Mary T. Keogan

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

PURPOSE To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. PATIENTS AND METHODS The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. RESULTS There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. CONCLUSION rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.

In vivo monitoring of tumor angiogenesis with MR imaging

Magnetic resonance (MR) imaging is a widely employed diagnostic method for the evaluation of patients with tumors. This method is noted for its remarkable soft-tissue definition, absence of ionizing radiation, high spatial and temporal resolution, and ability to generate images in any plane of the entire body. Equipment costs and, thus, examination costs are relatively high, however. MR imaging has been proposed and tested, both experimentally and clinically, as a method to characterize tumors regarding their state of angiogenesis. Multiple approaches to the challenge of MR imaging assays of angiogenesis have been proposed, some of which are potentially additive; all are intended to provide information regarding tumor microvessels. The quantitative end points that are sought include tissue plasma/blood volume, transendothelial permeability to water or solutes, perfusion/flow, and relative concentration of angiogenesis-specific molecules. The available approaches can be divided into intrinsic (non-contrast material enhanced) and contrast material-enhanced methods. The latter methods can be further divided by the type of contrast medium employed: small molecular agents that distribute rapidly in the extracellular space (so-called nonspecific or extracellular-fluid-space [ECF] agents), large molecular agents designed for prolonged intravascular retention (socalled macromolecular contrast media [MMCM] or bloodpool agents), and targeted agents intended to accumulate at the sites of concentrated angiogenesis mediator. Today, ECF contrast agents are commercially available and being used in clinical evaluations of antiangiogenesis drug treatments. Macromolecular contrast media are currently in clinical trials, but they are not now approved for use in humans. Molecular-targeted contrast media are in preclinical development. This section summarizes some of the many reports dealing with MR imaging assays of angiogenesis. For clarity, the discussion is divided by the specific MR imaging approach used. The rationale for that approach, limited information regarding the technique itself, accumulated experience, and limitations are provided, as well.

Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas

Background: Improved resectability is a major theoretical benefit of preoperative chemoradiation for pancreatic cancer. Since 1994, patients at Duke University Medical Center with locally advanced pancreatic cancer have been treated with multimodality preoperative therapy. The purpose of this study was to review our experience with preoperative therapy for locally advanced pancreatic cancer and determine if an aggressive neoadjuvant regimen would not only downstage these tumors pathologically but also improve the odds of complete surgical resection.Methods: The charts of 25 patients treated with neoadjuvant chemoradiation at Duke University Medical Center with biopsy-proven, locally advanced adenocarcinoma of the pancreas were reviewed. Tumors were defined as locally advanced based on radiographic or intraoperative evidence of disease that abuts the superior mesenteric artery or vein (n = 22) or involves lymph nodes that are within the proposed radiation field (n = 3). All 25 patients received external beam radiotherapy (median dose 4500 cGy) in daily fractions of 180 cGy over 5 weeks. All patients concurrently received 5-fluorouracil (FU), and many also received mitomycin C or cisplatin, or both. Patients were given a 3- to 4-week break before a restaging computed tomographic (CT) scan was performed. Three patients were not restaged: one died from metastatic disease; one was reclassified as having a neuroendocrine tumor; and one was lost to follow-up.Results: On restaging after neoadjuvant therapy, 64% of patients had stable or decreased primary tumor size. Radiographically, two patients appeared potentially resectable, and seven others developed evidence of metastatic disease. Eight patients underwent exploration, but only five could be resected. Of the five patients resected, only one had negative margins and negative lymph nodes. This patient had significant pancreatitis on initial exploration. After neoadjuvant therapy, he had a complete response radiographically, and there was no residual cancer in his resection specimen. Pathologic examination of the other resection specimens suggested that despite significant tumor fibrosis, malignant cells persist even at the periphery of the lesions.Conclusion: Although neoadjuvant chemoradiation has many theoretical advantages in managing pancreatic malignancy, true pathologic downstaging of locally advanced lesions into tumors that can be removed with negative nodes and margins appears to be a rare event with currently used therapeutic regimens.

