Asymptomatic recurrence detection with surveillance scanning in children with medulloblastoma.

PURPOSE: To assess the utility of surveillance neuroimaging in detecting recurrent disease in patients treated for medulloblastoma. PATIENTS AND METHODS: Records and scans of 59 consecutive patients treated for medulloblastoma between 1984 and 1993 in one institution were retrospectively reviewed. RESULTS: Nineteen of 59 patients had recurrence of tumor, of which 17 were available for this study. Eleven of the 17 recurrent patients were asymptomatic at the time of detection. The median time to recurrence was 13 months (range, 3 to 90). CONCLUSION: Surveillance scanning detected a majority of recurrences before onset of symptoms. Although the outcome of those with recurrent disease remains poor, early detection with minimum disease provides the best setting in which to test newer therapies. Patients and their parents also were more likely to elect pursuing further treatment when relapse was detected asymptomatically.

Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age.

PURPOSE: To test the efficacy of a protocol for poor-risk neuroblastoma that builds on the following: (1) our favorable previously reported results with dose-intensive use of cyclophosphamide; (2) our retrospective analysis of neuroblastoma chemotherapy reports, which supported the value of high-dose cisplatin and etoposide (VP-16); and (3) the Goldie-Coldman hypothesis that rapid cytoreduction plus the use of non-cross-resistant chemotherapy combinations will decrease the risk of drug resistance. PATIENTS AND METHODS: The N6 protocol included seven courses of high-dose chemotherapy plus surgical resection of bulk disease. Courses 1, 2, 4, and 6 consisted of 6-hour intravenous infusions of cyclophosphamide 70 mg/kg/d on days 1 and 2 (ie, 140 mg/kg per course), a 72-hour intravenous infusion of doxorubicin 75 mg/m2 and vincristine 0.1 mg/kg beginning day 1, and vincristine 1.5 mg/m2 intravenous bolus on day 9. Courses 3, 5, and 7 consisted of 2-hour intravenous infusions of VP-16 200 mg/m2/d on days 1 to 3 (ie, 600 mg/m2 per course), and 1-hour intravenous infusions of cisplatin 50 mg/m2/d on days 1 to 4 (ie, 200 mg/m2 per course). Courses were to start after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Response was defined by international criteria. RESULTS: Among 24 consecutive previously untreated patients diagnosed with stage 4 neuroblastoma at more than 1 year of age, 21 patients achieved a complete or very good partial remission; one patient had no evidence of disease except by iodine-131-metaiodobenzylguanidine (MIBG) scan, which was markedly improved; and one patient had resolution of extensive metastatic disease, but still had an incompletely resected primary tumor. The sole patient to have a poor response had clinical features at diagnosis that are atypical for neuroblastoma, namely, 8 years of age and an unknown primary tumor. Severe toxicities included myelosuppression, mucositis, and hearing deficits. CONCLUSION: The N6 approach reliably achieves significant cytoreduction against stage 4 neuroblastoma. This may eventuate in an improved cure rate, since consolidative treatments using myeloablative therapy, immunotherapy, or biologic response modifiers such as cis-retinoic acid are most likely to be effective against minimal residual disease.

Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy.

