Quality of life and clinical outcomes in rectal cancer patients treated on a 1.5T MR-Linac within the MOMENTUM study.

Background and purpose: This study assessed quality of life (QoL) and clinical outcomes in rectal cancer patients treated with magnetic resonance (MR) guided short-course radiation therapy (SCRT) on a 1.5 Tesla (T) MR-Linac during the first 12 months after treatment. Materials and methods: Rectal cancer patients treated with 25 Gy SCRT in five fractions with curative intent in the Netherlands (2019-2022) were identified in MOMENTUM (NCT04075305). Toxicity (CTCAE v5) and QoL (EORTC QLQ-C30 and -CR29) was primarily analyzed in patients without metastatic disease (M0) and no other therapies after SCRT. Patients who underwent tumor resection were censored from surgery. A generalized linear mixed-model was used to investigate clinically meaningful (≥10) and significant (P < 0.05) QoL changes. Clinical and pathological complete response (cCR and pCR) rates were calculated in patients in whom response was documented. Results: A total of 172 patients were included, of whom 112 patients were primarily analyzed. Acute and late radiation-induced high-grade toxicity were reported in one patient, respectively. CCR was observed in 8/64 patients (13 %), 14/37 patients (38 %) and 13/16 patients (91 %) at three, six and twelve months; pCR was observed in 3/69 (4 %) patients. After 12 months, diarrhea (mean difference [MD] -17.4 [95 % confidence interval [CI] -31.2 to -3.7]), blood and mucus in stool (MD -31.1 [95 % CI -46.4 to -15.8]), and anxiety (MD -22.4 [95 % CI -34.0 to -10.9]) were improved. Conclusion: High-field MR-guided SCRT for the treatment of patients with rectal cancer is associated with improved disease-related symptom management and functioning one year after treatment.

Patient reported outcomes following MR-guided radiotherapy for prostate cancer: a systematic review and meta-analysis.

PURPOSE: This systematic review provides an overview of literature on the impact of MR-guided radiotherapy (MRgRT) on patient reported outcomes (PROs) in patients with prostate cancer (PC). METHODS: A systematic search was performed in October 2023 in PubMed, EMBASE and Cochrane Library. The PICOS framework (i.e., patient, intervention, comparison, outcome, study design) was used to determine eligibility criteria. Included were studies assessing PROs following MRgRT for PC with sample size >10. Methodological quality was assessed using the ROBINS-I and RoB 2. Relevant mean differences (MD) compared to pre-RT were interpreted using minimal important differences (MID). Meta-analyses were performed using random-effects models. Between-study heterogeneity was assessed using the I2-statistic. RESULTS: Eleven observational studies and one randomized controlled trial (n=897) were included. Nine studies included patients with primary PC with MRgRT as first-line treatment (n=813) and three with MRgRT as second-line treatment (n=84). Substantial risk of bias was found in five studies. EORTC QLQ-C30 and EORTC QLQ-PR25 scores were pooled from three studies, and EPIC-26 scores from four studies. Relevant MDs for the urinary domain were found with the EPIC-26 (MD-10.0 [95%CI -12.0 - -8.1]; I20%) and the EORTC QLQ-PR25 (MD8.6 [95%CI -4.7-22.0]; I297%), both at end-RT to one month follow-up. Relevant MDs for the bowel domain were found with the EPIC-26 (MD-4.7 [95%CI -9.2 - -0.2]; I282%), at end-RT or one month follow-up, but not with the EORTC QLQ-PR25. For both domains, no relevant MDs were found after three months of follow-up. No relevant MDs were found in the general QoL domains of the EORTC QLQ-C30. CONCLUSION: MRgRT for PC results in a temporarily worsening of patient-reported urinary and bowel symptoms during the first month after treatment compared to pre-RT, resolving at 3 months. No clinically relevant changes were found for general QoL domains. These results provide important information for patient counseling and can serve as a benchmark for future studies.

