Biomedical subjects

Sandeep Kunwar

Publications and source records attributed to Sandeep Kunwar.

15 recordsLinked to original sources

PubMed2006

GNOSIS: guidelines for neuro-oncology: standards for investigational studies--reporting of surgically based therapeutic clinical trials.

We present guidelines to standardize the reporting of surgically based neuro-oncology trials. The guidelines are summarized in a checklist format that can be used as a framework from which to construct a surgically based trial. This manuscript follows and is taken in part from GNOSIS: Guidelines for neuro-oncology: Standards for investigational studies-reporting of phase 1 and phase 2 clinical trials [Chang SM, Reynolds SL, Butowski N, Lamborn KR, Buckner JC, Kaplan RS, Bigner DD (2005) Neuro-oncology 7:425-434].

Clinical Trials as Topic↗

PubMed2006

Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies.

OBJECTIVES: Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection. METHODS: Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the 123I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a 131I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography. CONCLUSIONS: Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.

Antibodies, Monoclonal↗

PubMed2006

Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.

OBJECT: Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells. METHODS: Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively. CONCLUSIONS: The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

Adult↗

PubMed2006

Chromosome transfer experiments link regions on chromosome 7 to radiation resistance in human glioblastoma multiforme.

Glioblastoma multiforme (GM) is the most lethal form of brain tumor, with a median survival of approximately 1 year. Treatment options are limited. Radiation therapy is a common form of treatment, but many tumors are resistant. In earlier studies, we found that gain of chromosome 7 is associated with radiation resistance in human primary GM. In this study, we extend that result to a model system in which we transferred chromosome 7 to recipient cells and confirmed radiation resistance as a function of chromosome 7 gain. We identified three candidate regions on chromosome 7 that conferred radiation resistance in our model system.

Brain Neoplasms↗

PubMed2006

Convection-enhanced delivery of interleukin-13 receptor-directed cytotoxin for malignant glioma therapy.

The treatment of patients with malignant brain tumors, in particular glioblastoma multiforme (GBM) is very challenging because of their diffuse infiltrative nature and the cytological heterogeneity. The median survival of patients with newly diagnosed GBM is only 12-15 months, and only 8-12% of them survive for two years. Novel approaches for brain tumor therapy are needed. Recently, targeted therapies have emerged as promising modality for cancer targeting. We have discovered that high affinity plasma membrane receptor for interleukin-13 (IL-13), an immune regulatory cytokine, is over-expressed in 60-80% of malignant brain tumors. To target these IL-13R, we generated a chimeric fusion protein, composed of human IL-13 and mutated Pseudomonas exotoxin (PE), termed IL-13 cytotoxin (IL13-PE), and tested its cytotoxicity to IL-13R-expressing GBM cells. IL-13 cytotoxin was highly potent and selective in killing IL-13R-expressing GBM cells. In contrast, normal cells including brain, immune, and endothelial cells were generally not affected by this cytotoxin due to no or low expression of IL-13R. In vivo pre-clinical studies for safety and toxicity were also performed in mice, rats, and monkeys, and IL-13 cytotoxin was found to be well tolerated by both systemic and intracerebral administrations. IL-13 cytotoxin was found to mediate remarkable efficacy in animal models of human brain tumors. Encouraged by these pre-clinical studies, four Phase 1/2 clinical trials in adult patients with recurrent malignant glioma have been completed. These clinical trials involved convection-enhanced delivery (CED) of IL-13 cytotoxin either intratumoral or intraparenchymal after resection of tumor. CED is a novel loco-regional drug delivery method for intracranial tumors that relies on a continuous pressure gradient to distribute drug into interstitial space. This route of IL-13 cytotoxin administration appears to be very well tolerated and have a good risk-benefit profile. Most recently, a randomized controlled Phase 3 clinical trial (PRECISE) with intraparenchymal IL-13 cytotoxin administration was completed and subjects are being monitored for safety and survival.

