VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA.

BACKGROUND: We investigated the safety and efficacy of bevacizumab combined with gemcitabine followed by infusional 5-fluorouracil (5-FU) in patients with advanced pancreas cancer (APCA). DESIGN: Patients with untreated APCA received bevacizumab 10 mg/kg, gemcitabine 1000 mg/m(2) over 100 min, and 5-FU 2400 mg/m(2) over 48 h on days 1 and 15 of each 28-day cycle. The primary end point was the proportion of patients with progression-free survival (PFS) at 6 months from initiation of therapy. If PFS at 6 months was ≥41%, the regimen would be considered promising. RESULTS: Forty-two patients were enrolled in the study; of which, 39 were evaluable for primary end point. PFS at 6 months was 49% (95% CI 34% to 64%). Median PFS was 5.9 months (95% CI 3.5 to 8.1) and median overall survival (OS) was 7.4 months (95% CI 4.7 to 11.2). Partial response and stable disease occurred in 30% and 45% of patients, respectively. Treatment-related hypertension and normal baseline albumin correlated with an improved response rate, PFS and OS. Grade 3 to 4 toxicities included fatigue (14%), hypertension (5%), and venous thrombosis (5%). CONCLUSIONS: The study met its primary end point. Further investigation of anti-VEGF therapy in combination with fluoropyrimidine-based therapy is warranted in APCA. Treatment-related hypertension and normal baseline albumin may predict for the efficacy of bevacizumab and should be investigated in prospective studies.

Robotic resection of pancreatic neuroendocrine tumor.

Computer-assisted surgical devices, or "surgical robots," have recently been approved for general surgical use. The device allows the surgeon remote control of multi-articulated instrument arms with a three-dimensional view. Here we report the first known case of pancreatic resection with use of a computer-assisted, or robotic, surgical device. A 46-year old woman presented with back pain and a complex cystic mass in the tail of the pancreas. The daVinci surgical robot was used to remove the lesion en bloc with the tail of the pancreas and spleen. The patient did well and returned to full activity promptly. In summary, robotic technology may enhance advanced laparoscopic procedures. Pancreatic resection is feasible, and future experience will determine the true benefits of this technique.

Computer-enhanced robotic telesurgery. Initial experience in foregut surgery.

BACKGROUND: A new type of computer-enhanced telemanipulator device for "robotic" laparoscopic surgery was recently approved. We prospectively evaluated the initial patients undergoing procedures with this new device at our institution. METHODS: Patient demographics, operative indications, port placement, operative time, robot time, complications, and hospital stay were recorded. Follow-up evaluation was appropriate for the individual procedure. RESULTS: Initially, 35 cases were managed. There were 22 anti-reflux procedures, 9 Heller myotomies, 1 pyloroplasty, 1 distal pancreatectomy with splenectomy, 1 esophagectomy with intrathoracic anastomosis, and 1 diagnostic laparoscopy. The operative times ranged from 88 to 458 min. The robot use times were between 16 and 185 min. There were no device-related complications. CONCLUSIONS: Computer-enhanced robotic telesurgery is a safe and effective treatment method for a variety of diseases of the proximal gastrointestinal tract. Further study is needed to determine the benefits of this approach as compared with current technology.

Computer-assisted robotic heller myotomy: initial case report.

PURPOSE: Our objective was to determine the efficacy of computer-assisted robotic laparoscopic Heller myotomy. METHODS: A 76-year-old woman with a significant history of achalasia was evaluated for laparoscopic Heller myotomy. The daVinci surgical system was used throughout the procedure. RESULTS: Computer assistance allowed scaling of hand motions from a range of 2:1 to 5:1. Successful dissection of the esophageal musculature was accomplished, and a Toupet-type fundoplication was performed. The patient was discharged from the hospital the day after surgery with five port incisions, each <1 cm. CONCLUSIONS: Telemanipulator computer-assisted surgical devices may have applications in procedures that require advanced and finely tuned motions, such as Heller myotomy. The benefits of extra magnification and three-dimensional imaging can help prevent esophageal perforation and identify residual circular muscle fibers.

Major pancreatic resections for chronic pancreatitis.