ALLIANCE A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer.

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after neoadjuvant therapy may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes. Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (+/- 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 296 evaluable patients (148 per arm) will provide statistical power of 90.5% to detect an 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse effects. Biospecimens including archival tumor tissue, plasma and buffy coat in EDTA tubes, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Discussion: Building off of data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed the current trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer. Trial Registration: Clinicaltrials.gov ID: NCT05610163 ; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Application of transport phenomena analysis technique to cerebrospinal fluid.

The study of hydrocephalus and the modeling of cerebrospinal fluid flow have proceeded in the past using mathematical analysis that was very capable of prediction phenomenonologically but not well in physiologic parameters. In this paper, the basis of fluid dynamics at the physiologic state is explained using first established equations of transport phenomenon. Then, microscopic and molecular level techniques of modeling are described using porous media theory and chemical kinetic theory and then applied to cerebrospinal fluid (CSF) dynamics. Using techniques of transport analysis allows the field of cerebrospinal fluid dynamics to approach the level of sophistication of urine and blood transport. Concepts such as intracellular and intercellular pathways, compartmentalization, and tortuosity are associated with quantifiable parameters that are relevant to the anatomy and physiology of cerebrospinal fluid transport. The engineering field of transport phenomenon is rich and steeped in architectural, aeronautical, nautical, and more recently biological history. This paper summarizes and reviews the approaches that have been taken in the field of engineering and applies it to CSF flow.

A community-based study of sleep and behaviour problems in 12- to 36-month-old children.

BACKGROUND: While evidence suggests sleep problems are common in young children and linked to behavioural problems, studies of toddlers are rare. This community-based cross-sectional study examined associations between sleep problems and daytime behaviour among 58 children aged 1 to 3 years who attended daycare centres. METHODS: Mothers and daycare providers completed four and three questionnaires, respectively, about children's sleep patterns and behaviour. Two hypotheses were tested: (1) children with higher sleep problem scores would have more behavioural problems by parental and daycare provider report; (2) problematic napping behaviours would be associated with night sleep problems. RESULTS: Mothers' reports of sleep problems were positively associated with children's behavioural problems at home and daycare providers' reports of nap problems were positively correlated with children's behavioural problems at daycare. Daycare providers' reports of children's behavioural problems at daycare were associated with maternal reports of behavioural problems. Older children in the sleep problem group had maternal reports of more behavioural problems. Daycare providers reported that children with sleep problems were less happy at daycare. Children who were happier following naps had less reported night settling difficulties. Children with difficulty settling for naps at daycare had maternal reports of more behavioural problems. CONCLUSIONS: Napping in daycare settings is an important component of toddlers' sleep. Crossover effects between children's sleep and behaviour at daycare and home indicate similarities in mothers' and daycare providers' perceptions. Findings suggest parent and daycare provider interactions include discussions about sleep problems and settling at home and in daycares. Parents and daycare providers would benefit from education about relationships between sleep and behavioural problems.

Recommendations for MRI-based contouring of gross tumor volume and organs at risk for radiation therapy of pancreatic cancer.

