaps survived. There was one flap failure in the entire series, which was a free rectus abdominis flap. This case resulted in the only limb loss noted. The follow-up period ranged from 1 to 50 months (average, 12.35 months). At the time of final follow-up, three patients were dead of disease and 17 were alive with intact extremities. The overall limb salvage rate in the setting of bone allograft and soft-tissue flap coverage was 95 percent (19 of 20). Reoperation for bone-related complications was required in 50 percent (two of four) of cases receiving delayed flap coverage compared with 19 percent (three of 16) of patients with primary flap coverage (statistically not significant). The results of this study support the use of soft-tissue flap coverage for allograft limb reconstruction. In this series, no limb was lost in the setting of a viable flap. Reoperation was markedly reduced in the setting of primary flap coverage. Pedicled or microvascular transfer of well-vascularized muscle can be used to wrap the allograft and minimize devastating wound complications potentially leading to loss of allograft and limb.

Adolescent↗

PubMed2002

Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients.

Synovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18;p11;q11), which usually represents either of two gene fusions, SYT-SSX1 or SYT-SSX2, encoding putative transcriptional proteins differing at 13 amino acid positions. Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with SYT-SSX1 tumors, but the study groups were too limited to be conclusive. To address this issue more definitively, we collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6-82) with synovial sarcoma. SYT-SSX1 and SYT-SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT-SSX1 and SYT-SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. Overall survival was significantly better among SYT-SSX2 cases (P = 0.03), among cases localized at diagnosis (P < 0.0001), and among patients with primary tumors < 5 cm in greatest dimension (P = 0.01). Age, sex, histological type, and axial versus peripheral primary site had no impact on overall survival. The impact of fusion type on survival remained significant when stratified for primary tumor size (P = 0.03) but was no longer significant when stratified for disease status at presentation. This may reflect the tendency for patients with SYT-SSX1 tumors to present more often with metastatic disease (P = 0.05). Cox regression identified disease status (P < 0.0001) and primary tumor size (P = 0.04) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors. Within the subset of patients with localized disease at diagnosis (n = 202), the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61% versus 13.7 years and 77%, respectively. Patients whose tumors contained the SYT-SSX2 fusion (P = 0.08) or were smaller (P = 0.12) showed a trend toward better survival by log-rank test, whereas tumor histology had no impact (P = 0.8). In a Cox regression analysis considering all of the factors, SYT-SSX fusion type emerged as the only independent significant factor (P = 0.04) for overall survival within the subset of 133 patients with localized disease at diagnosis who had information on all of the factors. Among other comparisons, there was a strong association of fusion type and morphology (P < 0.001), with almost all of the SYT-SSX2 tumors showing absence of glandular differentiation (monophasic histology) and almost all of the biphasic tumors containing SYT-SSX1. There was also a statistically significant association of fusion type and patient sex (P = 0.03); specifically, the male:female ratio of SYT-SSX1 cases was 1:1, whereas for SYT-SSX2 cases, it was close to 1:2. Overall, SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with localized disease at diagnosis. SYT-SSX fusion type also appears to exert part of its impact on prognosis before presentation through its association with stage at diagnosis. In addition, the associations of SYT-SSX fusion type with patient sex and tumor epithelial differentiation point to interesting mechanistic biological differences.

Adolescent↗

PubMed2002

Resection replantation of the arm for sarcoma: an alternative to amputation.

Resection-replantation for primary malignant tumors of the arm as an alternative to forequarter amputation first was reported in 1995. Segmental resection of the upper arm and replantation of the distal segment to the proximal humerus as an alternative to shoulder disarticulation for a large tumor of the humerus is reported. This procedure provides the patient with an aesthetically acceptable single-segment arm, which is useful for activities of daily living and recreation. There has been no local recurrence or metastasis at 5 years followup.

Arm↗

PubMed2002

Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience.

