Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity.

OBJECTIVE: The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals. DESIGN: Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism. SUBJECTS AND METHODS: Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR. RESULTS: The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable. CONCLUSIONS: These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated.

Bidirectional endoscopy in patients with fecal occult blood.

BACKGROUND: Current screening protocols for colorectal cancer depend primarily on fecal occult blood testing (FOBT). However, positive test results do not always indicate the presence of a colonic neoplasm. METHODS: We reviewed the results of 100 consecutive bidirectional (upper and lower) endoscopic procedures performed to evaluate positive FOBT results. Patients were excluded if they presented with gross bleeding, a history of bowel lesions, or previous intestinal operations. There were 31 women and 69 men whose mean age was 51 years. RESULTS: Major abnormalities were found on esophagogastroduodenoscopy (n = 24), colonoscopy (n = 13), or both studies (n = 2). Active bleeding was manifested in two patients, (Barrett's ulcer, duodenal arteriovenous malformation). Two other patients had malignancy: One had a cecal adenocarcinoma and the other a gastric adenocarcinoma. Various benign lesions also were identified in the stomach including esophagitis (n = 8), ulcers/erosions (n = 8) varices (n = 5), and arteriovenous malformations (n = 2). Colonic pathology included polyps (n = 8), arteriovenous malformations (n = 3), and rectal varices (n = 1). Diverticulosis and hemorrhoidal disease were present in 29 and 16 patients, respectively, but were not considered to be likely sources of a positive FOBT. CONCLUSION: Positive FOBT results may indicate the presence of either upper or lower intestinal pathology, and bidirectional endoscopy is an efficient and accurate technique for the comprehensive evaluation of occult bleeding.

Irofulven (6-hydroxymethylacylfulvene, MGI 114) induces caspase 8 and 9-mediated apoptosis in human pancreatic adenocarcinoma cells.

BACKGROUND: Irofulven (MGI 114) is a novel, clinically active sesquiterpene whose mechanism of action is not fully understood. We sought to identify apoptotic effectors induced by this agent in human pancreatic cancer cells. MATERIALS AND METHODS: MTT assay was used to assess IC50-Apoptosis was quantitated by flow cytometry and DAPI staining. Caspase activation was identified by western blot analysis. RESULTS: Irofulven was cytotoxic against all pancreatic cancer cell lines tested (IC50 1-18 microM), and induced 10-fold (4%+/- 2, vs. 41% +/- 5) induction of apoptosis. Irofulven-treated cells also demonstrated PARP3 cleavage and DAPI staining. Apoptosis was reduced to baseline levels by Z-VAD-FMK, a broad-spectrum caspase inhibitor. Western blot analysis revealed that caspases-3, -7, -8, and -9 were activated by irofulven. Time course evaluation demonstrated that caspases-8 and -9 were the initial species activated. CONCLUSION: Our data demonstrate that the cytotoxicity of irofulven in human pancreatic carcinoma cell lines is mediated by caspase-induced apoptosis.

Jejunoileal causes of overt gastrointestinal bleeding: diagnosis, management, and outcome.

Major bleeding from the small intestine is uncommon and difficult to localize. We examined its etiologies and assessed available diagnostic and therapeutic approaches. The records of all adults undergoing operation for small intestinal hemorrhage over a 10-year period (1/89-12/98) were reviewed. There were eight men and four women with a mean age of 54 years. Six patients presented with arteriovenous malformations. Preoperative diagnosis was by endoscopy (three of six), scintigraphy (two of two), and/or angiography (two of six). Intraoperative panendoscopy was used for localization in 5 cases. Three other patients had tumors (leiomyoma, leiomyosarcoma, and adenocarcinoma) by CT scan (two) and/or scintigraphy (two). All were resected but one patient died of recurrence. Two patients underwent resection of a Meckel's diverticulum, one after angiographic diagnosis. Another patient with Crohn's disease had a positive angiogram and colonoscopy before resection. There were no operative deaths but major morbidity occurred in five patients (42%) and hospitalization averaged 17 days. We conclude that jejunoileal lesions are a rare cause of intestinal bleeding but can be associated with substantial morbidity. Arteriovenous malformations and tumors remain the most common causes. An accurate diagnosis and definitive management depend on selective preoperative imaging and judicious operative exploration.

