Biomedical subjects

G Harsh

Publications and source records attributed to G Harsh.

13 recordsLinked to original sources

PubMed2001

Dose-escalation with proton/photon irradiation for Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial.

PURPOSE: The role of dose escalation with proton/photon radiotherapy in lower-grade gliomas was assessed in a prospective Phase I/II trial. We report the results in terms of local control, toxicity, and survival. MATERIALS AND METHODS: Twenty patients with Grade 2/4 (n = 7) and Grade 3/4 (n = 13) gliomas according to the Daumas-Duport classification were treated on a prospective institutional protocol at Massachusetts General Hospital/Harvard Cyclotron Laboratory between 1993 and 1996. Doses prescribed to the target volumes were 68.2 cobalt Gray equivalent (CGE, 1 proton Gray = 1.1 CGE) to gross tumor in Grade 2 lesions and 79.7 CGE in Grade 3 lesions. Fractionation was conventional, with 1.8 to 1.92 CGE once per day. Eligibility criteria included age between 18 and 70 years, biopsy-proven Daumas-Duport Grade 2/4 or 3/4 malignant glioma, Karnofsky performance score of 70 or greater, and supratentorial tumor. Median age of the patient population at diagnosis was 35.9 years (range 19-49). Ten tumors were mixed gliomas, one an oligodendroglioma. RESULTS: Five patients underwent biopsy, 12 a subtotal resection, and 3 a gross total resection. Median interval from surgery to first radiation treatment was 2.9 months. Actuarial 5-year survival rate for Grade 2 lesions was 71% as calculated from diagnosis (median survival not yet reached); actuarial 5-year survival for Grade 3 lesions was 23% (median 29 months). Median follow-up is 61 months and 55 months for 4 patients alive with Grade 2 and 3 patients alive with Grade 3 lesions, respectively. Three patients with Grade 2 lesions died from tumor recurrence, whereas 2 of the 4 survivors have evidence of radiation necrosis. Eight of 10 patients who have died with Grade 3 lesions died from tumor recurrence, 1 from pulmonary embolus, and 1 most likely from radiation necrosis. One of 3 survivors in this group has evidence of radiation necrosis. CONCLUSION: Tumor recurrence was neither prevented nor noticeably delayed in our patients relative to published series on photon irradiation. Dose escalation using this fractionation scheme and total dose delivered failed to improve outcome for patients with Grade 2 and 3 gliomas.

Adult↗

PubMed2001

Pedicled rhinotomy for clival chordomas invaginating the brainstem.

OBJECT: Clival chordomas are frequently midline lesions whose posterior growth may breach the dura and invaginate the brainstem. This precludes safe delivery of potentially curative high-dose fractionated proton radiotherapy. To avoid this problem, the authors performed pedicled rhinotomy to resect chordomas in 10 patients. METHODS: Pedicled rhinotomy is a midface transnasal route to the intercarotid sella and clivus from the tuberculum sellae to the mid-C-2 level. It involves a lateral rhinotomy incision, osteotomies of nasal bones and cartilage, lateral rotation of the nose, removal of the nasal septum and medial maxillary walls, opening of ethmoid and sphenoid sinuses, and dissection of nasopharynx and oropharynx to expose the clivus and craniovertebral junction. Tumors involving the sella, medial cavernous sinuses, middle and lower clivus, and C-1 arch and dens can be removed even if they traverse the dura. Closure involves dural repair, grafting of fat and split-thickness skin, rotation of a vascularized mucosal pedicle, and reattachment of nasal cartilage. Ten clival chordomas in adult patients were surgically removed via a pedicled rhinotomy approach. Seven patients had previously undergone a total of nine skull base procedures. In eight of the 10 patients, tumors compressing the brainstem were completely removed using this technique. One patient required an additional subtemporal resection of a suprasellar tumor before definitive radiotherapy could be undertaken. No patient sustained any new neurological deficit; in eight patients headache, diplopia, or hemiparesis improved. One patient developed postoperative cerebrospinal fluid leakage and meningitis that were successfully treated with antibiotic agents and shunt placement. CONCLUSIONS: Pedicled rhinotomy provides excellent shallow-field exposure of midline clival chordomas and permits relief of brainstem compression and the postoperative administration of potentially curative proton beam irradiation.

Adult↗

PubMed2001

Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma.

Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.

Adult↗

PubMed2000

Cranial reconstruction for metastatic breast cancer.