PURPOSE: To test intensive alkylator-based therapy in desmoplastic small round-cell tumor (DSRCT). PATIENTS AND METHODS: Patients received the P6 protocol, which has seven courses of chemotherapy. Courses 1, 2, 3, and 6 included cyclophosphamide 4,200 mg/m2, doxorubicin 75 mg/m2, and vincristine (HD-CAV). Courses 4, 5, and 7 consisted of ifosfamide 9 g/m2 and etoposide 500 mg/m2 for previously untreated patients, or ifosfamide 12 g/m2 and etoposide 1,000 mg/m2 for previously treated patients. Courses started after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Tumor resection was attempted. Post-P6 treatment options included radiotherapy and a myeloablative regimen of thiotepa (900 mg/m2) plus carboplatin (1,500 mg/m2), with stem-cell rescue. RESULTS: Ten previously untreated and two previously treated patients have completed therapy. The male-to-female ratio was 11:1. Ages were 7 to 22 years (median, 14). The largest masses were infradiaphragmatic (n = 11) or intrathoracic (n = 1). Other findings included serosal implants (n = 11), regional lymph node invasion (n = 8), ascites or pleural effusion (n = 7), and metastases to liver (n = 5), lungs (n = 4), distant lymph nodes (n = 3), spleen (n = 2), and skeleton (n = 2). Tumors uniformly responded to HD-CAV, but there were no complete pathologic responses. One patient died at 1 month from tumor-related Budd-Chiari syndrome. Of seven patients who achieved a complete remission (CR), five remain in CR 9, 12, 13, 33, and 38 months from the start of P6, one patient died of infection at 12 months (autopsy-confirmed CR), and one patient relapsed 4 months off therapy. Of four patients who achieved a partial remission (PR), one remains progression-free at 34 months and three developed progressive disease. Five patients received local radiotherapy: three were not assessable for response, but in two patients, antitumor effect was evident. Four patients received thiotepa/carboplatin: two were in CR and remain so, and two patients had measurable disease that did not respond. CONCLUSION: For control of DSRCT, our experience supports intensive use of HD-CAV, aggressive surgery to resect visible disease, radiotherapy to high-risk sites, and myeloablative chemotherapy with stem-cell rescue in selected cases.

High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing's sarcoma, and undifferentiated sarcoma.

PURPOSE: To improve response and survival rates in patients with high-risk rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma, and undifferentiated sarcoma, we used a short course of induction with multi-agent chemotherapy, hyperfractionated radiotherapy, and surgery when possible. Consolidation was with intensive chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Twenty-six patients (21 with RMS, three with undifferentiated sarcoma, and two with extraosseous Ewing's sarcoma) were entered onto the protocol between June 1990 and March 1994. Induction consisted of ifosfamide, etoposide, doxorubicin, dactinomycin, cyclophosphomide, and vincristine, and a split course of hyperfractionated radiotherapy. Patients who attained a complete response (CR) or good partial response (GPR) received consolidation with high-dose melphalan and etoposide followed by ABMT. RESULTS: Of 26 previously untreated patients 19 (73%) achieved a CR (n=13) or GPR (n=6) at the completion of induction and underwent ABMT. Two-year overall survival (OS) was 56% (95% confidence interval [CI], 36% to 76%) and progression-free survival (PFS) was 53% for the whole group (95% CI, 33% to 73%). CONCLUSION: Consolidation of response by myeloablative chemotherapy was well tolerated. Split-course hyperfractionated radiotherapy did not increase the rate of local control. The results of this short-course therapy were comparable to previous therapies of 1 to 2 years' duration. Induction and consolidation chemotherapy, as well as radiation dose, could be further intensified, since no death due to toxicity occurred among these patients.

High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis.

PURPOSE: To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES). PATIENTS AND METHODS: Thirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support. RESULTS: Of the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data. CONCLUSION: Consolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

18fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer.

PURPOSE: To determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer. PATIENTS AND METHODS: We retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool. RESULTS: Overall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85%, 90%, and 88%, respectively, by FDG PET; 54%, 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET. CONCLUSION: FDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.

Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.

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.

Heterogeneity of metabotropic glutamate receptors in autonomic cell groups of the medulla oblongata of the rat.