Operations for peptic ulcer disease: paradigm lost.

Over the past several decades, the pharmacologic and endoscopic treatment of peptic ulcer disease (PUD) has dramatically improved. To determine the effects of these and other changes on the operative management of PUD, we reviewed our surgical experience with gastroduodenal ulcers over the past 20 years. A computerized surgical database was used to analyze the frequencies of all operations for PUD performed in two training hospitals during four consecutive 5-year intervals beginning in 1980. Operative rates for both intractable and complicated PUD were compared with those for other general surgical procedures and operations for gastric malignancy. In the first 5-year period (1980 to 1984), a yearly average of 70 upper gastrointestinal operations were performed. This experience included 36 operations for intractability, 15 for hemorrhage, 12 for perforation, and seven for obstruction. During the same time span, 13 resections were performed annually for gastric malignancy. By the most recent 5-year interval (1994 to 1999), the total number of upper gastrointestinal operations had declined by 80% (14 cases), although the number of operations for gastric cancer had changed only slightly. Operations decreased most markedly for patients with intractability, but the prevalence of operations for bleeding, obstruction, and perforation was also decreased. We conclude that improved pharmacologic and endoscopic approaches have progressively curtailed the use of operative therapy for PUD. Elective surgery is now rarely indicated, and emergency operations are much less common. This changed paradigm poses new challenges for training and suggests different approaches for practice.

Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2.

In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-1R) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-1R was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-1R promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-1R mRNA in exponentially growing cells, thereby increasing the expression of IGF-1R to a level similar to that seen in quiescent cells. Increased IGF-1R signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-1 increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-1R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable.

The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma.

We evaluated the feasibility of dose escalation using external beam radiation therapy (RT) and 5-fluorouracil (5-FU) following pancreaticoduodenectomy for pancreatic carcinoma. Fourteen patients who underwent pancreaticoduodenectomy for stage I-III adenocarcinoma of the pancreas received postoperative high-dose chemoradiation. RT was given at 1.8-Gy daily fractions to total doses of 54 Gy for patients with negative surgical margins (n = 12), and 64.8 Gy for those with gross residual disease (n = 2). Concurrent 5-FU was given as a continuous infusion (CI) at 225 mg/m2 per day (n = 9) beginning or day 1 and continuing until the completion of RT, or by bolus injection at 500 mg/m2 per day (n = 5) during weeks 1 and 4 of RT. Follow-up ranged from 32 to 36 months (median, 35 months). All patients were able to complete the planned high-dose postoperative chemoradiation and none required a treatment break. No grade 4 acute toxicity was observed. Grade 3 acute toxicity was limited to 2 patients. Two patients developed grade 3 (n = 1) or 4 (n = 1) subacute toxicity, all gastrointestinal-related. There have been no fatal toxicities and no grade 3 or 4 late toxicity has been observed. The 3-year survival is 21%. Dose escalation of postoperative 5-FU chemoradiation following pancreaticoduodenectomy for pancreatic carcinoma is well tolerated. Further dose-intensification of postoperative adjuvant therapy in these patients appears feasible and is being evaluated in a recently activated national trial.

Blunt splenic injuries: dedicated trauma surgeons can achieve a high rate of nonoperative success in patients of all ages.