All women with advanced breast cancer who are medically stable despite their disease are candidates for tumor extirpation and reconstruction. Advanced breast cancer today is incurable, and many prognostic factors can be used to try to predict a clinical course and response to therapy; however, no guidelines are available. Our case report most likely represents a metastasis to the calvarium with intracranial extension, reported to occur in about 3 percent of primary breast cancer patients. As demonstrated here, tumor ablation with immediate, one-stage reconstruction of large scalp defects is possible without the need for free tissue transfer or a delay in adjuvant therapy. Local tissue rearrangement has been employed for coverage of defects up to 50 percent of the cranium. The resulting donor defects can be closed with split-thickness skin grafts over pericranium. Serial tissue expansion and rearrangement can be used secondarily to replace skin grafts with hair-bearing scalp. Bony defects can be managed with either autogenous or alloplastic materials. Split-calvarial bone grafts can be harvested from the same operative field and cover small to medium-sized defects. Other sources of autogenous grafts include split ribs and iliac bone. Metals, calcium ceramics, and polymers such as methylmethacrylate can be used to cover intracranial contents and restore calvarial contour when defects are large or when autogenous material is not available. Palliation from tumor burden, prevention of pathologic fracture and oncologic emergencies, controlling pain, and enhancing quality of life are the goals of the oncologic and reconstructive surgeons in cases of advanced breast cancer. These goals are becoming even more important as new forms and combinations of chemotherapy, radiation, and gene therapy are extending the life expectancy of women with breast carcinoma.

Adenocarcinoma↗

PubMed1999

Improved delineation of human brain tumors on MR images using a long-circulating, superparamagnetic iron oxide agent.

The purpose of this study was to corroborate experimental findings that long-circulating, superparamagnetic iron oxide contrast agents accumulate at the margins of human brain tumors, thereby improving their delineation on magnetic resonance (MR) images. This limited clinical study examined a total of four patients with brain tumors (three with primary gliomas and one with metastatic melanoma; n = 8 lesions) who were given a pharmaceutical formulation of a superparamagnetic, ultra-small-particulate iron oxide (USPIO, intravenous dose of 1.1 mg Fe/kg). The agent has a characteristically long plasma half-life and is currently undergoing Phase III clinical trials for liver disease (AMI-227, Advanced Magnetics, Cambridge, MA). MR (conventional spin-echo and gradient-echo) images of the brain were obtained before and 12, 24, and/or 36 hours after administration of the agent, with follow-up several weeks later. Twelve to 36 hours after IV administration of the USPIO, both primary and metastatic brain tumors showed readily detectable increases in signal intensity on T1-weighted spin-echo images. Unlike the pattern of enhancement with a gadolinium (Gd) chelate, which occurred immediately and decreased within hours, that with the USPIO occurred gradually, with a peak at 24 hours, and decreased over several days. Whereas the enhancing tumor margin with the Gd chelate blurred with time due to diffusion of the agent, the margin with the USPIO remained sharp, presumably due to the much lower diffusion coefficient (large size) of the particles and partly because of local endocytosis by tumor cells. Compared with Gd chelates, long-circulating, superparamagnetic iron oxide contrast agents can provide prolonged delineation of the margins of human brain tumors on MR images, which has implications for the targeting of diagnostic biopsies and the planning of surgical resections.

Adult↗

PubMed1999

Stereotactic proton radiosurgery.

The technique of stereotactic proton radiosurgery is discussed in depth in this article. The physics of the proton beam in radiosurgery is explained, and the different factors of beam delivery are examined. These key factors (correspondence to shape, accuracy of delineation of volume, correspondence to volume, and accuracy of delivery vary) with each of the radiosurgical techniques, from Gamma Knife surgery to linear accelerator therapy. Clinical series in the use of proton radiosurgery are also presented, with an emphasis on efficacy and uses.

Biophysical Phenomena↗

PubMed1998

The protein tyrosine phosphatase SHP-2 is expressed in glial and neuronal progenitor cells, postmitotic neurons and reactive astrocytes.

In this study we examined the distribution and developmental profile of the src homology 2 (SH2) domain-containing protein tyrosine phosphatase SHP-2 in the mouse brain. We found that SHP-2 is present in both mitotically active and postmitotic cells in the forebrains of embryonic day 12 (E12) mice. In a developmental study extending from embryonic day 12 to adulthood, Western blotting analysis demonstrated equivalent levels of SHP-2 protein at all of the ages examined. Expression of SHP-2 paralleled the level of enzymatic activity at the different developmental periods. In the adult brain SHP-2 was restricted to diverse classes of neurons, while the majority of glial cells did not express detectable levels of protein. However, reactive astrocytes in response to an ischemic brain injury showed SHP-2 immunolabelling. Our data suggest that SHP-2 may play a role in pathways of neuronal and glial progenitor cells, in a broad spectrum of neuronal responses in the adult brain and in the gliotic response to the injury.