PURPOSE: Local recurrence is a common and morbid event in patients with unresectable pancreatic adenocarcinoma. A more conformal and targeted radiation dose to the macroscopic tumor in nonmetastatic pancreatic cancer is likely to reduce acute toxicity and improve local control. Optimal soft tissue contrast is required to facilitate delineation of a target and creation of a planning target volume with margin reduction and motion management. Magnetic resonance imaging (MRI) offers considerable advantages in optimizing soft tissue delineation and is an ideal modality for imaging and delineating a gross tumor volume (GTV) within the pancreas, particularly as it relates to conformal radiation planning. Currently, no guidelines have been defined for the delineation of pancreatic tumors for radiation therapy treatment planning. Moreover, abdominal MRI sequences are complex and the anatomy relevant to the radiation oncologist can be challenging. The purpose of this study is to provide recommendations for delineation of GTV and organs at risk (OARs) using MRI and incorporating multiple MRI sequences. METHODS AND MATERIALS: Five patients with pancreatic cancer and 1 healthy subject were imaged with MRI scans either on 1.5T or on 3T magnets in 2 separate institutes. The GTV and OARs were contoured for all patients in a consensus meeting. RESULTS: An overview of MRI-based anatomy of the GTV and OARs is provided. Practical contouring instructions for the GTV and the OARs with the aid of MRI were developed and included in these recommendations. In addition, practical suggestions for implementation of MRI in pancreatic radiation treatment planning are provided. CONCLUSIONS: With this report, we attempt to provide recommendations for MRI-based contouring of pancreatic tumors and OARs. This could lead to better uniformity in defining the GTV and OARs for clinical trials and in radiation therapy treatment planning, with the ultimate goal of improving local control while minimizing morbidity.

The spatial distribution of immunotoxins in solid tumors: assessment by quantitative autoradiography.

The spatial distribution of i.v. administered immunotoxins in s.c. human rhabdomyosarcoma RD2 xenografts was studied. The toxin and immunotoxins were: (a) diphtheria toxin (DT); (b) a binding-deficient form of DT (CRM107) linked to a monoclonal IgG1 antibody (454A12) directed against the human transferrin receptor (454A12-107); (c) the binding-deficient form of DT linked to the Fab' fragment of 454A12 (Fab'-107); and (d) the binding-deficient form of DT coupled to MOPC21, a monoclonal IgG1 with no significant binding to RD2 cells. DT and the immunotoxins were radiolabeled with 125I and injected via the tail vein into tumor-bearing athymic mice (median tumor weight, 0.25 g). Tumors were removed 2, 6, and 24 h after injection of DT or immunotoxin. Film images of 20-microns frozen sections were digitized by video microscopy, and gray levels were converted to tissue concentrations based upon the film response to radioactivity standards and the specific activity of the radiolabeled toxins. Images of the tumors were characterized quantitatively by the kurtosis and the area above threshold; the kurtosis is a measure of the spatial heterogeneity of the radiolabeled immunotoxins, and the area above threshold is defined here as the fractional tumor area that reaches or exceeds 1.5% of the initial plasma concentration. The spatial distribution of DT in the tumors was extremely uniform, characterized by low kurtosis values. In contrast, the autoradiograms of 454A12-107 were punctate in appearance and were characterized by very high kurtosis values. Fab'-107, which has approximately one-half the molecular weight of the intact immunotoxin and binds only monovalently, also produced punctate images with kurtosis values similar to those for 454A12-107. The nonbinding immunotoxin distributed somewhat less uniformly than DT but much more homogeneously than either of the binding immunotoxins. DT, 454A12-107, and Fab'-107 have similar affinities for their respective receptors, but the concentration of binding sites for DT on RD2 cells (<3,000 receptors/cell) is much lower than the concentration of transferrin receptor (60,000 receptors/cell). Thus, the heterogeneous distribution of 454A12-107 and Fab'-107 probably reflects retarded penetration due to binding to the tumor cells. The area above threshold was greatest for DT and lowest for 454A12-107; the fragment and nonbinding immunotoxins had intermediate values. The lower area above threshold for the nonbinding immunotoxin as compared with DT may be due to the considerably large molecular weight and hence the lower capillary permeability and diffusion coefficient of the immunotoxin.(ABSTRACT TRUNCATED AT 400 WORDS)

Stereotactic radiosurgery for recurrent malignant gliomas.

PURPOSE: To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS: We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS: The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION: Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.

Central nervous system germinomas. A review.