BACKGROUND: Selective nonoperative management (NOM) of blunt splenic injuries is becoming a more prevalent practice. Inclusion criteria for NOM, which have been a source of controversy, continue to evolve. Age > or = 55 years has been proposed as a predictor for failure of and even a contraindication to NOM of blunt splenic trauma. Additionally, the high rate of NOM in children (up to 79%) has been attributed to their management by pediatric surgeons. We evaluated our experience with NOM of blunt splenic injury with special attention to these age groups. METHODS: By using our trauma registry, all patients with blunt splenic injuries (documented by computed tomography, operative findings, or both) cared for over a 36-month period, at a single American College of Surgeons verified Level I trauma center were reviewed. Detailed chart reviews were performed to examine admission demographics, laboratory data, radiologic findings, outcome measures, and patient management strategy. All patients were managed by nonpediatric trauma surgeons. We then compared our adult data with that in the recent literature and our pediatric data with that of the National Pediatric Trauma Registry over the same time period. RESULTS: We identified 251 consecutive patients with blunt splenic injuries. Eighteen patients who expired in the immediate postinjury period were excluded from statistical evaluation. No deaths occurred as a result of splenic injury. Of the remaining 233 patients, 73 patients (31%) required early celiotomy, 160 patients (69%) were selected for NOM, with 151 patients (94%) being successfully managed without operation. Blunt splenic injury occurred in 23 patients age 55 years or older. Eighteen patients (78%) were selected for NOM and 17 patients (94%) were successfully treated without operation. Blunt splenic injury occurred in 35 patients less than 16 years of age. Thirty-two patients (91%) were selected for NOM. Thirty-one patients (89% of all pediatric patients) were successfully treated without operation. CONCLUSION: Age > or = 55 years is not a contraindication to nonoperative management of blunt splenic injuries. Children with blunt splenic injuries can be successfully managed nonoperatively by nonpediatric trauma surgeons.

Characterization of a newly established human pancreatic carcinoma cell line, UK Pan-1.

BACKGROUND: A highly tumorigenic cell line designated as UK Pan-1 was established in a surgically removed human pancreatic adenocarcinoma and characterized as having many of the genotypic and phenotypic alterations commonly found in pancreatic tumors. METHODS: The cell line was characterized by its morphology, growth rate in monolayer culture and soft agar, tumorigenicity in nude mice, and chromosomal analysis. Furthermore, the status of p53, Ki-ras mutation and transforming growth factor (TGF)-/receptor expression were determined. The characteristics of UK Pan-1 were compared with those of other commonly used pancreatic carcinoma cell lines. RESULTS: Quiescent UK Pan-1 cells could be stimulated to proliferate in growth factor free nutrient media, indicating a growth factor independent phenotype. UK Pan- 1 cells grew in soft agar and rapidly formed tumors in nude mice. This cell line possesses a mutation at codon 12 of the c-Ki-ras-2 gene that is commonly found in pancreatic carcinoma. Fluorescence in situ hybridization showed that two alleles of p53 tumor suppressor gene were present in UK Pan-1. However, sequencing analysis revealed a mutation in one allele at exon 8, codon 273 (G to A; Arg to His). Additional growth assays indicated that the cell line was insensitive to negative growth regulation induced by exogenous TGF-beta. Molecular analysis of the TGF-beta signaling pathway showed that UK Pan-1 did not express appreciable levels of the TGF-beta receptor type I, II, or III mRNAs, but did express DPC4 mRNA. Karyotype analysis revealed an 18q21 deletion indicating a possible loss of heterozygosity for DPC4, as well as other chromosomal deletions and rearrangements. CONCLUSIONS: This study indicates that UK Pan-1 is a highly tumorigenic cell line possessing a molecularly complex pattern of mutations that may be used as a model to further the understanding of the mechanisms responsible for the development of pancreatic carcinoma.

Operative management of diverticular emergencies: strategies and outcomes.

HYPOTHESIS: A selective surgical approach using either a 1- or a 2-stage resection is relatively safe and effective in the management of acute complicated colonic diverticulosis. DESIGN: A consecutive cohort study. SETTING: A university hospital. PATIENTS: Eighty-nine consecutive patients who underwent emergency operations for diverticular disease between July 1, 1984, and June 30, 1999. There were 53 male and 36 female patients (mean age, 47 years). The ethnic background was predominantly Mexican American (58 patients [65.2%]). INTERVENTIONS: Resections of the affected colon (n = 83) plus construction of a Hartmann pouch or mucous fistula (n = 72) or primary anastomosis (n = 11). MAIN OUTCOME MEASURES: Morbidity, mortality, and length of hospital stay. RESULTS: Sixty-eight operations were performed for perforation at an annual rate that has increased greater than 75% in the past 15 years. Another 14 patients underwent operations for obstruction, and 7 underwent operations to control unremitting hemorrhage. Surgical therapy included resection of the affected segment of the bowel in 83 (93%) of the 89 patients, and a Hartmann pouch or mucous fistula was added in 72 (81%). A primary anastomosis was performed in 4 (80%) of 5 right-sided lesions but in only 7 (8%) of 84 left-sided lesions. Morbidity occurred in 38 (43%) of the 89 patients, and the mortality was 4%, with 4 deaths occurring secondary to sepsis in high-risk patients with perforations (n = 3) or obstructions (n = 1). The average length of hospital stay was 19.7 days (range, 5-80 days). CONCLUSIONS: Emergency operations for diverticular disease are uncommon but may be associated with substantial morbidity and occasional mortality. Complicated diverticulosis may present at a relatively young age, and perforated forms appear to be increasing rapidly in prevalence. Most diverticular lesions can be satisfactorily managed using a selective approach based on resection with either a primary anastomosis or a temporary colostomy.