Metabotropic glutamate receptors (mGluRs) in the medulla oblongata have been suggested to be involved in the regulation of autonomic function. The aim of the present study was to examine the localization and expression of four types of mGluRs: mGluRla, mGluR2/3, mGluR5, and mGluR7 in the dorsal and ventral autonomic nuclei of the medulla of the rat. The four mGluR subtypes studied were differentially distributed in distinct subnuclei in the nucleus of the solitary tract (NTS). mGluRla immunoreactivity was identified in cell bodies, dendrites, and axonal processes in the intermediate, dorsal lateral, and interstitial subnuclei of the NTS. No mGluRla immunoreactivity was observed in the commissural or medial NTS subnuclei. Immunoreactivity for mGluR2/3 and mGluR5 as observed in fibers and putative axonal processes in the interstitial, intermediate, and dorsolateral subnuclei of the NTS. In contrast, mGluR7 was expressed primarily in fibers and terminals in the central and commissural NTS subnuclei. Expression of mGluR2/3 was clearly evident in cell bodies, dendrites, and axonal processes within the area postrema. The vagal outflow nuclei were also studied. The dorsal motor nucleus of the vagus (DMN) contained mGluRla cell bodies, dendrites, and axonal fibers and light mGluR2/3 processes. Throughout the rostral-caudal extent of the compact and semicompact formation nucleus ambiguus, mGluRla was found in cell bodies and fibers. Within the caudal and rostral regions of the ventral lateral medulla, mGluRla was observed in cell bodies and fibers. Cell bodies containing mGluRla were found adjacent to cells staining positive for tyrosine hydroxylase (TH) in these regions but were not colocalized with the TH staining. However, mGluRla-expressing neurons in the ventral lateral medulla did appear to receive innervation from TH-containing fibers. These results suggest that the mGluRla-expressing neurons within the ventral lateral medulla are predominantly not catecholaminergic but may be innervated by catecholamine-containing fibers. These data are the first to provide a mapping of the different mGluR subtypes within the medulla and may facilitate predictions regarding the function of L-glutamate neurotransmission in these regions.

Tumor and target delineation: current research and future challenges.

In the past decade, significant progress has been made in the imaging of tumors, three dimensional (3D) treatment planning, and radiation treatment delivery. At this time one of the greatest challenges for conformal radiation therapy is the accurate delineation of tumor and target volumes. The physician encounters many uncertainties in the process of defining both tumor and target. The sources of these uncertainties are discussed, as well as the issues requiring study to reduce these uncertainties.

The relationship between the technical accuracy of stereotactic interstitial implantation for high grade gliomas and the pattern of tumor recurrence.

PURPOSE: To correlate the pattern of failure and subsequent survival with the technical accuracy of stereotactic brain tumor implantation. METHODS AND MATERIALS: The patterns of failure of 47 consecutive patients with primary or recurrent gliomas after stereotactic implantation delivering 60 Gy via removable high activity 125I sources were reviewed. When the tumor was covered at all levels by the chosen isodose distribution, the implant was considered to be "ideal." If the coverage was not complete, a numerical description of the volume of tumor outside the isodose was assigned. Criteria for "adequate" and "inadequate" implants were defined. Standard radiographic criteria, with pathologic confirmation in 26 cases, were used to categorize the patterns of failure into the following components: central, peripheral, distant (within the brain parenchyma), leptomeningeal, and spinal. A peripheral failure was scored as being in the "direction of error" when the prescribed isodose did not cover the tumor volume and the subsequent tumor progression was in this region. Survival was calculated from the date of implantation. RESULTS: Of 47 cases examined, 72% had an element of central and/or peripheral failure and 23% had a component of distant or meningeal failure. Among the patients with "adequate" or "inadequate" ("nonideal") implants who had a component of peripheral failure, only 19% were in the "direction of error." All patients with technically "inadequate" implants progressed in both the central and peripheral region. Among the groups who had "ideal," "adequate," and "inadequate" implants; 37%, 70%, and 75%, respectively, underwent reoperation [p = not significant (NS)]. Patients who underwent reoperation had a longer median survival than those who did not; 521 days vs. 298 days, respectively (p = 0.035). For patients with "nonideal" implants, a median survival of 470 days was found for patients undergoing reoperation vs. 184 days for those who did not (p = 0.016). CONCLUSIONS: (a) Patients with "inadequate" implants failed in both the central and peripheral region in all cases. This pattern, while less common in those with "ideal" or "adequate" implants, occurred in the majority of cases. (b) The technical excellence of the implant had no impact on survival. (c) Patients with "nonideal" implants were more likely to have reoperation than those with "ideal" implants, and this intervention was associated with a significant survival advantage.

The potential role of external beam radiation in preventing restenosis after coronary angioplasty.

The potential role of radiation in the prevention of coronary artery restenosis after angioplasty has generated much recent interest. Animal research and pilot clinical efforts have focused primarily on intraluminal methods of radiation delivery. This article reviews the experience to date with external beam radiation in restenosis prevention and suggests issues that should be considered from the standpoint of both external beam and intravascular radiotherapy. External beam radiation can certainly play an effective role in clinical studies of coronary artery restenosis, and a multicenter randomized trial of external beam radiation after coronary angioplasty has been initiated.

