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Biomedical subjects

P Rubin

Publications and source records attributed to P Rubin.

At least 55 records · Page 3Linked to original sources
PubMed1999

The molecular and cellular biologic basis for the radiation treatment of benign proliferative diseases.

Since its discovery, radiation has been used to treat numerous ailments, including many benign conditions. The most susceptible disorders have included keloids, heterotopic bone formation, and, most recently, vascular restenosis. These disorders are proliferative in nature and fall under the category of excessive wound healing or scar formation after trauma. In addition, radiation has been used for its immunosuppressive quality, eg, in organ transplantation to suppress graft rejection and in the treatment of autoimmune diseases. In this article, we have chosen keloids as an archetype for radiation use with benign conditions; the radiation inhibition of vascular restenosis will be used as a prototype to explore a paradigm for the molecular and cellular basis of radiation treatment for selected benign disorders. Vascular restenosis is currently one of the new frontiers of radiation therapy and offers opportunities to explore the role of inflammatory or immune cell responses in benign conditions that lead to excessive fibrogenesis and require treatment. The pathophysiology of surgical wound healing has not been avidly studied in the radiobiologic laboratory setting. However, the paradigm we propose for the effectiveness of radiation treatment for benign conditions is based on the model offered by Clark. He describes three phases of molecular and cellular events in which an inflammatory phase precedes the fibrogenic phase, occurs within hours of injury, and continues for weeks. We postulate that the radiosensitive targets within the vascular milieu are the monocyte/macrophages that would otherwise act as the trigger for the induced cytokine cascade, leading to the myofibroblast being recruited from a quiescent to a proliferative phase, resulting in fibrogenesis.

Constriction, Pathologic↗
PubMed1999

Circulating basic fibroblast growth factor declines during Cy/TBI bone marrow transplantation.

Basic fibroblast growth factor (bFGF) inhibits radiation-induced apoptosis, and radioprotects haematopoietic, cartilage growth plate, pulmonary and gastrointestinal tissues. Conversely, chronic overexpression of bFGF may promote fibrosis. We measured the endogenous circulating bFGF in blood of patients undergoing conditioning TBI. Twenty-six patients with haematopoietic malignancies were conditioned with cyclophosphamide/TBI for allogeneic BMT. Daily blood samples were collected each morning prior to, during, and for several days after TBI. bFGF levels in plasma of normal volunteers are 0.8-26 pg/ml. bFGF was below detectability in 22%, 30% and 45% of patients pre-TBI, during TBI or post-TBI respectively. Mean circulating plasma levels of bFGF decreased from a median of 52 pg/ml pre-TBI to 26 pg/ml during TBI, and to 5 pg/ml post-TBI. Among the 26 patients, 13 had more than one non-detectable plasma bFGF level, an additional five had at least one non-detectable level, and only eight patients had detectable levels in all daily samples. Naturally high levels of bFGF were observed in some patients undergoing fractionated TBI. In contrast, as many as 79% of patients had low bFGF levels in one or more samples. The impact of endogenous bFGF on the tolerance of normal tissues to irradiation is unknown, and warrants further study.

Adult↗
PubMed1999

Tarsal switch procedure for the surgical rehabilitation of the eyelid and socket deficiencies of the anophthalmic socket.

PURPOSE: To describe a tarsal transfer procedure, which we have named the "tarsal switch," to correct the eyelid malpositions and camouflage the socket defects of acquired anophthalmos. METHODS: The technique consists of an upper eyelid tarsectomy, with transfer of the autologous tarsoconjunctival graft to the posterior lamella of the lower eyelid. RESULTS: The operation was performed in 21 anophthalmic patients. In 16 patients with eyelid malpositions, excellent results (within 1 mm of the fellow eye) were attained in 100% of the patients with ptosis, and in 88% of patients with lower eyelid retraction. In the remaining 5 patients, orbital volume loss with secondary implant migration, inferior prosthetic displacement and eyelid asymmetry predominated. In these patients the anophthalmic orbital defects and eyelid asymmetry were masked well. Patient satisfaction was high and complications were few during an average follow-up interval of 16 months. CONCLUSION: The tarsal switch procedure is useful in managing the eyelid malpositions and masking the orbital deficiencies of the anophthalmic socket.

Adult↗
PubMed1999

Cortical brain dysfunction in early schizophrenia: secondary pathogenetic hierarchy of neuroplasticity, psychopathology and social impairment.