Endoscopically assisted "components separation" for closure of abdominal wall defects.

The repair of ventral hernia defects of the abdominal wall challenges both general and plastic surgeons. Ventral herniation is a postoperative complication in 10 percent of abdominal surgeries; the repair of such defects has a recurrence rate as high as 50 percent. The "components separation" technique has successfully decreased the recurrence rates of ventral abdominal hernias. However, this technique has been associated with midline dehiscence and a prolonged postoperative stay at the authors' institutions. The purpose of this study was to determine whether endoscopically assisted components separation could minimize operative damage to the vasculature of the abdominal wall and decrease postoperative wound dehiscence. The study group consisted of seven patients who underwent endoscopically assisted components separation; the control group consisted of 30 patients who underwent open components separation. The two groups were similar regarding demographic data and defect size. The endoscopic group had a higher initial success rate than the open group (100 versus 77 percent). Recurrence rates were not significantly different between the two groups. However, the endoscopically assisted components separation patients had fewer postoperative and long-term complications. In the authors' experience, endoscopically assisted components separation has proved to be a safe and effective method for the repair of complicated and recurrent midline ventral hernias.

Laparoscopic cholecystectomy for biliary tract emergencies: state of the art.

Although laparoscopic cholecystectomy is unusually safe and well tolerated in patients with routine symptomatic cholelithiasis, it can become a formidable procedure when used to manage biliary tract emergencies. Optimally, a reasoned and cautious approach and a low threshold for conversion can avoid major complications. One such emergency, acute cholecystitis, may be particularly hazardous because of the relatively common finding of severe inflammation with dense adhesions to adjacent viscera and gallbladder necrosis. Special modifications of technique may be required. Overall, urgent operation (within 72 hours) results in an acceptably low mortality (0.3%) but a somewhat higher conversion rate (16%) and longer hospital stay (3 days). Unnecessary delays may result in more adhesions and an increased level of operative difficulty. In patients who are at an especially high risk because of co-morbid disease, percutaneous cholecystostomy is an appropriate alternative strategy. Biliary pancreatitis may be associated with high mortality (9%) and has an unpredictable course. Accordingly, a multidisciplinary approach that may include both gastroenterologists and radiologists is generally advisable. Because common bile duct (CBD) stones are present in more than 20% of patients who present with biliary pancreatitis, endoscopic retrograde cholangiopancreatography (ERCP) can be used effectively on a selective basis during the preoperative or postoperative period; the preferred timing continues to be somewhat controversial. As an alternative approach, laparoscopic CBD exploration is gradually gaining wider acceptance. In eight reported series using a variety of techniques for stone extraction, major complications were infrequent (10%), and the conversion rate was low (5%). Acute suppurative cholangitis is a more fulminant problem that is best managed by expeditious ERCP with removal of all intraductal stones. Resuscitation should be continued until complete; laparoscopic cholecystectomy can follow at an appropriate interval.

Biliary pancreatitis: the era of laparoscopic cholecystectomy.

