Sequestration and release of basic fibroblast growth factor.
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Animals↗
Biomedical subjects
Z Fuks
Publications and source records attributed to Z Fuks.
Impact of adjuvant radiation on the patterns and rate of relapse in advanced-stage Hodgkin's disease treated with alternating chemotherapy combinations.
The role of adjuvant radiation therapy (RT) in the management of advanced-stage Hodgkin's disease (HD) was analyzed in 222 patients who attained a complete remission (CR) with alternating chemotherapy combinations. Mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) or MOPP/ABV alternating with the lomustine, melphalan, and vindesine combination (MOPP/ABV/CAD) were similarly effective in inducing a CR in 222 of 270 (83%) patients. These patients were scheduled to receive consolidative RT to bulky disease or other critical sites of initial nodal involvement to a total dose of 2,000 cGy, with an optional additional boost of 1,000 cGy. However, only 125 (56%) patients received radiation to all initial nodal sites of disease. In 69 (31%) patients, only selected nodal sites were included in the radiation fields, and 28 (13%) did not receive any RT. Of the 222 CR patients, 42 (19%) relapsed during a median follow-up period of 6.5 years (range, 2 to 15 years). Of these, 26 (62%) patients relapsed exclusively in unirradiated nodal sites, six (14%) within irradiated sites, and 10 (24%) both within and outside irradiated fields. The actuarial 10-year relapse-free survival (RFS) and overall survival (OS) for patients receiving radiation to all initially involved nodal sites were 89% and 94%, respectively, compared with 68% and 71% (P less than .0001) for patients who had only partial or no RT. Cox proportional hazards regression analysis showed that RT to all sites of initial disease was the most significant independent covariate (P less than .005) affecting RFS and OS. These data demonstrate that residual microscopic disease is relatively frequent in patients with apparent CR after alternating combination chemotherapy, and that irradiation of all sites of initial nodal involvement decreases relapse and improves survival in advanced-stage HD.
Actuarial Analysis↗
Three-dimensional conformal treatment: a new frontier in radiation therapy.
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Dose-Response Relationship, Radiation↗
Delayed central nervous system (CNS) radiation in childhood CNS acute lymphoblastic leukemia. Results of a pilot trial.
With the introduction of effective prophylactic central nervous system (CNS) therapy in childhood acute lymphoblastic leukemia (ALL), the incidence of CNS relapse has been significantly reduced. Nonetheless, there is a continuing need for effective CNS therapy for the 5% to 10% of children who escape prophylaxis and in whom active CNS disease develops. In July 1985, a pilot study was initiated whereby the consolidative CNS treatment, given in the form of craniospinal axis radiation, was delayed and administered after delivery of a prolonged course of intensive systemic and CNS chemotherapy. Ten leukemic patients with CNS relapse were treated according to this pilot study. One patient did not respond to pre-CNS consolidative therapy and died at 2 months with progressive disease. The remaining nine patients have completed the craniospinal axis radiation. Five patients are off all therapy and remain in remission at a median time of 38 months (range, 31 to 46 months). Two patients are near completion of therapy and are disease-free at 22 and 24 months. Testicular relapse occurred in two patients at 14 and 29 months. CNS chemotherapy, as used in this trial, appears to have allowed for a delay in the administration of the consolidative craniospinal radiation without negatively affecting the CNS remission rate or duration. In turn, this delay has allowed for the uncompromised delivery of intensive multiagent systemic chemotherapy, as well as the separation of those patients destined to early systemic relapse from those who will achieve a sustained complete remission. In both cases, a reduction in the need for multiple courses of potentially toxic CNS therapy as a result of CNS reseeding after radiation is anticipated.
Adolescent↗
Maintenance on extracellular matrix and expression of heparanase activity by human ovarian carcinoma cells from biopsy specimens.