Schizophrenia has the quality of a 'top-down' disorder with perturbation of self, and malattuned appraisal of basic experience of the outside world, and of intentionality. There is dissonance between the faculties of consciousness. The neuronal cortical network displays distributed activation of the sensory cortices during perception, and retroactivation during recall. This multimodal organization is sensitive to aberrations of structure and informational content during the metabolically dynamic phases of expansion and pruning in childhood and adolescence. There is substantial evidence of deviant function of the cortical network in schizophrenia. This includes increased neuronal density, reduced prefrontal capacity for activation, impaired fronto-temporal interaction during language production, defect monitoring of inner speech, activation of secondary sensory cortices during hallucinations, reduced cortical and thalamic volume, reduced thalamic activation (filtering) and sensitization of dopaminergic modulation. As a hypothesis the cortical defects lead to secondary causation of abnormalities at the levels of neuroplasticity, symptomatology and social competence. Suggestions for empirical testing are presented for the hypothesis that neocortical defects are primary, thalamic defects secondary and dopaminergic aberrations tertiary in the schizophrenic process. This testing of hypotheses involves prospective studies of patient groups at various ages of onset, as well as comparison of neurobiological measures in remitting vs. treatment-resistant cases.

Cerebral Cortex↗
PubMed1999

Neurological abnormalities in schizophrenic patients: a prospective follow-up study 5 years after first admission.

OBJECTIVE: The aim of this study was to examine the temporal stability of neurological abnormalities in first-episode schizophrenic patients, and to clarify the relationships between such abnormalities and psychopathology. METHOD: A total of 18 schizophrenic patients, 11 non-schizophrenic patients and 10 healthy volunteers were examined neurologically at first admission and 5 years later. RESULTS: A significant increase in the number of neurological abnormalities was seen in schizophrenic patients with genetic predisposition and in patients with a non-remitting course of disease. Birth complications had an impact on the occurrence of neurological abnormalities at first admission. CONCLUSION: The association between a deteriorating course of disease and neurological impairment supports the theory that any possible impairment of the brain in schizophrenia is aggravated during the first 5 years of disease.

Adolescent↗
PubMed1999

Progressive atrophy of the frontal lobes in first-episode schizophrenia: interaction with clinical course and neuroleptic treatment.

OBJECTIVE: This prospective study examined the interaction of clinical course of disease and brain structure with time in schizophrenic patients. METHOD: A total of 21 first-episode schizophrenic patients, 10 patients with other psychiatric disorders and a control group of 9 healthy volunteers had CT at first admission and at reinvestigation 5 years later. RESULTS: At first admission all of the patients had enlarged cortical fissures and sulci compared to controls, and the duration of untreated psychosis was significantly correlated with sulcal enlargement. At reinvestigation, frontal and central brain atrophy had progressed in schizophrenic patients. CONCLUSION: The study indicated that ongoing psychosis and lifetime dose of classical antipsychotics were the main candidates accounting for the finding of progressively disturbed brain structure during the first 5 years of schizophrenia.

Adolescent↗
PubMed1999

Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support.

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci (</= 2 v > 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases (</= 2 v > 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Adult↗
PubMed1999

The right stuff ... meeting your customer needs.

Meeting (and exceeding) your customers' needs is a requirement for competing in the current business world. New tools and techniques must be employed to deal with the rapidly changing global environment. This article describes the success of a global supply chain integration project for a division of a large multinational corporation. A state-of-the-art ERP software package was implemented in conjunction with major process changes to improve the organization's ability to promise and deliver product to their customers.

Commerce↗
PubMed1998

Radiation-induced changes in bone perfusion and angiogenesis.

PURPOSE: To determine whether blood flow of bone is altered by limb irradiation and whether bFGF, an angiogenic cytokine, might alleviate any flow or growth abnormality resulting from 30 Gy single fraction irradiation. METHODS AND MATERIALS: C3H mice received whole right hind limb radiation at doses of 0 to 30 Gy. Additional groups received 30 Gy, and then beginning 1 or 5 weeks later received intravenous bFGF at a dose of 6 microg/mouse, twice a week for 4 weeks. Serial X-ray films were taken to measure the tibias. At 33 weeks, laser Doppler flow (LDF) measurements were made of both limbs. Cytokine measurements were made using ELISA and RNase protection. RESULTS: Bone growth was reduced following radiation in a dose dependent manner. bFGF improved bone growth after radiation even when begun 5 weeks after radiation, however, we detected no significant improvement in LDF of the irradiated bone or periosteum. Muscle tissue surrounding bone of the irradiated leg showed no increase in isoforms of TGFbeta, TNF, or IFN. There was also no difference in the circulating plasma TGFbeta1 in irradiated mice. In contrast, LDF increased significantly as a function of radiation dose in the nonirradiated tibia. Systemic delivery of bFGF appears to further enhance the increase in flow seen in the nonirradiated limb. CONCLUSION: Radiation induces a chronic antiangiogenic effect contributing to reduced limb growth. At 33 weeks the antiangiogenesis was not associated with local soft tissue elevations of TNF, IFN, or TGFbeta. Radiation toxicity to bone is alleviated by bFGF therapy suggesting that powerful locally-acting antiangiogenic mechanisms are involved. We postulate that the increased LDF of the contralateral tibia is due to circulating angiogenesis factors that are elevated to compensate for the radiation-induced antiangiogenesis.