The germinoma represents a less malignant form of germ cell tumor. Depending on the individual's age, this neoplasm constitutes approximately 0.1% to 3.4% of all intracranial tumors. The embryologic origin remains a mystery; however, current theories implicate an aberration in primordial germ cell migration. Clinical presentation depends on tumor location and may involve endocrine, hypothalamic, visual, and cognitive dysfunction. In evaluating midline intracerebral masses, it is imperative that one be aware of the various radiologic appearances, endocrinologic changes, and chemical markers that help to distinguish germinomas from other neoplasms that appear in the pineal, suprasellar, and periventricular regions. Only through the careful evaluation of all available studies can the physician institute appropriate therapies such as biopsy, radiation, and chemotherapy. This article focuses on the epidemiology, embryology, clinical presentation, means of diagnosis, treatment, and outcome of this rare neoplasm.

Central nervous system infections in heart and heart-lung transplant recipients.

Infections, a major cause of morbidity and mortality in immunosuppressed heart and heart-lung transplant recipients, frequently involve the central nervous system and can produce devastating neurologic sequelae. Between 1980 and 1987, a total of 363 heart transplant and 54 heart-lung transplant recipients at the University of Pittsburgh sustained 13 intracranial infections two to 143 weeks after transplantation. Computed tomography demonstrated well-defined Nocardia and Aspergillus abscesses in four patients. Cerebrospinal fluid was normal in all cases studied, including in those patients in whom culture confirmed meningitis. Computed tomography-guided stereotactic surgery was used to diagnose and aspirate two nocardial brain abscesses. The prognosis for patients with central nervous system infections was related to their overall condition at the time of diagnosis. Both patients with nocardial abscesses and one patient with Listeria leptomeningitis survived, but all ten other patients died because of extensive multisystem infectious complications.

Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium.

Therapeutic options for the treatment of malignant brain tumors have been limited, in part, because of the presence of the blood-brain barrier. For this reason, the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium, the focus of which was the "Importance of Dose Intensity in Neuro-Oncology Clinical Trials," was convened in April 2000, at Government Camp, Mount Hood, Oregon. This meeting, which was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, brought together clinicians and basic scientists from across the U.S. to discuss the role of dose intensity and enhanced chemotherapy delivery in the treatment of malignant brain tumors and to design multicenter clinical trials. Optimizing chemotherapy delivery to the CNS is crucial, particularly in view of recent progress identifying certain brain tumors as chemosensitive. The discovery that specific constellations of genetic alterations can predict which tumors are chemoresponsive, and can therefore more accurately predict prognosis, has important implications for delivery of intensive, effective chemotherapy regimens with acceptable toxicities. This report summarizes the discussions, future directions, and key questions regarding dose-intensive treatment of primary CNS lymphoma, CNS relapse of systemic non-Hodgkin's lymphoma, anaplastic oligodendroglioma, high-grade glioma, and metastatic cancer of the brain. The promising role of cytoenhancers and chemoprotectants as part of dose-intensive regimens for chemosensitive brain tumors and development of improved gene therapies for malignant gliomas are discussed.

Maintaining accuracy in stereotactic radiosurgery.

PURPOSE: To provide the manufacture's specification for the base phantom of a commercially available stereotactic radiosurgery system so that its accuracy can be confirmed, and to describe a calibration device that allows the accuracy of the base phantom to be verified quickly and on a routine basis. Modifications to the target pointer system that make matching the pointer tips easier and less likely to damage the pointer tips are also described. METHODS AND MATERIALS: In stereotactic radiosurgery, spatial accuracy is the key factor for successful dose delivery. With some commercially available systems, this accuracy depends on the accuracy of the base phantom coordinate system, how closely the tip of the target pointer can be matched to the tip of the base phantom pointer, and how accurately the coordinates set on the isocentric subsystem match those set on the base phantom. Two major problems, usually overlooked when evaluating system accuracy are, first, the base phantom, which establishes the stereotactic coordinate system, is assumed to be completely accurate. This is a dangerous assumption because the base phantom is used frequently for routine patient treatments and for standard quality assurance tests. To exacerbate the problem, no independent device is provided with stereotactic systems to check the accuracy of the base phantom. Second, the accuracy of the isocenter coordinates set on the head support stand depends upon how closely the target pointer and the base phantom pointer can be aligned. The hardware provided with the system is difficult to use and easily leads to damage of the pointer tips. RESULTS: In this work, we provide the manufacturer's specifications for a popular stereotactic system, describe a device that can be used to check quickly and easily the accuracy of the base phantom, and describe a modification to the transfer pointer system that allows the pointer tips to be more easily aligned with reduced possibility of damage to the pointer tips. CONCLUSION: The methods and apparatus described in this paper should be useful to anyone using a base phantom for testing radiosurgery accuracy.