A routine procedure has been developed for the isolation and maintenance in culture of human ovarian carcinoma cells derived from biopsy specimens. Cell attachment, plating efficiency and initial outgrowth were greatly improved by seeding the cells on a basement-membrane-like extracellular matrix (ECM) deposited by cultured corneal endothelial cells. These effects were most significant in serum-free conditions which markedly reduced the rate of cell attachment and growth on regular tissue culture plastic. In 60-80% of the cases and regardless of the patient's age, cells cultured on ECM in the absence of serum divided actively and formed a tightly packed epithelial cell monolayer. Fibroblast overgrowth and cell detachment often occurred on ECM in the presence of serum. Incubation of the human ovarian carcinoma cells with sulfate-labelled ECM, resulted in the release of heparan sulfate degradation fragments, 4- to 7-fold smaller than intact heparan sulfate side chains. This degradation was brought about by endoglycosidase (heparanase) activity expressed to a higher extent by cells that were first maintained in primary cultures as compared with cell aggregates taken directly from the biopsy specimen. In most cases, cells derived from metastatic tumors expressed a higher heparanase activity than cells from the primary ovarian tumor. This result corroborates previous studies, performed with cell lines, on the possible involvement of heparanase in tumor cell invasion and metastasis.
Autoradiography↗
Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis.
Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a solid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM produced in vitro and in basement membranes of the cornea and blood vessels in vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.
Animals↗
125iodine reimplantation for locally progressive prostatic carcinoma.
We treated 13 patients with a second 125iodine implant for local recurrence of prostatic carcinoma. All patients had biopsy proved palpable recurrence without evidence of distant metastases. Full doses of irradiation were used (median matched peripheral dose 170 Gy.). Six patients had complete regression of palpable recurrence, 2 had partial regression, 2 had no apparent response and 3 were unevaluable for local response. Actuarial freedom from local disease progression at 5 years was 51%. Despite a relatively high rate of local disease control the actuarial rate of distant metastases reached 100% at 6 years after reimplantation. There were 2 severe rectal complications and 4 instances of mild to moderate urinary incontinence among the 13 patients. Local regression of recurrent prostatic carcinoma may be achieved with 125iodine reimplantation but most patients still had distant metastases.
Brachytherapy↗
Beneficial effects of x-irradiation on recovery of lesioned mammalian central nervous tissue.
We examined the potential of x-irradiation, at clinical dose levels, to manipulate the cellular constituents and thereby change the consequences of transection injury to adult mammalian central nervous tissue (rat olfactory bulb). Irradiation resulted in reduction or elimination of reactive astrocytes at the site of incision provided that it was delivered within a defined time window postinjury. Under conditions optimal for the elimination of gliosis (15-18 days postinjury), irradiation of severed olfactory bulbs averted some of the degenerative consequences of lesion. We observed that irradiation was accompanied by prevention of tissue degeneration around the site of lesion, structural healing with maintenance of the typical cell lamination, and rescue of some axotomized mitral cells (principal bulb neurons). Thus radiation resulted in partial preservation of normal tissue morphology. It is postulated that intrusive cell populations are generated in response to injury and reactive astrocytes are one such group. Our results suggest that selective elimination of these cells by irradiation enabled some of the regenerative processes that are necessary for full recovery to maintain their courses. The cellular targets of these cells, their modes of intervention in recovery, and the potential role of irradiation as a therapeutic modality for injured central nervous system are discussed.
Animals↗
Radiation therapy for locally advanced breast cancer: prognostic factors and complication rate.
A retrospective analysis was carried out in 100 patients with locally advanced breast cancer without distant metastases treated by radiotherapy between 1960 and 1979. The primary tumor was irradiated to a total dose of 60 Gy in 76 patients and to doses ranging between 60 and 80 Gy in 24 patients. The regional lymphatics were treated with doses between 50 and 60 Gy. Following radiotherapy, chemotherapy was administered to 58 patients and hormonal therapy to 29, while 13 patients received no further therapy. Locoregional recurrences were documented in 29% and distant metastases in 49% of patients. The actuarial survival was 56% at 5 years, 21% at 10 years and 14% at 15 years. At 10 years 90% of the surviving patients had some degree of radiation damage.