Animals↗

PubMed2006

The "yo-yo" technique to prevent cerebrospinal fluid rhinorrhea after anterior clinoidectomy for proximal internal carotid artery aneurysms.

OBJECTIVE: Resection of the anterior clinoid process is important for the exposure of aneurysms on clinoidal and supraclinoidal segments of the internal carotid artery. Cerebrospinal fluid (CSF) rhinorrhea can complicate anterior clinoidectomy when the optic strut is pneumatized and its removal communicates the subarachnoid space with the sphenoid sinus. We present a technique for repairing this defect and preventing CSF rhinorrhea. METHODS: A suture is secured around a strip of temporalis muscle, which is then pushed through the opening in the optic strut completely into the sphenoid sinus. The ends of suture that trail the muscle are used to retract the muscle from the sphenoid sinus back into the optic strut. The suture is trimmed and the repair is covered with sealant or fibrin glue. RESULTS: During an 8-year period in which 127 patients with proximal internal carotid artery aneurysms that required anterior clinoidectomy were treated, pneumatized optic struts were encountered in 14 patients (11%). Four patients were treated with the "yo-yo" technique, none of whom experienced CSF rhinorrhea. Before using this technique, 10 patients were managed with standard packing techniques (wax, muscle, and gel foam) and four of these patients subsequently experienced CSF rhinorrhea (40%). In these four patients, all required reoperation with either craniotomy and packing with pericranium (one patient), Couldwell-Luc procedure (one patient), or endoscopic transnasal obliteration of the sphenoid sinus with fat (two patients). CONCLUSION: The "yo-yo" technique of tightly wedging a muscle plug into the optic strut proved to be simple, fast, and effective, preventing CSF rhinorrhea in all patients in whom it was applied. Although experience with this technique is limited, reversing the direction of packing and pulling muscle from the sphenoid sinus into the optic strut eliminated a complication that occurred in 40% of patients with standard packing techniques.

Carotid Artery, Internal↗

PubMed2006

Extended bifrontal craniotomy for midline anterior fossa meningiomas: minimization of retraction-related edema and surgical outcomes.

OBJECTIVE: Meningiomas of the anterior cranial base can be approached with a variety of techniques. The extended bifrontal approach is often thought to be associated with increased morbidity because of the need for extensive removal of the bone and longer surgical times. The authors have attempted to quantitate retraction-related edema occurring after surgery to determine whether the extra bone removal limits retraction and reduces the chance of brain injury. METHODS: Charts were reviewed for patients who underwent extended bifrontal craniotomies performed for meningiomas at the University of California, San Francisco, between 1997 and 2005. Magnetic resonance imaging scans obtained before and after surgery were reviewed for brain edema as indicated by fluid-attenuated inversion recovery/T2 abnormality and grouped into four categories: A, no edema; B, edema restricted to the gyrus rectus; C, edema beyond the gyrus rectus; and D, extensive bifrontal edema. RESULTS: Forty-five patients were identified. Fifty-four percent of patients had tumors with a diameter of more than 4 cm. Simpson Grade 2 or 3 resection was achieved in 82% of patients, and the average operative time was 12.3 hours. Vision outcome was favorable in 74% of patients. Extent of fluid-attenuated inversion recovery abnormality remained unchanged in 87.5%, with 91% of patients in categories A or B edema remaining in those categories after surgery. There were no infections and there were two cerebrospinal fluid leaks. CONCLUSION: The extended bifrontal approach is a safe surgical procedure with limited morbidity that the authors think: 1) prevents secondary brain injury from excessive retraction; 2) offers great flexibility of view for the surgeon; and 3) should be considered the preferred approach compared with the standard bifrontal craniotomy for large tumors of the anterior cranial base.

Adult↗

PubMed2005

Brain metastases of breast cancer.