Impact of a multileaf collimator on treatment morbidity in localized carcinoma of the prostate.

PURPOSE: To evaluate the effectiveness of variable multileaf collimation, three-dimensional treatment planning, and computer-controlled conformal radiation therapy of prostate cancer. METHODS AND MATERIALS: Two hundred and forty-five patients with locally advanced prostate cancer have completed treatment over a 9-year time span using a multileaf collimator and conformal treatment techniques on the University of Washington cyclotron. All patients had three-dimensional treatment planning with computed tomography scans in the treatment position, and had treatment fields individually shaped to the target volume with a continuously variable multileaf collimator. Treatment was delivered under computer control with network transfer of the multileaf collimator settings from the treatment planning computer to the cyclotron control system. RESULTS: The multileaf collimator combined with three-dimensional treatment planning results in elegant dose distributions. These neuron dose distributions resulted in a reduced local/regional tumor failure rate with no increase in complications when compared to control treatment with photons in a randomized trial. Neutron treatment delivered at other institutions without conformal beam shaping resulted in the same improvement in local-regional tumor control rates, but was associated with a significantly higher normal tissue complication rate than seen with conformal neutron beam delivery techniques (grade 3 and 4 cumulative late normal tissue toxicity rates of 39% vs. 10%, p = 0.0007). CONCLUSIONS: Conformal treatment of prostate cancer using a multileaf collimated neutron beam results in increased local/regional tumor control rates with low normal tissue toxicities. This experience is directly applicable to the conformal treatment of prostate cancer with photons.

Medulloblastoma: long-term results for patients treated with definitive radiation therapy during the computed tomography era.

PURPOSE: We performed a retrospective evaluation of the patterns of failure and outcome for medulloblastoma patients treated with craniospinal irradiation therapy during the computed tomography (CT) era. MATERIALS AND METHODS: The records of 100 patients treated at Memorial Sloan-Kettering Cancer Center between 1979 and 1994 were reviewed. CT scans or magnetic resonance imaging were used to guide surgical intervention and evaluate the extent of resection postoperatively. All patients were treated with conventional fractionation (1.8 Gy/day) and the majority received full-dose neuraxis radiation therapy and > 50 Gy to the primary site. RESULTS: With a median follow-up of 100 months, the median, 5-year, and 10-year actuarial overall survival for the entire group were 58 months, 50%, and 25%, respectively. The median, 5- and 10-year actuarial disease-free survivals were 37 months, 41%, and 27%, respectively. Patients with localized disease (no evidence of disease beyond the primary site) had significantly improved overall (p < 0.02) and disease-free (p < 0.02) survivals compared to those with nonlocalized disease. For patients with localized disease, the 5- and 10-year overall survival rates were 59% and 31%, whereas the disease-free survivals were 49% and 31%, respectively. Disease-free and overall survivals at similar intervals for patients with nonlocalized disease were 29% and 30% (5 years), and 29% and 20% (10 years), respectively. Sixty-four of 100 patients failed treatment. Local failure as any component of first failure occurred in 35% of patients or 55% (35 of 64) of all failures and as the only site of first failure in 14% or 22% (14 of 64) of all failures. For patients presenting with localized disease (n = 68), local failure as any component of first failure occurred in 32% (22 of 68) and in 18% (12 of 68) as the only site. A multivariate analysis showed that M stage was the only prognostic factor to influence overall survival. For disease-free survival, M stage and the extent of resection were prognostic factors. Ventriculoperitoneal shunting and the use of chemotherapy were associated with a poor outcome; however, these results were confounded by the positive impact of chemotherapy in decreasing the risk of extraneural metastases and the use of these therapies in the more advanced patients. CONCLUSION: These long-term follow-up data represent one of the largest series of patients with complete follow-up who were treated with a consistent radiation therapy treatment policy during the CT era. Local failure in patients with localized disease, the persistent risk of late failures, treatment-related toxicity, and the ever-present risk of secondary malignancies demonstrate the limitations of standard therapies. Strategies used to increase the total dose to the primary site should be pursued along with other adjuvant therapies such as intensive chemotherapy.

