A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Twofold improved tumor-to-brain contrast using a novel T1 relaxation-enhanced steady-state (T1RESS) MRI technique.

A technique that provides more accurate cancer detection would be of great value. Toward this end, we developed T1 relaxation-enhanced steady-state (T1RESS), a novel magnetic resonance imaging (MRI) pulse sequence that enables the flexible modulation of T1 weighting and provides the unique feature that intravascular signals can be toggled on and off in contrast-enhanced scans. T1RESS makes it possible to effectively use an MRI technique with improved signal-to-noise ratio efficiency for cancer imaging. In a proof-of-concept study, "dark blood" unbalanced T1RESS provided a twofold improvement in tumor-to-brain contrast compared with standard techniques, whereas balanced T1RESS greatly enhanced vascular detail. In conclusion, T1RESS represents a new MRI technique with substantial potential value for cancer imaging, along with a broad range of other clinical applications.

Skill performance in open videoscopic surgery.

INTRODUCTION: Application of minimally invasive surgery represents the future of modern surgical care. Previous studies by our group provided a novel way for viewing open surgery using a rigid endoscope attached to charged coupled device (CCD) camera in proximity to the surgical field using a robotic arm (AESOP) and a stabilizing fulcrum (Alpha port). MATERIALS AND METHODS: This study is a follow-up to investigate the technical feasibility, advantages, and disadvantages of relying only on video images displayed on standard monitors in performing open surgical procedures instead of direct binocular eye vision. This study used two surgeons as participants with training in basic surgical skill and previous experience in performing an intestinal anastomosis in an ordinary fashion. The standard task consisted of anastomosing porcine intestine in two layers with digital viewing of the operative field. A total of 40 anastomoses (20 by each surgeon) were compared with 10 control performances using direct vision of the field. RESULTS: All the resulting anastomoses were accurate, well coapted, and fully patent with no leakage. Time for task performance was approximately twice as long (p < 0.05) with videoscopic vision as with direct vision. DISCUSSION: These findings suggest it is technically feasible to conduct open surgeries with visualization of the open surgical field limited to video display on standard monitors.

Telementoring versus on-site mentoring in virtual reality-based surgical training.

BACKGROUND: Telementoring can be an adjunct to surgical training using virtual reality surgical simulation. Telementoring is hypothesized to be as effective as a local mentor for surgical skills training. METHODS: In this study, 20 Romanian medical students trained using a virtual reality surgical simulator (LapSim) with a telementor or local mentor. All the students watched an instructional module at the beginning of the exercise. The telementor, in the United States, interacted by videoconferencing. Before and after training sessions, tool path length and time for task completion were measured. RESULTS: Instructional media and training with mentoring resulted in similar levels of performance between locally mentored and telementored groups. Right- and left-hand path length and time decreased significantly within each group from the initial to the final evaluation (p < 0.05) for most tasks (grasping, cutting, suturing). No significant difference was achieved for clip-applying. CONCLUSIONS: Integration of instructional media with telementoring can be as effective for the development of surgical skills as local mentoring.

Preparation of viable islet cells from dogs by a new method.

A new method for the preparation of viable islet cells from the normal dog pancreas is described, based on the perfusion of the pancreatic duct with collagenase. Exposure of the acinar tissue to the highest concentrations of collagenase results in improved islet yield with decreased acinar contamination. After the selective digestion of the gland by ductal perfusion, mechanical dissociation liberates single cells and clumps. Analysis of the procedure by insulin yield and amylase attrition indicates a 57% B-cell recovery and a sixfold enrichment in B-cell concentration. The cells have been transplanted as autografts into dogs after pancreatectomy. In 5 of 7 transplanted dogs, normoglycemia was achieved postoperatively.

Allotransplantation of islet endocrine aggregates.

Dissociated pancreatic islets form endocrine aggregates from single-cell suspension by rotation culture. Islet cell aggregates, or neoislets, can provide endocrine reconstitution for diabetic rats and enjoy prolonged graft survival when neoislets are transplanted across a major histocompatibility barrier (Lewis to ACI). Long-term survival of grafted neoislets was obtained in 71% of recipients without any immunosuppression and in 100% of recipients with minimal immunosuppression. As predicted by cell-cell recognition in rotation-mediated aggregation, neoislets apparently exclude mesenchymal cells that bear la antigens. Therefore, reduced immunogenicity is accomplished.

Structure, function, and immune properties of reassociated islet cells.

Rat islets were mechanically dissociated to single cells and allowed to form aggregates by rotation-mediated cell-cell interaction. The aggregates, or neoislets, demonstrated insulin release in response to 20 mM glucose and 10 mM theophylline that was comparable to that of intact islets cultured for a similar time. However, basal insulin release was considerably greater than that from freshly isolated islets. The microscopic structure of the neoislets revealed sorting into a B-cell domain at the surface with A-cells interior to the aggregate. The neoislets generated no mitogenic response in allogeneic lymph node lymphocytes. Reassociation of single islet cells provides stable, functional endocrine units with substantial reduction of immunogenicity.