OBJECTIVE: Indications for major pancreatic resections have been expanded to include complicated chronic pancreatitis (CP). We assessed clinical findings and outcomes and evaluated histology in patients who had major pancreatic resections for CP. We also determined if histologic findings were associated with persistent postoperative pain. DESIGN: We reviewed charts and slides from 44 patients who underwent major pancreatic resections for CP between 1989 and 1999. RESULTS: The etiology for disease included alcohol (n = 15), hereditary (n = 5), idiopathic (n = 6), pancreas divisum (n = 3), stricture (n = 2), trauma (n = 2), systemic lupus erythematosus (n = 1), and unknown (n = 10). Patients included 20 men and 24 women; ages ranged from 22 to 76 years. Perioperative mortality and morbidity were 0% and 4.5%, respectively. Persistent pain was present in 25 (57%) of the 44 patients, and pain was encountered more frequently in patients with alcoholic pancreatitis (67%) versus other etiologies (52%), and in those who underwent Whipple/Beger or total resections (68%) versus distal or subtotal pancreatectomy (42%). Metaplastic changes were present in 14 cases, and ductal atypia was seen in 9 cases. No malignancies were found. Acinar necrosis and acute inflammation were seen more often in patients with persistent pain than in those who were pain free (P =.081). CONCLUSION: Major pancreatic resection for CP can be performed with low morbidity and mortality. This procedure relieves pain in nearly half the patients. There is a wide spectrum of histopathologic changes seen in CP, including ductal atypia and metaplastic changes. Acute exacerbations of CP identified histologically at the time of surgery and alcohol as etiology for CP may be associated more frequently with intractable pain.

Ultrasonography incorrectly diagnoses gallbladder polyps.

To determine the accuracy of ultrasound-diagnosed polypoid lesions of the gallbladder in their institution, the authors reviewed the records of 41 patients with polypoid lesions of the gallbladder who underwent cholecystectomy, and collected data concerning age, sex, symptoms, and histopathologic diagnosis. Histopathologic evaluation confirmed polyps in only two patients (4.9%) categorized as having polypoid lesions of the gallbladder. Most specimens from patients with ultrasonography reports suggesting small polyps manifested cholesterolosis (17 of 41) or cholelithiasis (15 of 41). No specimen harbored malignancy. Mean patient age was 47.4 years, and the most common symptoms were pain (85%), nausea (44%), vomiting (29%), and abnormal liver function test results (14%). The accuracy of sonography for diagnosing polypoid lesions of the gallbladder was poor. Many of the small polyps seen on sonography most likely represented a stone embedded in the gallbladder wall or other abnormality. Because of the likelihood of cholelithiasis, the authors recommend that patients with biliary symptoms and ultrasonography findings suggesting polypoid lesions of the gallbladder undergo cholecystectomy.

Transmission of live laparoscopic surgery over the Internet2.

BACKGROUND: Video broadcasting of surgical procedures is an important tool for education, training, and consultation. Current video conferencing systems are expensive and time-consuming and require preplanning. Real-time Internet video is known for its poor quality and relies on the equipment and the speed of the connection. The Internet2, a new high-speed (up to 2,048 Mbps), large bandwidth data network presently connects more than 100 universities and corporations. We have successfully used the Internet2 to broadcast the first real-time, high-quality audio/video program from a live laparoscopic operation to distant points. METHODS: Video output of the laparoscopic camera and audio from a wireless microphone were broadcast to distant sites using a proprietary, PC-based implementation of H.320 video conferencing over a TCP/IP network connected to the Internet2. The receiving sites participated in two-way, real-time video and audio communications and graded the quality of the signal they received. RESULTS: On August 25, 1998, a laparoscopic Nissen fundoplication was transmitted to Internet2 stations in Colorado, Pennsylvania, and to an Internet station in New York. On September 28 and 29, 1998, we broadcast laparoscopic operations throughout both days to the Internet2 Fall Conference in San Francisco, California. Most recently, on February 24, 1999, we transmitted a laparoscopic Heller myotomy to the Abilene Network Launch Event in Washington, DC. CONCLUSIONS: The Internet2 is currently able to provide the bandwidth needed for a turn-key video conferencing system with high-resolution, real-time transmission. The system could be used for a variety of teaching and educational programs for experienced surgeons, residents, and medical students.

