Biomedical subjects
Publications and source records attributed to J Garvin.
An international flotilla of spacecraft are to be sent to Mars over the next decade in an effort to understand the planet's geology and climate history, and to determine whether some form of life ever started there. At least two spacecraft will be sent at each launch opportunity, and at times up to four spacecraft may be operating simultaneously at the planet.
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Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.
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PURPOSE: To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. PATIENTS AND METHODS: Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. RESULTS: Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. CONCLUSION: A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.
OBJECTIVE: Pediatric oncology patients who undergo intensive chemotherapy develop anemia caused by myeloid suppression that necessitates transfusions that, in turn, cause iron deposition in the reticuloendothelial system. We describe MR imaging of iron overload in pediatric patients who underwent such chemotherapy and who have solid and hematologic tumors. MATERIALS AND METHODS: The MR appearance of the liver, spleen, and bone marrow was evaluated in 13 children with both solid (n = 10) and hematologic (n = 3) malignant lesions using known criteria for the presence of iron deposition. Findings were correlated with transfusional history, chemotherapeutic regimens, and ferritin levels. RESULTS: MR imaging obtained after chemotherapy and transfusional therapy revealed signs of iron deposition in the liver and spleen, particularly on T2-weighted images. Bone marrow signal intensity varied among patients. Pancreatic signal intensity was normal. Ferritin levels were elevated in all patients. CONCLUSION: Reticuloendothelial system iron deposition present in follow-up MR imaging of pediatric solid and hematologic malignant lesions reflected the intensity of the chemotherapeutic regimen, the degree of myeloid suppression, and the resultant transfusional requirements. Such iron deposition appeared to have no effect on cardiac, liver, or pancreatic function.
Stage IV neuroblastoma is associated with high mortality; an exception are patients whose stage IV status includes distant positive nodes, but no skeletal metastases-stage IVN neuroblastoma. We describe our experience with preoperative MRI in three patients with extensive abdominal neuroblastoma without cortical bony involvement but with unsuspected metastatic involvement to the left supraclavicular (Virchow's) node. We review findings of left supraclavicular nodal spread in five earlier cases of IVN neuroblastoma.
We have recently presented evidence that endogenous nitric oxide (NO) and prostaglandins (PGs) modulate angiotensin II (Ang II) action in microperfused afferent arterioles (Af-Arts). Because flow may be a physiological stimulus of endothelial release of NO and PGs, we tested the hypothesis that flow through the lumen of the Af-Art stimulates the endothelium to produce NO and PGs, which in turn modulate the action of Ang II. We microdissected the terminal segment of an interlobular artery together with two Af-Arts, their glomeruli and efferent arterioles (Ef-Art). The two Af-Arts were perfused simultaneously from the interlobular artery, while one Ef-Art was occluded. Since the arteriolar perfusate contained 5% albumin, oncotic pressure built up in the glomerulus with the occluded Ef-Art and opposed the force of filtration, resulting in little or no flow through the corresponding Af-Art. Thus this preparation allowed us to observe Ang II action in free-flow and non-flow Af-Arts simultaneously. Ang II-induced constriction was weaker in free-flow than non-flow Af-Arts, with the luminal diameter decreasing by 8 +/- 2% and 23 +/- 3% at 10(-9) M, respectively (P < 0.013 free-flow vs. non-flow; N = 9). Disrupting the endothelium augmented Ang II action in free-flow (33 +/- 5.1%; P < 0.01 vs. intact endothelium) but not non-flow Af-Arts (31 +/- 5.3%), thus abolishing the differences between them (N = 8). Pretreatment with an inhibitor of either NO synthase (N-nitro-L-arginine methyl ester) or cyclooxygenase (indomethacin) augmented Ang II action more in free-flow than non-flow Af-Arts, likewise abolishing the differences between them. These results suggest that intraluminal flow modulates the vasoconstrictor action of Ang II in Af-Arts via endothelium-derived NO and PGs. Thus flow may be important in the fine control of glomerular hemodynamics.
PURPOSE: This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS: Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS: Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION: The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.
Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, as an indication of potential hepatotoxicity. However, acute and chronic studies with a limited number of animal models have not demonstrated hepatotoxicity. The present study compared the cytotoxicity in hepatocyte cultures of tacrine with structurally (proflavine and 9-aminoacridine) or pharmacologically similar compounds (physostigmine), as well as structurally modified tacrine to determine if there was a structure activity relationship with regards to toxicity. Cytotoxicity was assessed by determination of extra- and intracellular amounts of lactate dehydrogenase. Cytotoxicity was assessed after a four-hour exposure over a test compound concentration range of 0 to 3 mM. Concentration-dependent cytotoxicity occurred with tacrine and all structurally related compounds. Physostigmine which is pharmacologically similar, but structurally different, did not induce cytotoxicity. Cytotoxic potency did not appear to be related to acetylcholinesterase inhibitory activity, while compounds with acridine structures induced cytotoxicity. Thus, in this in vitro model, cytotoxicity appears to be related to structure and not pharmacological action. Results of this study indicate that compounds structurally related to tacrine are cytotoxic because of the heterocyclic ring structure. Neither unsaturation of an aromatic ring of the heterocyclic compound, amino substitution of the heterocyclic rings, N-hydroxylation of the amino group, nor ring hydroxylation dramatically alter cytotoxicity.
Flow may be a physiological stimulus of the endothelial release of nitric oxide (NO) and prostaglandins (PGs). We tested the hypothesis that pressure-induced constriction of the glomerular afferent arteriole (Af-Art) is modulated by luminal flow via endothelial production of NO. We microdissected the terminal segment of an interlobular artery together with two Af-Arts, their glomeruli (GL) and efferent arterioles (Ef-Art). The two Af-Arts were perfused simultaneously from the interlobular artery, while one Ef-Art was occluded. Since the arteriolar perfusate contained 5% albumin, oncotic pressure built up in the glomerulus with the occluded Ef-Art and opposed the force of filtration, resulting in little or no flow through the corresponding Af-Art. Thus this preparation allowed us to observe free-flow and no-flow Af-Arts simultaneously during stepwise 30-mmHg increases in intraluminal pressure (from 30 to 120 mmHg). Pressure-induced constriction was weaker in free-flow than no-flow Af-Arts, with the luminal diameter decreasing by 11.1 +/- 1.7 and 25.6 +/- 2.3% (n = 30), respectively, at 120 mmHg. To examine whether flow modulates myogenic constriction through endothelium-derived NO and/or PGs, we examined pressure-induced constriction before and after (a) disruption of the endothelium, (b) inhibition of NO synthesis with NW-nitro-L-arginine methyl ester (L-NAME), or (c) inhibition of cyclooxygenase with indomethacin. Both endothelial disruption and L-NAME augmented pressure-induced constriction in free-flow but not no-flow Af-Arts, abolishing the differences between the two. However, indomethacin had no effect in either free-flow or no-flow Af-Arts. These results suggest that intraluminal flow attenuates pressure-induced constriction in Af-Arts via endothelium-derived NO. Thus flow-stimulated NO release may be important in the fine control of glomerular hemodynamics.
BACKGROUND: Extraskeletal mesenchymal chondrosarcoma is a rare tumor characterized by undifferentiated mesenchymal cells with islands of mature hyaline cartilage. Considering all sites, long-term survival is approximately 30%. Only seven cases of orbital mesenchymal chondrosarcoma have been reported. METHODS: The records of three cases of orbital mesenchymal chondrosarcoma treated at the Columbia-Presbyterian Medical Center, and the seven previously reported cases of this tumor were reviewed to determine clinical characteristics and appropriate therapy. RESULTS: Nine of the 10 patients were female; age of onset ranged from 10 to 35 years. Of eight patients with at least 2 years of observation, five survived 5 or more years after resection, or after resection plus adjuvant therapy. Two patients died of metastatic disease 2 and 5 years, respectively, after the initial treatment, and one died of pneumonia 6 months after surgery. Review of the histology of the three cases treated at Columbia-Presbyterian Medical Center did not identify distinct histologic types that might guide therapy. Presenting symptoms were typical of symptoms of an orbital mass: proptosis, pain, diplopia, change in visual acuity, ptosis, and tearing. CONCLUSION: The small number of reported cases of mesenchymal chondrosarcoma of the orbit prevents definitive conclusions, but it appears that resection is adequate therapy in some cases. Extraskeletal mesenchymal chondrosarcoma of the orbit may have a better prognosis than tumors in other sites.