PURPOSE: Irinotecan is a novel antineoplastic agent that works by inhibiting the enzyme, topoisomerase 1. Although not extensively studied in children, preclinical studies and several phase I trials indicate activity against a variety of relapsed solid tumors when administered on a protracted schedule. This report describes an institutional experience with irinotecan for the treatment of pediatric solid tumors. PATIENTS AND METHODS: Twenty-two heavily pretreated children with multiply relapsed tumors were treated with courses of irinotecan at 20 mg/m2 per day for 10 days [(every day x 5) x 2]. RESULTS: Of the 19 patients evaluable for response, four achieved an objective response, including two complete responses and one partial response among four patients with rhabdomyosarcoma and one additional patient with an undifferentiated sarcoma with rhabdomyoblastic features, and one patient with a fibrosarcoma had stable disease. Among three patients with non-Hodgkin lymphoma, one achieved a partial response and one had stable disease. Diarrhea was the most commonly observed toxicity. CONCLUSION: Irinotecan appears to have promising single-agent activity, particularly against rhabdomyosarcoma. with minimal hematopoietic toxicity, making it ideal for further evaluation in patients at high risk with newly diagnosed disease, particularly in combination with other active agents with nonoverlapping toxicities.

Adolescent↗

PubMed2002

Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma.

PURPOSE: Methylthioadenosine phosphorylase (MTAP) is an enzyme essential in the salvage of cellular adenine and methionine synthesis. The MTAP gene is located in the 9p21 chromosomal region and its loss is frequently associated with deletion of the tumor suppressor genes p15(INK4b) and p16(INK4a). The aim of this study was to investigate the frequency of molecular alterations in MTAP in osteosarcoma. EXPERIMENTAL DESIGN: Samples from patients with high-grade osteosarcoma (n = 96) and three osteosarcoma cell lines (HOS, SaOS-2, and U2OS) were analyzed. Genomic DNA was analyzed for MTAP gene deletions by PCR, RNA expression was measured by semiquantitative reverse transcription-PCR, and the protein levels were measured by immunohistochemistry. RESULT: Deletion of at least one MTAP exon was found in 36 of 96 (37.5%) osteosarcoma patient samples and in one of the three cell lines (HOS). In all cases in which an MTAP gene deletion was observed, there was absence of detectable mRNA and protein. Furthermore, in four osteosarcoma patients, an MTAP deletion which was not evident at diagnosis was detected in subsequent tumor samples. CONCLUSIONS: The MTAP gene is commonly deleted in osteosarcoma patient samples, leading to an absence of mRNA and protein expression; these results indicate that inhibitors of de novo purine synthesis or methionine depletion may be effective as treatments for osteosarcoma patients whose tumors fail to express MTAP.

Adolescent↗

PubMedDate not supplied

Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity.

BACKGROUND: We reviewed single-institution experience using brachytherapy alone for primary high-grade soft tissue sarcoma of the extremity. METHODS: Between July 1982 and September 1997, 202 adult patients with primary high-grade soft tissue sarcoma of the extremity were treated with limb-sparing surgery and adjuvant brachytherapy. All patients underwent complete gross resection, but the margin of resection was microscopically positive in 18% of patients. The median dose of brachytherapy was 45 Gy delivered over 5 days. Tumors located in the shoulder or groin were defined as central location. Complications were assessed in terms of wound complications, bone fracture, and peripheral nerve damage. RESULTS: With a median follow-up of 61 months, the 5-year local control, distant relapse-free survival, and overall survival rates were 84%, 63%, and 70%, respectively. On multivariate analysis, poor local control correlated with shoulder location, positive microscopic margins of resection, and nonshoulder upper extremity site. The 5-year actuarial rates of wound complications requiring reoperation, bone fracture, and grade > or = 3 nerve damage were 12%, 3%, and 5%, respectively. CONCLUSIONS: Adjuvant brachytherapy provides adequate local control and acceptable morbidity that compares favorably with data reported for external beam radiation. Shoulder tumor location was identified as an independent prognostic factor for poor local control, mandating further improvement in the local management of these tumors.

Adolescent↗