Animals↗

PubMed1995

An alternative role for the src-homology-domain-containing phosphotyrosine phosphatase (SH-PTP2) in regulating epidermal-growth-factor-dependent cell growth.

The association of the src homology 2 (SH2) domain-containing tyrosine phosphatase (SH-PTP2) with the activated epidermal growth factor (EGF) and platelet-derived growth factor receptors, as well as the insulin receptor substrate 1 and growth-factor-receptor-bound protein 2 and its intrinsic tyrosine phosphatase activity suggests an important role for this phosphatase in signal transduction. Previous studies have shown a positive role for SH-PTP2 in growth-factor-mediated cell signaling. We show here that SH-PTP2 can also function to negatively regulate EGF-mediated signal transduction in the human glioma cell line SNB19. We demonstrate this by showing that, in SNB19 cells, which lack the ability to proliferate in response to EGF but retain the ability to bind EGF and also activate the EGF receptor as well as allow for the association of SH-PTP2 with the phosphorylated receptor, stable overexpression of an interfering SH-PTP2 mutant can restore the ability of these cells to proliferate in response to EGF.

Amino Acid Sequence↗

PubMed1993

Beta test site report: gamma plan.

We describe our preliminary experience with a beta-test version of the Leksell Gamma Plan (LGP) treatment planning system. During this testing phase we used the LGP system to find an acceptable treatment plan and then transferred coordinates to the KULA system for final calculation. We find that the LGP system offers a fast way of optimizing shot placement and weighting, especially for complex treatments. The ability to display many MR and CT images on screen and to superimpose isodose lines on these images, as soon as the dose distribution has been calculated, allows adjustments to be made more rapidly than with the plotting approach used by the KULA system. This software is in beta-test, and is undergoing modification. Problems relating to our hardware configuration have been addressed with a newer workstation specified for the production system.

Computer Graphics↗

PubMed1990

Two G protein oncogenes in human endocrine tumors.

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Amino Acid Sequence↗

PubMed1990

Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein.

Activating mutations in the gene for the alpha-chain of Gs, the stimulatory regulator of adenylyl cyclase, have been identified in human GH-secreting pituitary tumors. Using the polymerase chain reaction and allele-specific oligonucleotide hybridization, we screened 25 GH-secreting tumors for the presence of the activating mutations. We also reviewed the clinical charts of the patients from whom the tumors were removed. Of 25 tumors, 10 (40%) contained activating mutations. Patients in the mutation-positive group came to surgery with smaller tumors and had lower GH levels. The activating mutations identify a subgroup of GH-secreting pituitary tumors that probably arise from a shared oncogenic mechanism.

Acromegaly↗

PubMed1986

Evidence for rearrangement, amplification, and expression of c-myc in a human glioblastoma.

Amplified cellular genes are frequently manifested in one of two cytologically recognizable forms, double minutes or homogeneously staining regions. Additionally, evidence is accumulating that aberrant expression of cellular genes (including oncogenes) may be mediated by gene amplification. We now describe the amplification and expression of the cellular oncogene c-myc in double-minute-containing cells from a patient with glioblastoma multiforme, and we have shown that the amplification is associated with rearrangement of the c-myc gene. This finding further supports the common association of the myc gene family in neurogenic tumors and provides evidence of myc gene amplification in human brain cancer.

Cell Line↗

PubMedDate not supplied

Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7.

RMP-7, a bradykinin analog, has been shown to selectively open the blood-tumor barrier for the delivery of chemotherapeutic drugs to brain tumors. In contrast to bradykinin, RMP-7 has no hypotensive effects and has been approved for human use. This study was initiated to determine whether RMP-7 would open the blood-tumor barrier to virus vectors encoding tumor-killing genes in an experimental model. The herpes virus vector used, hrR3, which encodes virus thymidine kinase gene and the lacZ reporter gene, is defective in a gene encoding ribonucleotide reductase, replicates selectively in dividing tumor cells and not in postmitotic neural cells. It was determined that an optimum dose of RMP-7 (1.5-3.0 microg/kg over 10-15 minutes) enhanced viral delivery to brain tumors in rats bearing intracranial 9 L gliosarcomas when infused through the carotid artery immediately prior to virus vector application. Maximum expression of the lacZ reporter gene occurred at 3 days after intracarotid infusion. By 8 days, transgene expression was largely confined to tumor foci away from the main tumor mass. Viral delivery was essentially specific to tumor cells, with little transgene expression elsewhere in the brain. Minimal uptake and pathology was noted in the kidney, spleen, and liver. These findings indicate that intracarotid delivery of RMP-7 can augment the selective delivery of virus vectors to brain tumors in an experimental rat model, with the potential for application to human brain tumors.

Animals↗