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas.

PURPOSE: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. METHODS AND MATERIALS: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Preliminary assessment of turbo spectroscopic imaging for targeting in brain biopsy.

BACKGROUND AND PURPOSE: Brain biopsy remains an integral and necessary component in the diagnosis of brain lesions. We assessed the ability of turbo spectroscopic imaging (TSI) to provide a physiologically based target for tissue sampling. METHODS: TSI was performed in 26 anesthetized patients immediately before MR-guided brain biopsy. In 10 patients, single-voxel spectroscopy was performed on the TSI-indicated target and correlated with the TSI findings. Biopsy samples were taken from the imaging and spectroscopically defined target(s) under MR guidance, and pathologic findings were compared with preoperative spectra. RESULTS: TSI alone provided a definitive target based on a region of elevated choline in 17 of 21 patients in whom a neoplasm was confirmed. The remaining four neoplasms exhibited relatively low metabolic levels and were difficult to distinguish from the five cases of radiation necrosis seen in this study. TSI findings were in qualitative agreement with those obtained at single-voxel spectroscopy, although TSI spectra exhibited more contamination. Quantitative spectral analysis of TSI data is limited by low spectral resolution. CONCLUSION: TSI is helpful for determining an appropriate biopsy target in heterogeneous lesions. Coupling TSI targeting with conventional imaging and intraoperative confirmation of needle positioning resulted in a 100% diagnostic success rate and increased the clinician's confidence in the histologic findings.

Radiologic diagnosis, staging, and follow-up of adult central nervous system primary malignant glioma.

Glioma represents the most common primary intra-axial brain tumor. Currently, magnetic resonance (MR) imaging is the study of choice for the radiographic evaluation of patients with primary central nervous system glioma prior to and following therapeutic intervention. Computed tomography and MR imaging are frequently used for stereotactic biopsy and mapping. MR spectroscopy and/or thallium-201 single photon emission computed tomography may prove helpful in differentiating recurrent malignancy from radiation-induced necrosis.

Targeted toxin therapy for malignant astrocytoma.

The poor prognosis associated with malignant astrocytoma has led investigators to seek new, innovative methods of treatment. Targeted toxins represent a unique form of therapy that has two components, a carrier molecule with high specificity for tumor-associated antigens and a potent protein toxin. These compounds are extremely cytotoxic to malignant astrocytoma cell lines in vitro. Animal studies have shown prolongation of survival and complete tumor regression when targeted toxins were administered by a variety of routes. The promising results seen in vivo have formed the basis for proceeding with clinical trials in humans with leptomeningeal neoplasia and malignant brain tumors, in which these agents are administered intrathecally or directly into tumor, respectively. To date, in these clinical trials, targeted toxins have been delivered safely without significant neurological toxicity, and cytological analysis of cerebrospinal fluid and radiological findings have shown evidence of a therapeutic response. These studies have confirmed the existence of a therapeutic window between normal brain tissue and malignant cells that can be exploited with targeted therapy directed against the transferrin receptor. The successful delivery of targeted toxins directly into malignant brain tumors has established this route of administration as practical and feasible. Identification of other receptors that are preferentially expressed on brain tumors, such as the interleukin-4 receptor, has resulted in the creation of a fusion protein against this receptor that contains a modified toxin from the bacteria Pseudomonas aeruginosa. This chimeric fusion toxin is currently under investigation in a Phase I clinical trial with patients with recurrent malignant astrocytoma, and other targeted toxins are under development for the treatment of these uniformly fatal tumors. Owing to these recent advances in targeted toxin therapy for malignant primary brain tumors, a review of the development of these agents for practicing neurosurgeons seems timely.