Adult↗
Expression of basic fibroblast growth factor in normal human tissues.
The distribution of basic fibroblast growth factor (bFGF) was studied immunohistochemically in fresh frozen sections of normal human tissues. Immunodetection was performed with a specific anti-bFGF mouse monoclonal antibody that was found to react with recombinant human bFGF in Western blot analysis, and to specifically neutralize the mitogenic activity of bFGF on bovine vascular endothelial cells. Expression of bFGF on normal human tissues was ubiquitously detected in the basement membranes of all size blood vessels, but was not found in epidermal or epithelial basement membranes of a variety of tissues tested. Intensity and patterns of localization in blood vessels was consistent in various tissues, but varied among different regions of the vascular bed. Whereas homogeneous and intense immunoreactivity were observed in large and intermediate size blood vessels, heterogeneity of expression was found in capillaries. The most intense immunoreactivity was observed in branching capillaries. Endothelial cell staining was heterogeneous and varied in different regions. Strong staining for bFGF was also found in cardiac muscle fibers, smooth muscle cells of mid-size blood vessels, the gut and the myometrium, in central nervous system neurons and cerebellar Purkinje cells, and on epithelial cells of the bronchi, colon, endometrium, and sweat gland ducts of the skin. The presence of bFGF in the extracellular compartment of a diverse variety of organs may play a role in angiogenesis. However, the function of bFGF in parenchymal cells remains to be determined.
Adult↗
Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells.
The effects of radiation on the release of mitogenic factors into the media of cultured endothelial cells of bovine, porcine, and human origins were studied. Although unirradiated controls revealed a significant background activity, single doses of irradiation (20-60 Gy) resulted in a dose-related increased release of growth factor activity, measured by the mitogenic effects of the conditioned media on both 3T3 mouse fibroblasts and unirradiated endothelial cells serving as target cells. Receptor binding competition assays for the platelet-derived growth factor receptor revealed that 12-28% of the total mitogenic activity was due to platelet-derived growth factor-like mitogens. Mitogenic assays using endothelial cells and specific antibody mediated inhibition assays suggested that another component of the mitogenic activity was due to a fibroblast growth factor-like factor. Although radiation resulted in a significant increase in cell death, the enhanced growth factor activities did not appear to result from cell lysis-related leakage of intracellular stores of growth factor. Instead, our data suggest that the growth factors were synthesized de novo and secreted at elevated levels by the cells which maintained postradiation a high level of metabolic activity. Time course studies demonstrated that the growth factors accumulation in the conditioned media started within the first 24 h after radiation and reached a plateau within 72 h after treatment. Radiation-induced release of endothelial cell-derived growth factors may be involved in the pathogenesis of both early vascular damage and the late fibrosis which represents a prominent feature of late radiation damage in normal tissues.
Animals↗
Reduced incidence of the somnolence syndrome in leukemic children with steroid coverage during prophylactic cranial radiation therapy. Results of a pilot study.
Chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL) include a remission induction period with high, daily doses of prednisone among other agents. A period of central nervous system (CNS) prophylaxis follows, during which steroids are often tapered entirely before cranial radiation (CRT) is completed or even initiated. The somnolence syndrome (SS) has been described 4 to 6 weeks after completion of CRT in up to 60% of the children with doses as low as 1800 cGy. A pilot study of continuous steroid coverage during CRT in childhood ALL was conducted. From July 1984 to July 1986, 38 children entered on Children's Cancer Study Group ALL protocols received CRT of 1800 cGy (180 cGy x 10). All patients received oral prednisone throughout the entire course of CRT at daily doses varying from 3.0 to 60.0 mg/m2. The overall incidence of the SS was 13% (five patients). The development of the syndrome was steroid dose-dependent: greater than or equal to 15 mg/m2/d (one of 32 patients), 3% incidence; less than 15 mg/m2 (four of six patients), 67% incidence. The presence of headache during CRT was also steroid dose-related: greater than or equal to 15 mg/m2, one of 32 patients; less than 15 mg/m2, six of six patients. Of the seven patients with headache during CRT, five developed the SS. The two patients (both of the less than 15 mg/m2 group) who did not develop the SS were the only cases treated with increased steroid doses at the onset of headache symptoms. Steroid coverage at a dose of greater than or equal to 15 mg/m2 during CRT appears to significantly reduce the incidence of acute radiation reactions and the SS. A prospective randomized study is planned to confirm these initial findings.