OBJECTIVE: To investigate the possibility that neuroepithelial tumors in Turcot's syndrome are caused by pleiotropic mutations in the gene for adenomatous polyposis coli (APC), a tumor-suppressor gene implicated in colonic cancer. METHODS: We studied the inheritance patterns of genetic markers for the chromosome 5q21 region in 12 members of a Turcot's syndrome kindred with five affected members. We performed linkage analysis to detect linkage between the disease phenotype and DNA markers. RESULTS: Marker D5S346, located 30 to 70 kilobases from the APC locus, showed evidence highly suggestive of linkage to the disease phenotype (lod score = 1.92). CONCLUSIONS: The data provide evidence that the tumor-suppressor gene implicated in APC and sporadic colon cancers may also cause malignant neuroepithelial tumors in Turcot's syndrome.
Cervical neuroblastoma, a disease primarily of infants, has a favorable prognosis. Eleven patients are reported. Clinical presentations (other than mass) included stridor and swallowing problems. Masses when felt were commonly mistaken for infectious adenitis. Imaging studies (US, CT, MRI) showed solid masses with vascular displacement and narrowing; intraspinal extension was absent though extension into the adjacent sites of mediastinum and skull occurred. Horner syndrome was seen in five patients with accompanying heterochromia iridis in one. Five tumors had calcification. A high index of suspicion will lead to biopsy and less delay in diagnosis once a mass is felt or imaged.
Invasive embryonal rhabdomyosarcoma of the prostate often extends superiorly into the bladder base requiring partial cystectomy as part of excision of the primary tumor. Three patients were studied with ultrasonography CT and MRI and showed the extension of the tumor superiorly and anterior to the bladder in the prevesical space of Retzius. Complete excision with bladder sparing was successful in two of the patients. The imaging of pelvic tumors in children (although well studied with ultrasonography, CT) is helped by MRI in the sagittal plane and/or lateral films of intravenous pyelograms and cystograms to establish the relation of the tumor to the bladder.
Abdominal neuroblastoma is reviewed in terms of its diagnosis, including in utero, at birth, and through infancy into childhood. Age at diagnosis remains the best predictor of survival, with infants under 1 year of age having almost 100% cure. Ultrasonography and magnetic resonance imaging (MRI) are the recommended diagnostic modalities to stage the abdominal primary, although computed tomography (CT) (including myelography) is still widely and efficiently used. Examples are given of each stage.
The effects of endothelin on fluid and bicarbonate absorption and Na+/K+ ATPase activity in the proximal straight tubule were investigated. During the control period, fluid absorption was 0.59 +/- 0.03 nL/mm.min when tubules were perfused at 4.76 nL/mm.min. After treatment with 10(-9) M endothelin, fluid absorption fell to 0.36 +/- 0.06 nL/mm.min when perfused at a similar flow rate. During the control period, bicarbonate absorption was 67.9 +/- 3.6 pmol/mm.min. After treatment with endothelin, it fell to 42.8 +/- 4.3 pmol/mm.min, an inhibition of 38%. To test whether inhibition of fluid and bicarbonate absorption was due to suppression of Na+/K+ ATPase activity, the effect of endothelin on pump activity was investigated. In control tubules, Na+/K+ ATPase activity was 85 +/- 5 pmol/mm.min. In endothelin-treated tubules, Na+/K+ ATPase activity was 68 +/- 4 pmol/mm.min, a reduction of 20%. From these data, it was concluded that endothelin inhibits fluid and bicarbonate transport in the proximal tubule and that this inhibition is in part due to suppression of Na+/K+ ATPase activity.
The authors determined the levels of N-myc oncogene amplification and RNA expression in three infants with metastatic neuroblastoma. By clinical staging Patients 1 and 2 were Stage IV-S, a disease with limited metastatic potential and generally favorable outcome; Patient 3 was Stage IV. Southern blots of chromosomal DNA showed normal N-myc copy number in the primary tumor of Patient 1, extensive (200-fold) gene amplification in the primary tumor from Patient 2, and intermediate (100-fold) gene amplification in the primary tumor and metastatic lesions from Patient 3. N-myc RNA was expressed in all of the primary and metastatic tumor tissues tested. The level of N-myc RNA expression roughly corresponded to the extent of N-myc gene amplification in Patients 2 and 3 and was overexpressed from a single N-myc gene copy in Patient 1. N-myc gene amplification and RNA expression levels were approximately the same in the primary and metastatic lesions for each of the patients tested. The two patients with N-myc gene amplification had a poor outcome, but the patient with normal N-myc gene copy number had no evidence of disease. Despite the clinical picture in Patient 2 of Stage IV-S neuroblastoma, the pattern of N-myc amplification and expression more closely resembled that of Patient 3 (Stage IV neuroblastoma) than that of Patient 1 (bona fide Stage IV-S neuroblastoma).