Brain metastases of breast cancer remain a difficult problem for clinical management. Their incidence appears to be increasing, which is likely due to longer survival times for advanced breast cancer patients as well as additional and improved tools for detection. Molecular features of tumors associated with this syndrome are not yet understood. In general, survival may be improving for brain metastases due to better local control in the CNS, as well as improvements in systemic disease management. Selected patients with brain metastases are able to undergo surgical resection, which has been associated with extended disease control in some patients. However, whole-brain radiation has been the mainstay for treatment for most patients. Stereotactic radiosurgery is playing an increasing role in the primary treatment of brain metastases, as well as for salvage after whole-brain radiation. Recent series have reported median survivals of 13 months or longer with stereotactic radiosurgery. Further improvements in radiation-based approaches may come from ongoing studies of radiosensitizing agents. The ability of systemic treatments to impact brain metastases has been debated, and specific treatment regimens have yet to be defined. New approaches include chemotherapy combinations, biologic therapies and novel drug-delivery strategies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma.

OBJECT: Convection-enhanced delivery (CED) is a novel method for delivering therapeutic agents to infiltrative brain tumor cells. For agents administered by CED, changes on magnetic resonance (MR) imaging directly resulting from catheter placement, infusion, and the therapeutic compound may confound any interpretation of tumor progression. As part of an ongoing multiinstitutional Phase I study, 14 patients with recurrent malignant glioma underwent CED of interleukin (IL) 13-PE38QQR, a recombinant cytotoxin consisting of human IL-13 conjugated with a truncated Pseudomonas exotoxin. Serial neuroradiographic changes were assessed in this cohort of patients. METHODS: Patients were treated in two groups: Group 1 patients received IL13-PE38QQR before and after tumor resection; Group 2 patients received infusion only after tumor resection. Preoperative and postinfusion MR images were obtained prospectively at specified regular intervals. Changes were noted along catheter tracks on postresection MR images obtained in all patients. A simple grading system was developed to describe these changes. When MR imaging changes appeared to be related to IL1 3-PE38QQR, patients were followed up without instituting new antitumor therapy. CONCLUSIONS: As CED of therapeutic agents becomes more common, clinicians and investigators must become aware of associated neuroimaging changes that should be incorporated into toxicity assessment. We have developed a simple grading system to facilitate communication about these changes among investigators. Biological imaging modalities that could possibly distinguish these changes from recurrent tumor should be evaluated. In this study the authors demonstrate the challenges in determining efficacy when surrogate end points such as time to tumor progression as defined by new or progressive contrast enhancement on MR imaging are used with this treatment modality.

ADP Ribose Transferases↗

PubMed2004

Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.

The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.

Adult↗

PubMed2004

Cavernous and inferior petrosal sinus sampling in the evaluation of ACTH-dependent Cushing's syndrome.

OBJECTIVE: Central venous sampling (CVS) is used frequently in the evaluation of ACTH-dependent Cushing's syndrome. However, several controversies exist including the diagnostic accuracy, the sampling site of choice (cavernous sinus vs. inferior petrosal sinus) and the use of lateralization data in tumour localization. We have analysed our experience with CVS to address these controversies. DESIGN: We retrospectively reviewed CVS data in patients with ACTH-dependent Cushing's syndrome, in whom cavernous sinus sampling (CSS), inferior petrosal sinus sampling (IPSS) and IPSS after administration of ovine corticotrophin releasing hormone (oCRH) were performed. PATIENTS: Data on 95 patients were analysed, including 79 patients with suspected Cushing's disease (CD) and 16 patients with suspected ectopic ACTH syndrome (EAS). RESULTS: For the differential diagnosis of ACTH-dependent Cushing's syndrome, the diagnostic accuracy of IPSS after oCRH stimulation was 97% compared to 86% for CSS. While no single sampling site was perfect in diagnostic accuracy, sampling both CS and IPS achieved a combined diagnostic accuracy of 100%. Lateralization data predicted tumour location in 62-68% of the patients with various central venous drainage patterns and in 77-80% of the patients with symmetrical drainage. CSS was not significantly superior to IPSS in tumour lateralization. In patients with suspected CD based on CVS and in whom an adenoma was not found on magnetic resonance imaging (MRI) and not located by the surgeon intraoperatively, hemihypophysectomy based on lateralization data was successful in only 10 of the 18 patients (56%) with various central venous drainage patterns and in 5 of 10 patients with symmetrical drainage. CONCLUSION: CVS is a powerful method for differentiating CD from the EAS. CSS without oCRH was not superior to IPSS after oCRH stimulation; however, we achieved a 100% diagnostic accuracy if at least two sites were sampled. Tumour localization by CVS did not accurately predict the tumour site at surgery and should not be used to guide surgical resection.