Adolescent↗
New intraoperative brachytherapy techniques for positive or close surgical margins.
Tumors attached or adjacent to critical structures can often not be completely resected or resected with adequate surgical margins. Sites involving major blood vessels, the paravertebral spaces, or critical abdominal structures often present technical difficulties for standard brachytherapy procedures using I-125 or Ir-192 implants. These techniques allow for a high-dose delivery to the tumor bed with minimal normal tissue toxicity. A relatively simple and accurate method is described using I-125 seeds in Vicryl suture threaded through Gelfoam. These permanent implant procedures with radioactive I-125 seeds effectively treat small residual tumors or suspicious margins where standard brachytherapy techniques may be unsatisfactory and technically difficult to perform.
Adult↗
Measurement of platelet and megakaryocyte interaction with the subendothelial extracellular matrix.
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Animals↗
Definitive irradiation for localized non-Hodgkin's lymphoma of breast.
A diagnosis of primary non-Hodgkin's lymphoma (NHL) confined to the breast or breast and ipsilateral lymph nodes was biopsy proven in 19 patients who presented to our institution between 1970 and 1984. Four patients were treated with a modified radical mastectomy, and one with chemotherapy only. The remaining 14 patients comprise the basis of this study. All patients were clinically staged. There were 12 patients with 1A-E disease and two with IIA-E disease. All patients were treated with breast radiation. The axillary nodes were included in seven of the patients and two, in addition, received "mantle" irradiation. The majority of the patients received between 3500-4400 cGy, but four received lower doses. One patient, with Stage IIA-E disease, received 6 months of systemic chemotherapy, followed by 3500 cGy to the breast and axilla. Three of the 14 patients relapsed within the treated area, with a local control rate of 78%. One was salvaged with a mastectomy and remains alive and well 15 years after diagnosis. Seven of the 14 patients relapsed distantly, including two with local failures, but only three have died of disease. An additional two patients have died of other causes without evidence of disease, for a survival of 66% at 48 months (Kaplan-Meier Calculations).
Aged↗
Total lymphoid irradiation, high-dose chemotherapy and autologous bone marrow transplantation for chemotherapy-resistant Hodgkin's disease.
Seventeen patients with advanced stage Hodgkin's disease who relapsed or failed to respond to multiple regimens of combination chemotherapy (mostly Mechlorethamine, Vincristine, Procarbarzine, Prednisone and Adriamycin, Bleomycin, Vinblastine, Dacarbazine) were treated with accelerated hyperfractionated total lymphoid irradiation (TLI) and high-dose chemotherapy followed by autologous bone marrow transplantation (AuBMT). Candidates for the protocol did not have prior radiation therapy and had no evidence of bone marrow involvement. Their bone marrow was initially harvested and cryopreserved. The treatment protocol consisted of reinduction with conventional doses of combination chemotherapy followed by boost local field irradiation to areas of residual disease (1500 cGy within 5 days) and total lymphoid irradiation (2004 cGy given in 12 fractions of 167 cGy each t.i.d. delivered within 4 days). The patients were treated with Etoposide (250 mg/m2/day I.V. X 3 days) and high-dose Cyclophosphamide (60 mg/kg/day I.V. X 2 days). Cryopreserved (unpurged) autologous bone marrow was infused 48 hr after completion of chemotherapy. Of the 17 patients treated, four were in relapse and 13 refractory to multiple regimens of combination chemotherapy. Four patients died during the immediate peritransplant period (2--septicemia, 2--pulmonary complications). Of the 13 surviving patients, 12 entered a complete remission and one had a partial remission and died of disease 6 months later. One patient relapsed 5 months after treatment and is currently alive with disease. Eleven patients (65%) are alive with no evidence of disease 4-35 months (median 20 months) following completion of therapy. Treatment with this protocol results in a high rate of complete remission and a potential for long-term disease-free survival in previously unirradiated patients with advanced stage refractory or relapsed Hodgkin's disease who have exhausted conventional modes of chemotherapy.