OBJECTIVE: To evaluate the efficacy and safety of a combined approach to the treatment of biliary pancreatitis using laparoscopic cholecystectomy and selective endoscopic retrograde cholangiopancreatography (ERCP). DESIGN: Consecutive case series. SETTING: Tertiary care center. PATIENTS: All patients undergoing primary operations for biliary pancreatitis during 2 time periods were included. In the open era (June 1982 through May 1988), there were 276 patients; in the laparoscopic era (January 1996 through June 1997), there were 114 patients. INTERVENTIONS: Open cholecystectomy with or without common bile duct exploration (CBDE); laparoscopic cholecystectomy with selective ERCP and/or laparoscopic CBDE. MAIN OUTCOME MEASURES: Two periods were compared for morbidity, mortality, the duration of preoperative and postoperative stays, and the total length of hospitalization. RESULTS: Both groups were demographically similar and had the same mortality (1.9%). Laparoscopic cholecystectomies provided a preoperative stay comparable to open cholecystectomy (6.4 vs 5.8 days), a shorter postoperative stay (1.5 vs 8.5 days), a lower incidence of CBDE (6.6% vs 26%), and a lower morbidity (8% vs 13.7%). The addition of an ERCP to laparoscopic cholecystectomy was associated with prolongation of the preoperative stay (7.4 vs 5.0 days), a comparable postoperative stay, a lower conversion rate (7.5% vs 13%), and fewer CBDEs (3% vs 13%). In 27 (42%) of the 64 ERCP cases, no stones were found. CONCLUSIONS: Treatment of biliary pancreatitis with combined laparoscopic cholecystectomy and selective ERCP is safe and effective and is associated with a shorter hospitalization and fewer CBDEs than open cholecystectomy. Unnecessary ERCPs can be reduced by improved selection criteria or greater dependence on operative CBDE.

Biliary sludge formation during enteral nutrition: prevalence and natural history.

BACKGROUND: Total parenteral nutrition is an etiologic factor in the formation of biliary sludge. We studied whether enteral nutrition is also a risk factor for sludge. METHODS: Fifty patients with a needle catheter jejunostomy (NCJ) placed during a major abdominal operation underwent preoperative and weekly postoperative ultrasonography until NCJ feedings were discontinued (1 to 6 weeks). RESULTS: All patients were men. The mean age was 63.2 +/- 1.6 years. Fourteen asymptomatic patients (28.0%) had biliary sludge within 2 weeks of beginning enteral feedings through a NCJ. Complete ultrasonographic resolution of sludge was observed in 13 of the 14 positive patients within 1 to 2 weeks of resuming an oral diet. One patient was lost to follow-up after 14 week; a positive sonogram had persisted but the patient remained asymptomatic. During the period of observation, no other patient had signs of biliary tract disease. CONCLUSIONS: (1) Biliary sludge may form in some patients during enteral feeding with NCJ. (2) Sludge is cleared by the gallbladder once an oral diet is resumed. (3) There appears to be little risk of complications during postoperative enteral feeding.

Ward evaluations: should they be abandoned?

Even in the era of the objective structured clinical examination (OSCE), the predominant method of resident evaluation is the faculty ward evaluation (WE), despite many concerns about its reliability. The aim of this study was to determine the value of the WE as a measurement of clinical competence in terms of both reliability and validity. In a one-year period, surgery faculty members evaluated 72 residents. An average of 7 faculty members evaluated each resident. The evaluation form contained 10 specific performance ratings and an overall evaluation. Inter-rater reliability of the overall performance ratings was calculated by using the intraclass correlation. Validity of the WE was evaluated in four ways. Inter-rater reliability of the overall performance rating was 0.82; the reliability of a single overall rating was 0.39. (1) A discriminant function analysis indicated that residents at advanced levels of training received more positive evaluations than residents at less advanced levels (P < 0.0001). (2) The overall rating was significantly correlated (r = 0.55, P < 0.0001) with the overall score of a concurrent OSCE. (3) A factor analysis showed high correlations among the items, indicating a lack of discrimination between the skills. (4) Overall ratings were insensitive to performance deficiencies. Only 1.3% of the ratings were unsatisfactory or marginal. The WE was sufficiently reliable to estimate the faculty's view of each resident. The fact that the ratings tended to differentiate residents by level of training and that ratings significantly correlated with the OSCE provides strong evidence of their validity. However, factor analysis indicated that the faculty members were making one global, undifferentiated judgment and that these ratings did not identify deficient performance skills. We conclude that ward evaluations have a place in the assessment of residents.

Residents' evaluation of a problem-based learning curriculum in a general surgery residency program.