Isolating the elusive islet.

The lack of a technique that allows mass isolation of intact, viable human islets is part of the reason that islet transplantation has not become available to the human diabetic. This report outlines the history of islet isolation and presents two new technical modifications that have been developed in the dog. Many of the current problems in islet isolation are presented, including the difficulty in obtaining enough human pancreatic tissue with minimal warm-ischemia time; inadequate distention of the pancreas to provide sufficient disruption for maximal enzymatic reaction to release intact islets; inefficient chopping methods; the use of collagenase of variable composition; different digestion methods for obtaining isolated islets; and inefficient methods for separating and purifying the islets from the ductal, acinar, and fibrous components. The first new modification involves distention of the dog pancreas through the venous system of the gland rather than the ductal system. This results in improved intralobular disruption, which improved the yield of isolated dog islets by permitting more efficient collagenase digestion. The second new modification eliminates the concept of isolating intact islets: the dog pancreas is digested by trypsin to a single-cell preparation that is partially purified by Ficoll gradients; further purification of the endocrine cells results from selective aggregation using rotational culture. This process produces pseudoislets that contain all the islet cell types and can be kept in culture for up to 4 wk, releasing their hormones in response to appropriate stimuli. These modifications may assist in the struggle to isolate the elusive human islet for safe and effective islet transplantation in the diabetic patient.

Suppression, stress, and accommodation of transplanted islets of Langerhans.

Successful intrasplenic islet autotransplantation in dogs requires an islet cell mass considerably greater than what might be expected based on studies of subtotal pancreatectomy. Grafts of marginal function ultimately fail, suggesting severe limitations in the capacity of an islet graft to adapt. Accommodation was tested in established intrasplenic grafts by either chronically stressing the graft with mild carbohydrate intolerance induced by exogenous corticosteroids or chronically suppressing the graft with exogenous insulin. After these manipulations, insulin output into the portal vein in response to intravenous (i.v.) glucose was measured and compared with that of normal dogs and dogs receiving islet autografts with no further treatment with either steroids or insulin. Transplanted islets tolerated the two manipulations well in that neither exogenous steroid nor insulin led to failure of the graft as a consequence of either stress or protracted diminished demand. The major determinant of successful islet grafting is the endocrine competence of the initial graft. If that competence is provided at the outset, the graft can adapt to a considerable range of demand for insulin secretion.

The independence of insulin release and ambient insulin in vitro.

The effect of insulin on its own secretion was tested in three independent experimental models using insulin concentrations that approached physiologic values. The collected secretions from glucose-stimulated islet tissue had no effect on insulin release from other islets. Perifused insulin had no effect on the release of endogenous insulin even when the assay was completely controlled for dilutional effects. Perifused insulin had no effect on the release of prelabeled insulin from glucose-stimulated islets. Similarly, proinsulin did not affect insulin release. Porcine insulin did not affect the function of porcine or canine islets. These studies strongly support the independence of glucose-stimulated insulin secretion and ambient insulin.

Ergonomics and human factors in endoscopic surgery: a comparison of manual vs telerobotic simulation systems.

BACKGROUND: Minimally invasive surgical techniques expose surgeons to a variety of occupational hazards that may promote musculoskeletal disorders. Telerobotic systems for minimally invasive surgery may help to reduce these stressors. The objective of this study was to compare manual and telerobotic endoscopic surgery in terms of postural and mental stress. METHODS: Thirteen participants with no experience as primary surgeons in endoscopic surgery performed a set of simulated surgical tasks using two different techniques--a telerobotic master--slave system and a manual endoscopic surgery system. The tasks consisted of passing a soft spherical object through a series of parallel rings, suturing along a line 5-cm long, running a 32-in ribbon, and cannulation. The Job Strain Index (JSI) and Rapid Upper Limb Assessment (RULA) were used to quantify upper extremity exposure to postural and force risk factors. Task duration was quantified in seconds. A questionnaire provided measures of the participants' intuitiveness and mental stress. RESULTS: The JSI and RULA scores for all four tasks were significantly lower for the telerobotic technique than for the manual one. Task duration was significantly longer for telerobotic than for manual tasks. Participants reported that the telerobotic technique was as intuitive as, and no more stressful than, the manual technique. CONCLUSIONS: Given identical tasks, the time to completion is longer using the telerobotic technique than its manual counterpart. For the given simulated tasks in the laboratory setting, the better scores for the upper extremity postural analysis indicate that telerobotic surgery provides a more comfortable environment for the surgeon without any additional mental stress.

Reversal of postoperative anuria by decompressive celiotomy.

Postoperative oliguria or anuria can rarely be attributed to an increase in intra-abdominal pressure. In this documented case, postoperative anuria responded to reduction in abdominal pressure by celiotomy. Actual abdominal pressure measurements are not available but probably would not be useful. However, hemodynamic measurements that were not consistent with diminished renal blood flow in a middle-aged patient were nevertheless associated with anuria, which responded to release of the abdominal pressure. Because of the association of regional pressure and acute renal decompensation, release of abdominal tension should be considered as a therapeutic option when hemodynamic measurements cannot explain a rapid decline in urine production.