Animals↗
PubMed1998

Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06.

PURPOSE: This study was conducted to see what fraction of prostate cancer patients with biopsy-proven nodes are free of cancer 10 years after radiation treatment. METHODS AND MATERIALS: RTOG protocol #75-06 included 90 patients with biopsy-proven pelvic nodal involvement treated with radiation. They have been continuously follow-up since treatment. When feasible, current prostate-specific antigen (PSA) levels have been solicited from patients clinically cancer-free (no evidence of disease, NED) at 10 years, to confirm cure. RESULTS: The 10-year survival was 29%, the 10-year clinical NED survival 7%. PSA levels were obtained in 2 of 5 10-year clinical NED patients, they were both less than 0.8 ng/ml. The 2 proven cures were both clinical stage T-3, Gleason Score 6 and 8, and had 2 and 1 positive nodes, respectively. Multivariate analysis showed Gleason sum was significantly associated with clinical survival without disease. CONCLUSION: A small fraction of node-positive patients are cured at 10-year follow-up by radiation therapy (2 of 90 with PSA +3 of 90 by clinical endpoints). Innovative treatment programs should be directed at node-positive patients in an effort to improve the fraction cured.

Disease-Free Survival↗
PubMed1998

Cellular and molecular mechanisms of radiation inhibition of restenosis. Part I: role of the macrophage and platelet-derived growth factor.

PURPOSE: The major radiobiological issue in determining the rationale for the use of radiation to inhibit vascular restenosis is the identification of the target cell(s) and/or cytokine(s) responsible for neointimal hyperplasia and vascular remodeling. The central hypothesis of this report is that the macrophage/monocyte and PDGF are key elements in the process of neointimal hyperplasia seen following angioplasty, similar to their role in lesion formation and progression found in atherosclerotic thickening. Specific immunohistochemical and cytochemical stains were applied to a rat carotid model in a temporal series after balloon angioplasty to determine macrophage activity vs. smooth muscle cell proliferation, the latter being classically thought to be the cell responsible for restenosis. METHODS AND MATERIALS: Neointimal hyperplasia was created in an established rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via high dose rate (HDR) brachytherapy, the 192Ir source being placed externally to the vessel. Radiation was delivered to a length of 2 cm of the injured vessel at doses of 5, 10, and 15 Gy, and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with the primary antibodies CD11b, mac-1, anti-PDGF, and alpha-smooth muscle actin. RESULTS: Immediately (24 h) postinjury, there is an apparent migration of macrophages seen in the adventitia; after 1 week, proliferation and migration of macrophages could be seen clearly within all the vessel layers, especially in the intima; by 3 weeks, when there was evidence of neointimal hyperplasia, macrophages could still be seen, mainly in the intima scattered among the smooth muscle cells and myofibroblasts, and to a lesser degree at 6 months. There was corresponding expression of PDGF, whenever and wherever there were zones of activation/neointimal hyperplasia. Alpha-smooth muscle actin staining identified the smooth muscle cells distinct from the macrophages, and these SMCs exhibited activation in the neointimal hyperplasia zones at all later time points. Furthermore, we showed that radiation significantly reduced the macrophage population, while the onset of neointimal hyperplasia was accompanied by a return of the macrophage population. CONCLUSION: Our results suggest that the activated adventitial macrophage/monocyte are the key cells responsible for initiating the arterial neointimal hyperplasia and vascular remodeling developing postangioplasty as they are in the initiation and perpetuation of atheromatous thickening. Irradiation delivered immediately postinjury is, therefore, highly effective, because the macrophage population is exquisitely radiosensitive.

Animals↗
PubMed1998

MR image-guided portal verification for brain treatment field.