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine theutilityof staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Local recurrence of rectal cancer: Evaluation with F-18 fluorodeoxyglucose PET imaging

Abstract.Background: Positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) is a useful technique for detection of malignancy. The purpose of this study was to determine if FDG-PET scanning using visual and quantitative analyses can identify patients with recurrent colorectal tumor following abdominoperineal resection. Methods: Eighteen patients were evaluated for possible local recurrence of rectal carcinoma following abdominoperineal resection. The clinical presentation included rising carcinoembryonic antigen levels (n = 5), increasing size of a presacral mass on computed tomography or magnetic resonance (n = 13), or local symptoms (n = 3). Axial PET images of the pelvis were obtained following an injection of 10 mCi of FDG prior to biopsy. Quantitative analysis was performed by calculation of a standardized uptake ratio (SUR), and the images were interperated by two radiologists in consensus. FDG-PET findings were correlated with histological or cytological findings and with the clinical outcome. Results: Recurrent malignancy was confirmed in 13 patients by surgery (n = 8) or percutaneous biopsy (n = 5). Benign lesions were confirmed in five patients by surgery (n = 1), biopsy (n = 3), or clinical follow up (n = 1). Visual analysis of the FDG-PET data had a sensitivity of 92.3% (12/13) for recurrent disease (95% confidence limits; 63.9%, 99.8%) and a specificity of 80% (4/5; 95% confidence limits; 28.3%, 99.4%). SUR values were significantly higher in malignant lesions (range = 2.92–19.74, mean = 6.89) than in benign ones (range = 1.40–3.47, mean = 1.96; p= 0.002). Conclusion: FDG-PET is an accurate technique for detection of locally recurrent colorectal carcinoma. Visual analysis is equivalent to quantitative analysis for detection of disease.

Linkage of a Gene Causing Familial Membranoproliferative Glomerulonephritis Type III to Chromosome 1

Membranoproliferative glomerulonephritis (MPGN) type III is a chronic progressive renal disease of unknown cause. The diagnosis is based on renal pathologic features (specifically immunofluorescence staining patterns and ultrastructural appearance). Mesangial cell proliferation and subendothelial and subepithelial deposits characterize the renal disease. Although the actual prevalence of this disease is not known, the disease is rare and usually sporadic. The clinical features of MPGN include the nephrotic syndrome and hematuria, with renal dysfunction occurring in approximately 50% of patients. Progression to end-stage renal disease is variable, and some patients exhibit stabilization or even improvement. Here is presented an Irish family in which there are eight affected members in four generations, suggesting autosomal dominant inheritance. This is the only reported family with an inherited form of MPGN type III. To evaluate the disease in this family, a genome-wide scan was performed with a panel of 402 polymorphic microsatellite markers, defining a grid with an average resolution of 10 cM (centimorgans). Significant evidence for linkage was observed on chromosome 1q31-32, with a maximal logarithm of the odds score of 3.86 at theta = 0.00 for microsatellite marker GATA135F02. Recombination events among affected individuals, as detected by haplotype analysis, established a 22-cM minimal candidate region flanked by markers D1S3470 and GATA124F08. The data provide evidence for a gene for familial MPGN on chromosome 1q.

Magnetic Resonance Imaging for the Evaluation of Acute Abdominal Pain in Pregnancy

The investigation of acute abdominal pain in pregnancy is challenging. The use of ultrasound may be limited due to the patients change in body habitus and computed tomography is not desirable due to fetal irradiation. Magnetic resonance imaging (MRI) has thus become increasingly popular in the evaluation of such patients, due to its lack of ionizing radiation, multiplanar capability and high contrast resolution. This review will detail the MRI technique required to image the pregnant abdomen and describe the MRI features of common causes of acute abdominal pain in pregnancy.

Interobserver variability in the interpretation of unenhanced helical CT for the diagnosis of ureteral stone disease.