Inhibition of rat mixed lymphocyte pancreatic islet cultures with anti-Ia immunotoxin.

Studies reported here indicate that an anti-Ia immunotoxin can eliminate the allostimulatory subpopulation of cells present within the islets of Langerhans without damaging the hormone-secreting cells. Such studies made use of an in vitro correlate of transplantation rejection, the mixed lymphocyte islet cell (MLIC) reaction. Using the MLIC, it was demonstrated that an anti-Ia immunotoxin removed cells capable of stimulating the MLIC in a dose-dependent fashion without altering the hormone-secreting functions of the remaining cells when challenged with glucose and theophylline. These studies suggest the feasibility of using such anti-Ia immunotoxins in islet allograft transplantation models to circumvent problems inherent in complement-mediated cytotoxicity, a previously documented effective form of inducing islet allotransplantation tolerance.

Adrenal medullary disease in multiple endocrine neoplasia type 2. Appropriate management.

This article discusses screening for pheochromocytoma and timing of surgery, unilateral versus bilateral adrenalectomy. Anterior, posterior, and laparoscopic operative techniques are reviewed also.

Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature.

With the increased use of nonprescription vitamin supplementation, physicians involved in critical care must be aware of the potential complications of these medications. We report the case of a 31-year-old African-American man presenting to the emergency department with acute renal failure. He had previously been well and initially denied the use of any drugs except for vitamin C tablets obtained at a local health food store. This case report and review of the literature is utilized to illustrate the importance of historical data in patients presenting with acute renal failure to a critical care service.

Neural regulation of heterotopic islets of Langerhans.

The possibility of vagal reinnervation to intrasplenic islet grafts was examined by measuring portal insulin response to electric stimulation of the dorsal vagus nerve in autografted dogs. Grafted islets responded appropriately to an exogenous cholinergic agent given intravenously. However, no insulin secretory response could be observed in grafted dogs after vagal stimulation, which markedly increased portal insulin levels in control dogs. Therefore, intrasplenic islets are not under direct vagal control. At the basal state, normal oscillatory release of insulin was observed in the animals with grafts, suggesting that the mechanism of rhythmic basal insulin release is intrinsic to the islet of Langerhans with no regulatory input from the vagus nerve or any element of pancreatic structure.

Failure of canine islet allografts and autografts with cyclosporine.

Intrasplenic autotransplantation of islet fragments prepared by ductal perfusion constitutes a reproducible system for islet delivery to apancreatic dogs. The animals are normoglycemic from the time of grafting, and graft failure is rare. In this study, apancreatic dogs received islet autografts (controls), autografts plus oral cyclosporine, and allografts plus oral cyclosporine. Therapeutic blood levels of cyclosporine were documented by radioimmunoassay. However, allografts and autografts ceased to function after initial normoglycemia in all animals that received cyclosporine, and four out of six autografts failed. Normoglycemia persisted in the control-autografted animals for the duration of the study. Microscopic sections of the failed grafts demonstrated meager tissue survival but no evidence of rejection by cellular infiltration.

Nonfunctioning islet cell carcinoma of the pancreas.

BACKGROUND: Nonfunctioning islet cell carcinoma of the pancreas has a variable and often indolent natural history, which has resulted in a wide range of treatment recommendations. To more clearly define the natural history and appropriate treatment of this disease, we reviewed our institutional experience over the last 39 years. METHODS: The records of all patients confirmed to have a nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Kaplan-Meier life tables were constructed and log-rank comparisons were performed. RESULTS: The 73 patients studied had an overall 5-year actuarial survival rate of 50%. Patients with localized disease at presentation (n = 39) had a significantly higher survival rate (p = 0.03) compared with patients with metastatic disease (n = 34). The 19 patients who underwent a potentially curative resection of the primary tumor had a significantly higher survival rate (p = 0.03) compared with the 20 patients with locally advanced, unresectable, nonmetastatic disease. Nine of these 20 patients died of complications of the primary tumor. In contrast, only 2 of 22 cancer-related deaths in the 34 patients with metastatic disease at diagnosis were due to the primary tumor. CONCLUSIONS: (1) Surgical resection should be performed in patients with resectable nonmetastatic disease. (2) Resection of the primary tumor in the presence of metastatic disease is rarely indicated. (3) Innovative treatment strategies are needed for patients with locally advanced, unresectable, nonmetastatic tumors of the pancreatic head.

Pseudoxanthoma elasticum and polyposis coli: a novel co-mutation.

Pseudoxanthoma elasticum and polyposis coli are inherited conditions not, to our knowledge, previously reported to coexist. The spontaneous appearance of both conditions in a 62-year-old woman may represent a novel mutation. The defective cell in both pseudoxanthoma and some of the extracolonic manifestations of Gardner's syndrome is the fibroblast; therefore, this case may represent a unique variation of Gardner's syndrome.