Neutron radiotherapy for adenoid cystic carcinoma of minor salivary glands.

PURPOSE: To examine the efficacy of fast neutron radiotherapy for the treatment of patients with locally advanced, adenoid cystic carcinoma of minor salivary glands and to identify prognostic variables associated with local control, overall survival, and cause specific survival. METHODS AND MATERIALS: Eighty-four patients having adenoid cystic carcinoma of minor salivary glands were treated with fast neutron radiotherapy during the years 1985-1994. All patients had either unresectable disease or gross disease remaining after attempted surgical extirpation. Seventeen patients had previously received conventional radiotherapy and their subsequent treatment fields and doses for neutron radiotherapy were modified for critical sites (brainstem, spinal cord, brain). Although the median doses (tumor maximum and tumor minimum) only varied by < or = 10%, treatment portals were substantially smaller in these patients because of normal tissue complication considerations. Twelve patients (13%) had distant metastases at the time of treatment and were only treated palliatively with smaller treatment portals and lower median tumor doses (< or = 80% of the doses delivered to curatively treated patients). Seventy-two patients were treated with curative intent, with nine of these having recurrent tumors after prior full-dose radiotherapy. The median duration of follow-up at the time of analysis was 31.5 months (range 3-115). Sites of disease and number of patients treated per disease site were as follows: paranasal sinus-31; oral cavity-20; oropharynx-12; nasopharynx-11; trachea-6; and other sites in the head and neck-4. RESULTS: The 5-year actuarial local-regional tumor control rate for all patients treated with curative intent was 47%. Patients without involvement of the cavernous sinus, base of skull, or nasopharynx (51 patients) had a 5-year actuarial local-regional control rate of 59%, whereas local-regional control was significantly lower (15%) for patients with tumors involving these sites (p < 0.005). In the latter cases, normal tissue injury considerations precluded delivery of the full dose to the entire tumor. Patients with no history of prior radiotherapy (63 patients) had an actuarial local control rate of 57% at 5 years compared to 18% for those (9 patients) who had been previously irradiated with conventional photons (p = 0.018). Eliminating the dose-limiting factors of prior radiation therapy and/or high risk sites of involvement, the 5-year actuarial local-regional control rate for these 46 patients was 63%, with an actuarial cause specific survival rate of 79%. Lymph node status was a predictor of distant metastasis: 57% of node positive patients developed distant metastases by 5 years compared to 15% of patients with negative nodes (p < 0.0005), and patients who had nodal involvement developed distant metastases sooner than node negative patients (p < 0.0001). The 5-year actuarial overall survival and cause specific survival for the 72 patients treated with curative intent were 59% and 64%, respectively. CONCLUSIONS: Fast neutron radiotherapy offers high local-regional control and survival rates for patients with locally advanced, unresectable adenoid cystic carcinomas of minor salivary glands. It should be considered as initial primary treatment for these patients, as well as for other patients in whom surgical extirpation would cause considerable morbidity.

Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer.

PURPOSE: Evidence supports the inclusion of the taxanes in the treatment of breast cancer. A recent randomized trial has shown a survival advantage to the addition of paclitaxel in the adjuvant treatment of node-positive patients. Several studies have suggested diminished local control if adjuvant radiation is delayed, while in vitro and in vivo studies have demonstrated a benefit of concurrent administration of taxanes with radiation. For these reasons, we began in 1995 to administer radiation therapy concurrently with the taxanes in advanced breast cancer. This retrospective review examines the feasibility of such treatment. METHODS AND MATERIALS: Forty-four patients were treated with concurrent radiation and either paclitaxel (29 patients) or docetaxel (15 patients). One patient received both paclitaxel and docetaxel. Eighteen patients were treated for recurrent disease, 9 had received prior radiation. Toxicity was assessed by the RTOG scale for acute and late effects. RESULTS: Concurrent radiation and taxane chemotherapy was well tolerated. Nine patients (20%) experienced Grade 3 acute skin toxicity. This was more likely with docetaxel than paclitaxel (p = 0. 04). Among patients undergoing breast conservation, there were no Grade 3 toxicities. With a median follow-up of 11 months, 1 patient has developed breast fibrosis. CONCLUSION: Concurrent administration of both paclitaxel and docetaxel with radiation resulted in acceptable toxicity. Overall, the acute skin toxicity seen with docetaxel was more pronounced. However, among patients undergoing breast conservation the taxanes were both well tolerated. Further study is necessary to assess the impact of concurrent treatment on long-term outcome.

Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography.

PURPOSE: Recent clinical investigations have shown a strong correlation between pretreatment tumor hypoxia and poor response to radiotherapy. These observations raise questions about standard assumptions of tumor reoxygenation during radiotherapy, which has been poorly studied in human cancers. Positron emission tomography (PET) imaging of [F-18]fluoromisonidazole (FMISO) uptake allows noninvasive assessment of tumor hypoxia, and is amenable for repeated studies during fractionated radiotherapy to systematically evaluate changes in tumor oxygenation. METHODS AND MATERIALS: Seven patients with locally advanced nonsmall cell lung cancers underwent sequential [F-18]FMISO PET imaging while receiving primary radiotherapy. Computed tomograms were used to calculate tumor volumes, define tumor extent for PET image analysis, and assist in PET image registration between serial studies. Fractional hypoxic volume (FHV) was calculated for each study as the percentage of pixels within the analyzed imaged tumor volume with a tumor:blood [F-18]FMISO ratio > or = 1.4 by 120 min after injection. Serial FHVs were compared for each patient. RESULTS: Pretreatment FHVs ranged from 20-84% (median 58%). Subsequent FHVs varied from 8-79% (median 29%) at midtreatment, and ranged from 3-65% (median 22%) by the end of radiotherapy. One patient had essentially no detectable residual tumor hypoxia by the end of radiation, while two others showed no apparent decrease in serial FHVs. There was no correlation between tumor size and pretreatment FHV. CONCLUSIONS: Although there is a general tendency toward improved oxygenation in human tumors during fractionated radiotherapy, these changes are unpredictable and may be insufficient in extent and timing to overcome the negative effects of existing pretreatment hypoxia. Selection of patients for clinical trials addressing radioresistant hypoxic cancers can be appropriately achieved through single pretreatment evaluations of tumor hypoxia.

High-dose chemotherapy with autologous marrow rescue for malignant brain tumors: analysis of the impact of prior chemotherapy and cranio-spinal irradiation on hematopoietic recovery.

The relative impact of age, sex, nucleated cell dose, prior chemotherapy, prior cranio-spinal irradiation (CSI) and bone marrow harvest (BMH) site on hematological recovery after ABMT were analyzed in a multivariate model. The study population comprised 100 patients with a median age of 9 years who underwent ABMT for malignant brain tumors. Two engraftment parameters were evaluated: number of days post ABMT before (1) an absolute neutrophil count (ANC) > or = 0.5 x 10(9)/l and (2) a platelet count > or = 50 x 10(9)/I were achieved for the third consecutive day without transfusions. Increasing cell dose correlated significantly with a more prompt recovery of platelet counts and ANC. Previous chemotherapy significantly delayed both neutrophil and platelet engraftment. The group of patients who also received CSI had a very delayed platelet recovery with a median time to engraftment of 72 days. Neutrophil engraftment was also significantly delayed and occurred at a median of 23 days. This effect of CSI was independent of cell dose or prior chemotherapy. In 20 of these patients, marrow was harvested at least partially from the posterior iliac crests, which might have received significant doses of irradiation. We conclude that engraftment is significantly faster if bone marrow is harvested prior to any chemotherapy administration, and that patients who receive prior CSI may have significant engraftment delay, particularly of the platelet lineage. In this latter group of patients, marrow should not be harvested from the posterior iliac crests. Strategies that might enhance both neutrophil and platelet count recovery should be considered in patients with irradiation damage to a substantial proportion of the total hematopoietic tissue.

Membrane properties of area postrema neurons.