PURPOSE The purpose of this study was to analyze interobserver agreement in the interpretation of unenhanced helical CT (UHCT) for the evaluation of ureteral stone disease and obstruction. METHOD One hundred three UHCT examinations were independently and retrospectively reviewed by five readers including attending radiologists, a radiology resident, and an attending urologist. Examinations were interpreted as positive, negative, or indeterminate for ureteral stone disease and obstruction. The Cohen kappa test was used to measure interobserver agreement. The accuracy of the readers was also assessed. RESULTS The kappa value ranged from 0.67 to 0.71 among the three attending radiologists and from 0.65 to 0.67 among the radiology attending physicians and radiology resident. Although the urologist tended to agree less well with the other readers (kappa range: 0.33-0.46), there was no statistically significant difference (p < 0.05) in the accuracy among all five readers. The percentage of cases interpreted as indeterminate ranged from 8 to 25% and almost invariably involved difficulty distinguishing phleboliths from minimally obstructing distal ureteral calculi. The percentage of UHCT scans correctly interpreted as positive and correctly interpreted as negative ranged from 73% (n = 27) to 86% (n = 32) and 63% (n = 22) to 86% (n = 30), respectively. CONCLUSION Interobserver agreement was very good among the radiology attending physicians and resident and moderate with the urologist. The examination is an accurate technique in the evaluation of ureteral stone disease, although limitations exist, particularly in the diagnosis of minimally obstructing distal ureteral calculi.

Outcome Analysis of Patients with Acute Pancreatitis by Using an Artificial Neural Network

RATIONALE AND OBJECTIVES The authors performed this study to evaluate the ability of an artificial neural network (ANN) that uses radiologic and laboratory data to predict the outcome in patients with acute pancreatitis. MATERIALS AND METHODS An ANN was constructed with data from 92 patients with acute pancreatitis who underwent computed tomography (CT). Input nodes included clinical, laboratory, and CT data. The ANN was trained and tested by using a round-robin technique, and the performance of the ANN was compared with that of linear discriminant analysis and Ranson and Balthazar grading systems by using receiver operating characteristic analysis. The length of hospital stay was used as an outcome measure. RESULTS Hospital stay ranged from 0 to 45 days, with a mean of 8.4 days. The hospital stay was shorter than the mean for 62 patients and longer than the mean for 30. The 23 input features were reduced by using stepwise linear discriminant analysis, and an ANN was developed with the six most statistically significant parameters (blood pressure, extent of inflammation, fluid aspiration, serum creatinine level, serum calcium level, and the presence of concurrent severe illness). With these features, the ANN successfully predicted whether the patient would exceed the mean length of stay (Az = 0.83 +/- 0.05). Although the Az performance of the ANN was statistically significantly better than that of the Ranson (Az = 0.68 +/- 0.06, P < .02) and Balthazar (Az = 0.62 +/- 0.06, P < .003) grades, it was not significantly better than that of linear discriminant analysis (Az = 0.82 +/- 0.05, P = .53). CONCLUSION An ANN may be useful for predicting outcome in patients with acute pancreatitis.

Pancreatitis complicated by gland necrosis: evolution of findings on contrast-enhanced CT.

PURPOSE The purpose of this work was to investigate the natural history of pancreatic necrosis on contrast-enhanced CT in patients managed nonoperatively. METHOD A computer-based radiology information search revealed 32 patients with pancreatic necrosis who had had serial contrast-enhanced CT scans and were managed nonoperatively. There were 23 men and 9 women with a mean age of 51 years. One hundred forty-five contrast-enhanced CT scans were retrospectively reviewed for the location and extent of necrosis. The medical records of all patients were reviewed. RESULTS The 32 patients had a mean Ranson clinical grade of 5.8 (range 3-8). Eighteen of these 32 patients were managed nonoperatively, and 14 patients required a necrosectomy after initial nonoperative management. In the 32 patients, the location of necrosis was in the head (3), body (6), tail (2), head/body (2), head/body/tail (9), body/tail (9), and head/tail (1). Extent of necrosis was 0-25% (9), 26-50% (6), 51-75% (6), and 76-100% (11). The extent of necrosis remained stable during follow-up in 22 (69%) patients and increased during follow-up in 10 (31%). Necrosectomy was performed in six (60%) patients in whom there was an increase in necrosis and eight (36%) patients in whom necrosis was stable. No patient had restoration of normal enhancement in an area that was previously necrotic. There were five patients who were managed nonoperatively (mean follow-up 318 days) in whom the necrosis eventually resorbed, forming a focal parenchymal cleft reminiscent of a scar. Five of the 32 patients died. CONCLUSION Pancreatic necrosis as demonstrated by CT tends to remain stable in most patients treated nonoperatively. If the extent of necrosis increases, patients are more likely to require a necrosectomy. In some patients managed nonoperatively, the pancreatic necrosis will resorb, resulting in a fat-replaced cleft reminiscent of a scar.