ACTH Syndrome, Ectopic↗

PubMed2003

Endoscopic adjuncts to intraventricular surgery.

Recently, endoscopic intraventricular surgery has been performed successfully in several clinical series. Although the therapeutic results must be compared with conventional surgery, neuroendoscopy seems to be a safe surgical technique when performed by surgeons with appropriate experience and refined endoscopic tools. Rigid or flexible endoscopes equipped with various-sized working channels should be selected depending on the nature of the pathologic findings. The well-proven tenets of microsurgery must not be sacrificed for the sake of more rapid surgical time and noninvasiveness; thus, endoscopic surgery must adhere to the principles of microsurgery. The improved visualization and lower morbidity have established neuroendoscopy in the management of specific disease processes, such as obstructive hydrocephalus. Its further use in the management of intraventricular cysts and tumors is dependent on long-term follow-up and the development of even better instrumentation.

Cerebral Ventricles↗

PubMed2003

Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Adult↗

PubMed2002

Phase II study of high central dose Gamma Knife radiosurgery and marimastat in patients with recurrent malignant glioma.

PURPOSE: To assess the outcome of high central dose Gamma Knife radiosurgery plus marimastat in patients with recurrent malignant glioma. METHODS AND MATERIALS: Twenty-six patients with recurrent malignant glioma were enrolled in a prospective Phase II study between November 1996 and January 1999. The radiosurgery dose was prescribed at the 25-30% isodose surface to increase the dose substantially within the tumor's presumably hypoxic core. Marimastat was administered after radiosurgery to restrict regional tumor progression. Survival was compared with that of historical patients treated at our institution with standard radiosurgery. RESULTS: The median times to progression after radiosurgery for Grade 3 and 4 patients was 31 and 15 weeks, respectively. The corresponding median survival time after radiosurgery was 68 and 38 weeks. The median survival time after radiosurgery in the historical patients was 59 and 44 weeks. CONCLUSION: The dual strategies of using high central dose radiosurgery to overcome tumor hypoxia together with marimastat to inhibit local tumor invasion may offer a small survival advantage for recurrent Grade 3 tumors; they do not offer an advantage for recurrent Grade 4 tumors.

Adult↗

PubMedDate not supplied

Stereotactic radiosurgery and interstitial brachytherapy for glial neoplasms.

The application of focal radiation therapies in the management of malignant gliomas has gone through a number of stages. Earlier efforts to improve local control of malignant gliomas involved the use of brachytherapy. Despite some early encouraging results, Phase 3 studies did not prove a significant survival benefit for the addition of brachytherapy for newly diagnosed glioblastoma. Most recently radiosurgery has been employed using the same rationale in that improved local control may improve survival. Results of the RTOG Phase 3 study are pending final publication, but early abstracted reports are negative. While radiosurgery and brachytherapy continue to be used as a form of therapy for selected patients with recurrent gliomas, new information from metabolic imaging studies suggests our problem with these techniques in part may be related to targeting. This paper reviews the recent literature and results of the use of brachytherapy and radiosurgery in the management of newly diagnosed and recurrent malignant gliomas.

Brachytherapy↗