Intrinsic membrane properties, voltage-dependent sodium and voltage-dependent potassium currents of area postrema neurons in culture have been characterized with respect to their voltage dependence, time dependence and sensitivity to specific blocking agents. The area postrema is a hindbrain circumventricular organ which is known to have an important role in the central regulation of cardiovascular function. This study is the first to describe the biophysical properties of ion channels present in rat area postrema neurons. Recordings in current-clamp mode revealed a mean resting membrane potential of -55.0 +/- 1.6 (n = 24) mV and an input resistance of 213.6 +/- 23 M omega. For the 24 neurons tested, the evoked action potential had a mean threshold of 38.8 +/- 2 mV and a mean amplitude of 107.3 +/- 15 mV. Our results show that the area postrema possesses only one principle sodium current which is completely abolished by 5 microM tetrodotoxin (TTX) (n = 28). This current activated near -50 mV and reached peak amplitude at -30 mV. The area postrema does not possess a TTX insensitive sodium current. The area postrema has at least two types of potassium currents. All area postrema neurons studied with tetraethylamonium (TEA) (n = 40) showed the presence of a slowly activating outward current which was present at voltages greater than -40 mV and was blocked by 10 mM TEA. In addition, 75% of the neurons studied (n = 30/40) also showed a rapidly inactivating, 4-AP sensitive IA type current which activated near -30 mV. Angiotensin II attenuated both the peak and the steady-state potassium currents, suggesting that angiotensin II may modulate area postrema activity by inhibiting voltage-gated potassium channels.

Metabotropic glutamate receptor inhibition of visceral afferent potassium currents.

The effects of metabotropic glutamate receptor activation (mGluR) on voltage-gated potassium currents have been characterized in visceral sensory afferent neurons. L-Glutamate is known to be a primary neurotransmitter in visceral afferents which terminate at the level of the nucleus of the solitary tract (NTS). Synaptic communication between these afferents and the NTS has been shown to involve both postsynaptic ionotropic and presynaptic metabotropic glutamate receptor activation. The purpose of the present study was to determine the effects of mGluR activation on voltage-gated potassium currents in visceral sensory neurons. Application of mGluR agonist t-ACPD inhibited both the peak and the steady state voltage-gated potassium current in 39 out of 56 visceral afferent neurons tested (70%) by 22.0 +/- 3 and 22.8 +/- 2%, respectively. Voltage and pharmacological protocols were utilized to isolate the potassium current affected by mGluR activation. Increasing the holding potential from -100 mV to -30 mV only partially attenuated the inhibitory effects of t-ACPD (decreased effect by 11%), suggesting that t-ACPD modulates both a voltage insensitive and a voltage-sensitive potassium current. In addition, 4-aminopyridine (5 microM) was applied to eliminate the 4-AP sensitive transient current. Also, this protocol only partially attenuated the inhibitory effects of t-ACPD (decreased effect by 6.3%), suggesting that mGluR activation inhibits both a 4-AP-sensitive and 4-AP-insensitive potassium current in visceral afferent neurons. Results from this study suggest that mGluRs may regulate visceral sensory afferent neuronal activity through inhibition of voltage-gated potassium channels.

Specific binding of [3H]L-glutamate to cerebellar membranes: evidence for recognition site heterogeneity.

The kinetics of interaction of excitatory amino acid analogues and reputed antagonists with a specific binding site for [3H]L-glutamate, having a Kd of 600 nM, were examined in washed cerebellar membranes incubated at 37 degrees C. Displacement curves were analyzed by an iterative computer program for a non-cooperative two-site competitive inhibition model. L-Glutamate, D-glutamate and D-aspartate exhibited simple, mass action kinetics with Hill coefficients near unity and Kis of 1.1, 9.3 and 23.3 microM, respectively. Quisqualate, ibotenate and cyclopentylglutamate had Hill coefficients less than 0.85 and bound to an high affinity component with KHS of 0.4, 0.8 and 1.7 microM, respectively. Neither N-methyl-D-aspartate nor derivatives of kainate, with the exception of a-keto kainate, had KiS less than 0.1 mM. Linear analogues of glutamate with reputed antagonistic properties all exhibited shallow displacement curves with Hill coefficients less than 0.6 and KHS varying from 0.5 to 6.6 microM. Notably, 2-amino-6-phosphonocaproic acid had negligible affinity for the site in contrast to the valeric and pimelic phosphono analogues. The results indicate that [3H]L-glutamate labels a single class of sites that can be resolved into subpopulations by agonists and antagonists and provide additional evidence of excitatory amino acid receptor heterogeneity.