Adult↗
Treatment of primary unresectable carcinoma of the pancreas with I-125 implantation.
Between January 1 1974 and October 31 1987, 98 patients with biopsy proven unresectable adenocarcinoma of the pancreas were treated with I-125 implants during laparotomy. Presenting symptoms were pain (57 patients), jaundice (45 patients), and weight loss (34 patients). All patients underwent laparotomy and surgical staging. Thirty patients had T1NoMo disease, 47 patients had T2-3NoMo disease, and 21 patients had significant regional lymph node involvement (T1-3N1Mo). The surgical procedure performed was biopsy only (16 patients), gastric bypass (36 patients), biliary bypass (49 patients), and partial or total pancreatectomy with incomplete resection (5 patients). The total activity and the number of seeds used were determined from the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Stereoshift localization X ray films were taken 3-6 days after operation. The mean activity, minimal peripheral dose (MPD), and volume of the implants were 35 mCi, 13,660 cGy, and 53 cm3, respectively. In addition, 27 patients received postoperative external irradiation and 27 patients received chemotherapy. Postoperative complications were observed in 19 patients. These included post-operative death (1 patient), biliary fistula (4), intraabdominal abscess (4), GI bleeding (3), gastric or small bowel obstruction (6), sepsis (5), and deep vein thrombophlebitis (4). Pain relief was obtained in 37/57 patients (65%) presenting with pain. A multivariate analysis showed that four factors significantly affected survival: T stage, N stage, administration of chemotherapy, and more than 30% reduction in the size of the implant on follow-up films. The median survival for the entire group was 7 months. A subgroup of patients with T1No stage disease who received chemotherapy survived 18.5 months. The indications for I-125 seed implantation in unresectable carcinoma of the pancreas are discussed.
Adenocarcinoma↗
Palliative hemiskeletal irradiation for widespread metastatic prostate cancer: a comparison of single dose and fractionated regimens.
Between 1986 and 1987 patients with hormone refractory metastatic adenocarcinoma of the prostate were treated with hemiskeletal irradiation. One group of 15 patients was treated with a fractionated regimen of 2500-3000 cGy in 9 to 10 fractions. A second group of 14 patients received a single dose of 600 cGy or 800 cGy depending upon whether the upper or lower hemiskeleton was irradiated. Both groups were similar with respect to their initial Karnofsky performance status and extent of disease. With the exception of one patient in the single dose group, all patients treated achieved complete or partial relief shortly after completion of their respective courses of therapy. Of the patients treated with single dose therapy, 10 of 14 (71%) ultimately needed retreatment in the region initially irradiated because of recurrent bone pain or spinal cord compression. In contrast, only 2 of 15 (13%) of the patients receiving the fractionated treatment course needed retreatment (p = .001). Although the median survival of both groups from the time of initial treatments was similar (10 and 11 months), the median duration for palliation was greater for those patients receiving the fractionated regimen as compared with single dose therapy (8.5 months vs 2.8 months). The incidence of treatment related toxicity was similar for both groups. We conclude that fractionated hemiskeletal radiation is a more effective means of palliation when compared to single dose therapy.
Adenocarcinoma↗