PURPOSE: To investigate a method for the generation of digitally reconstructed radiographs directly from MR images (DRR-MRI) to guide a computerized portal verification procedure. METHODS AND MATERIALS: Several major steps were developed to perform an MR image-guided portal verification procedure. Initially, a wavelet-based multiresolution adaptive thresholding method was used to segment the skin slice-by-slice in MR brain axial images. Some selected anatomical structures, such as target volume and critical organs, were then manually identified and were reassigned to relatively higher intensities. Interslice information was interpolated with a directional method to achieve comparable display resolution in three dimensions. Next, a ray-tracing method was used to generate a DRR-MRI image at the planned treatment position, and the ray tracing was simply performed on summation of voxels along the ray. The skin and its relative positions were also projected to the DRR-MRI and were used to guide the search of similar features in the portal image. A Canny edge detector was used to enhance the brain contour in both portal and simulation images. The skin in the brain portal image was then extracted using a knowledge-based searching technique. Finally, a Chamfer matching technique was used to correlate features between DRR-MRI and portal image. RESULTS: The MR image-guided portal verification method was evaluated using a brain phantom case and a clinical patient case. Both DRR-CT and DRR-MRI were generated using CT and MR phantom images with the same beam orientation and then compared. The matching result indicated that the maximum deviation of internal structures was less than 1 mm. The segmented results for brain MR slice images indicated that a wavelet-based image segmentation technique provided a reasonable estimation for the brain skin. For the clinical patient case with a given portal field, the MR image-guided verification method provided an excellent match between features in both DRR-MRI and portal image. Moreover, target volume could be accurately visualized in the DRR-MRI and mapped over to the corresponding portal image for treatment verification. The accuracy of DRR-MRI was also examined by comparing it to the corresponding simulation image. The matching results indicated that the maximum deviation of anatomical features was less than 2.5 mm. CONCLUSION: A method for MR image-guided portal verification of brain treatment field was developed. Although the radiographic appearance in the DRR-MRI is different from that in the portal image, DRR-MRI provides essential anatomical features (landmarks and target volume) as well as their relative locations to be used as references for computerized portal verification.

Brain Neoplasms↗
PubMed1998

Influence of bromodeoxyuridine radiosensitization on malignant glioma patient survival: a retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group trials (RTOG) for glioblastoma multiforme and anaplastic astrocytoma.

PURPOSE: To examine the effect of treatment using Bromodeoxyuridine (BrdU) during radiation therapy on malignant glioma patient survival by comparing historical survival data from several large clinical trials. METHODS: A retrospective analysis of patient data from Radiation Therapy Oncology Group (RTOG) trials 74-01, 79-18, and 83-02 and the Northern California Oncology Group (NCOG) study 6G-82-1 was conducted. Patient data was supplied by both groups, and analyzed by the RTOG. Pretreatment characteristics including age, extent of surgery, Karnofsky Performance Status (KPS), and histopathology were collected; the only treatment variable evaluated was the use of BrdU during radiation therapy. Radiation dose, dose-fractionation schedule, use of chemotherapy, and/or type of chemotherapy was not controlled for in the analyses. Univariate and multivariate analyses were conducted to examine the potential treatment effect of BrdU on patient survival. RESULTS: Data from 334 patients treated with BrdU on NCOG 6G-82-1 and 1743 patients treated without BrdU on 3 RTOG studies was received. Patients were excluded from the review if confirmation of eligibility could not be obtained, if the patient was ineligible for the study they entered, if central pathology review was not done, or if radiotherapy data was not available. Patients treated according to the RTOG studies had to start radiotherapy within 4 weeks of surgery; no such restriction existed for the NCOG studies. To ensure comparability between the studies, patients from the NCOG studies who began treatment longer than 40 days from surgery were also excluded. The final data set included 296 cases from the NCOG studies (89%) and 1478 cases from the RTOG studies (85%). For patients with glioblastoma multiforme (GBM) the median survival was 9.8 months in the RTOG studies and 13.0 months in the NCOG trial (p < 0.0001). For patients with AA the median survival was 35.1 months for the RTOG studies and 42.8 months in the NCOG trial (p = 0.126). Univariate results showed consistent results favoring BrdU among patients over 30 years of age, across the extent of surgery, and for GBM patients. A proportional hazards regression model that included treatment, histopathology, KPS, age, and extent of surgery demonstrated that treatment with BrdU was included in the best model only for the GBM group of patients (risk ratio 0.83). CONCLUSIONS: Because of the heterogeneity of the treatment groups, including potentially important differences in pathology reviewers assessment of nonglioblastoma cases, differences in radiation dose and schedules, and chemotherapy during or after radiation, these analyses cannot provide the definitive answer as to whether BrdU given during radiation therapy improves survival in patients with malignant glioma. There does appear to be a favorable treatment effect seen in patients with GBM, with a lesser effect in patients with AA.

Adolescent↗