Rapid detection of transferrin receptor expression on glioma cell lines by using magnetic microspheres.

A rapid method for detecting the presence of transferrin receptors (TR) on human glioblastoma-derived cell lines is presented. The development of new treatment modalities, such as immunotoxins for central nervous system cancer, requires the identification of appropriate surface antigens on tumor cells. Seven established human glioblastoma-derived cell lines were assayed for the presence of TR with antibody-coated magnetic microspheres (immunobeads). The immunobeads bound to glioblastoma cells in the presence of human anti-TR monoclonal antibodies to a significantly greater degree than to control cell lines (P < 0.0001). The expression of TR was confirmed by standard immunocytochemical techniques. A 9L rat gliosarcoma cell line was used as a nonhuman control and did not demonstrate TR expression by either the immunobead assay or immunocytochemistry. This assay represents a simple, sensitive way to detect TR expression on malignant cells, which may be useful for the identification of other cell surface antigens that can be exploited by targeted therapies.

Subarachnoid-pleural and subarachnoid-mediastinal fistulae.

Subarachnoid-pleural fistula and subarachnoid-mediastinal fistula are rare complications of chest trauma. One case each of subarachnoid-mediastinal fistula and subarachnoid-pleural fistula is described. Both patients were young children who suffered severe longitudinal distraction injuries to their thoracic spine and exhibited complete cord transection without radiographic evidence of vertebral column injury. Progressive mediastinal widening and enlarging pleural effusion in the absence of angiographic evidence of aortic injury suggested the diagnosis of an intrathoracic cerebrospinal fluid fistula. Myelograms identified the site of spinal cord rupture and cerebrospinal fluid leakage. The diagnosis, management, and outcome of these rare fistulae are discussed.

Anaplastic ganglioglioma in an infant: case report and review of the literature.

A 6-month-old girl had a gradually increasing head circumference. A preoperative computed tomographic (CT) scan of the head revealed an enhancing calcified partially cystic right frontal mass that was removed through a right frontotemporal craniotomy. On microscopic examination, the tumor was composed of sheets of neurons in a glial background alternating with highly cellular anaplastic areas. The diagnosis of anaplastic ganglioglioma was made. The child has done well for the 20 months since the operation without any evidence of tumor recurrence on subsequent CT scans. Because of the immaturity of the child's developing central nervous system, we have elected not to initiate radiotherapy at this time. The pertinent literature regarding gangliogliomas is reviewed.

Antisense oligonucleotides for central nervous system tumors.

The poor prognosis associated with malignant primary brain tumors has led investigators to seek and develop new, innovative treatment modalities. Current adjuvant therapies lack tumor specificity, which can lead to toxic central nervous system side effects. Advances in molecular biology now allow specific gene sequences to be inserted or targeted in the malignant cell genome. Antisense oligodeoxynucleotides represent complementary nucleic acid sequences that can recognize and bind to target genes, resulting in the arrest of deoxyribonucleic acid transcription or the translation of messenger ribonucleic acid. Although the use of antisense oligodeoxynucleotides is still in the experimental stages, these molecules enter cells in tissue culture by simple diffusion or active endocytosis and temporarily inhibit cell proliferation in a time- and dose-dependent fashion. The ability of antisense oligodeoxynucleotides to recognize specific gene sequences and to down-regulate gene expression make them ideal agents for use in targeting oncogenes, such as c-myb, that are expressed in central nervous system neoplasms.