METHODS: To determine residents' satisfaction with problem-based learning and its tutors, to determine how residents prepare for sessions, and to identify the characteristics of both effective sessions and tutors, we analyzed 132 evaluations from 24 residents who completed 1 or more of the 9 cases presented during the first 9 months of our program. The 38-item evaluation questionnaire asked residents to rate tutor characteristics, various aspects of the sessions, and methods used to prepare for the sessions. RESULTS: Residents were well satisfied with the problem-based learning sessions and with the logistics of our program; they found the overall quality of the tutor more important than that of the case; they valued an active, thought-provoking tutor more than a traditional facilitator; and they most often used standard textbooks to prepare for the sessions. CONCLUSIONS: Problem-based learning is a practical, enjoyable graduate curricular vehicle when implemented with well-written cases and active tutors.

The multidisciplinary structured clinical instruction module as a vehicle for cancer education.

BACKGROUND: The Structured Clinical Instruction Module (SCIM) modifies the Objective Structured Clinical Examination (OSCE) for teaching purposes. This study determined the effectiveness of a breast cancer SCIM in enhancing residents' clinical skills. METHODS: Twenty-five residents, 15 faculty members, and 12 breast cancer patients (simulated and actual) participated in the multistation, multidisciplinary SCIM. Afterward, faculty members, residents, and patients evaluated the SCIM. Residents completed an 18-item self-assessment of their skills before and after the SCIM. RESULTS: All residents, faculty members, and patients rated the SCIM as either outstanding or above average as an educational experience. The residents' self-assessments of their skills were significantly higher after the SCIM than before. CONCLUSIONS: This study shows that residents are aware of their deficiencies in breast cancer management. The SCIM provides an excellent format for residents to improve their clinical skills.

Measuring the ability of residents to manage oncologic problems.

BACKGROUND: An OSCE was used to measure the ability of a cohort of residents to manage oncologic problems. METHODS: Nine oncologic clinical problems were presented to 56 surgical residents. Each problem contained a 5-minute data-gathering period (DGP) and a 5-minute data-interpretation period (DIP). A performance score was determined for each resident for each problem. Reliability was estimated by coefficient alpha; validity, by the construct of experience. Wilks's lambda criterion was used to determine whether training level could be identified by OSCE performance. RESULTS: The DGP reliability was 0.80; the DIP, 0.49. Senior residents performed significantly better than junior residents (P = 0.0001), who performed significantly better than interns (P = 0.0009). Of the residents, 62% were competent on the DGP, but only 21% on the DIP. Important deficits in knowledge and clinical skills were apparent at all levels of training. CONCLUSION: The education and evaluation of residents in oncology need improvement.

Efficacy of p120 antisense-mediated therapy for pancreatic cancer.

p120 antisense oligodeoxynucleotides were used to determine whether they inhibited cell growth of MIA PaCa-2, a highly tumorigenic human pancreatic carcinoma cell line. Growth inhibition assays were determined in vitro by the ability of these oligomers to inhibit DNA synthesis and cell growth. For in vivo studies, nude mice were injected with cells and palpable tumors were found in 16 of 20 animals by day 14. Sixteen animals (8 in each group) were then treated daily (25 mg/kg intraperitoneally) for up to 40 days with nonsense control oligomers or p120 antisense oligomers. p120 Antisense oligomers inhibited the in vitro proliferation of MIA PaCa-2 cells in a dose-dependent manner, and optimal growth inhibition of greater than 90% was achieved at an antisense oligomer concentration of 100 micromol/L. The tumor volume was calculated for antisense- and nonsense-treated animals. Fifteen days after the beginning of treatment, control animals had a significantly greater (P=0.0035) tumor volume (425=244 mm3 above baseline) as compared to p120 antisense-treated animals (166+/-116 mm3). Seven of the eight control animals formed tumors that had a volume greater than 1200 mm3 45 days after treatment was begun, whereas only three of eight p120 antisense-treated animals had tumors that were this large. Two of the latter three animals had relatively large, palpable tumors (>150 mm3) prior to treatment. Twenty days after treatment was stopped (day 60), all animals had tumors larger than 1200 mm3. p120 Antisense oligomers were effective for inhibiting in vitro growth of the pancreatic cancer cell line MIA PaCa-2. In preliminary studies, p120 antisense oligomers appeared to inhibit the rate of growth in nude mice; however, no cures were achieved. The most effective response was seen in animals with initial low tumor burden.