Identification of MEN1 mutations in sporadic enteropancreatic neuroendocrine tumors by analysis of paraffin-embedded tissue.

Gastrinomas and other gastrointestinal neuroendocrine tumors may occur sporadically or as part of the inherited syndrome multiple endocrine neoplasia type 1 (MEN1). Mutations in the recently identified MEN1 gene have been described in sporadic gastrinomas and insulinomas. This study describes techniques used to identify mutations in the MEN1 gene in DNA extracted from paraffin-preserved tissue. Two novel mutations are identified in the MEN1 gene from nine archived paraffin-embedded neuroendocrine tumors, demonstrating that retrospective genetic analysis can be used to identify mutations in the MEN1 gene from preserved tissue. Conditions are provided by which paraffin-embedded tissue can be used as a source of genetic material for sequence information of sufficient quality for mutational studies of the MEN1 gene. It should also be possible to apply this retrospective genetic analysis of paraffin-embedded tissue to other disease models.

Outcome analysis of long-term survivors following pancreaticoduodenectomy.

The long-term sequelae of pancreaticoduodenectomy are not completely understood. In the present study nutritional status, pancreatic function, and subjective quality-of-life parameters were evaluated in 45 patients who had previously undergone either pylorus-preserving pancreaticoduodenectomy (PPPD) or standard pancreaticoduodenectomy (SPD). Quality-of-life parameters, as measured by the Short Form-36 health survey, demonstrated no significant differences between the subgroups and normal control subjects in six of the eight domains for physical and mental health. Patients who had undergone SPD were noted to have significantly lower scores for general health and vitality than either age-matched control subjects or those who had undergone PPPD. No differences in nutritional parameters or indicators of pancreatic exocrine function between the two groups were identified. An elevated hemoglobin A1c value was seen in only one patient who was not diabetic preoperatively. Our data indicate that long-term survivors of pancreaticoduodenectomy generally feel as good as their normal counterparts, although SPD may result in some health satisfaction deficits. Nutritional status and pancreatic exocrine function are not improved in patients undergoing a pylorus-preserving procedure, and postoperative pancreatic endocrine dysfunction is unusual in both groups.

Therapeutic alternatives in metastatic neuroendocrine tumors.

In the treatment of neuroendocrine tumors that cannot be resected for cure two goals must be addressed: (1) the control of symptoms related to hormonal hypersecretion and (2) the prolongation of survival by destruction of tumor of the limitation of its growth. Clinical approaches, medical and surgical, have been developed in recent years to meet these goals. Surgical options in the face of metastatic disease include resection of hepatic metastases, cryoablation, and liver transplantation. Medical therapy includes treatment of symptomatic hypersecretory states and systemic chemotherapeutic and immunomodulatory regimes. Hepatic artery chemoembolization has also been used successfully in the treatment of hepatic metastases of neuroendocrine tumors.

Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism?

Pentose phosphate pathways (PPP) are considered important in tumor proliferation processes because of their role in supplying tumor cells with reduced NADP and carbons for intracellular anabolic processes. Direct involvement of PPP in tumor DNA/RNA synthesis is not considered as significant as in lipid and protein syntheses. Currently, PPP activity in tumor cells is measured by lactate production, which shows a moderate activity: about 4% to 7% compared with glycolysis. Recent data generated in our laboratory indicate that PPP are directly involved in ribose synthesis in pancreatic adenocarcinoma cells, through oxidative steps (< 31%) and transketolase reactions (69%). These findings raise serious questions about the adequacy of lactate in measuring PPP activity in tumors. We hypothesize that ribose, not lactate, is the major product of PPP in tumor cells. Control of both oxidative and nonoxidative PPP may be critical in the treatment of cancer. PPP are substantially involved in the proliferation of human tumors, which raises the prospect of new treatment strategies targeting specific biochemical reactions of PPP by hormones related to glucose metabolism, controlling thiamine intake, the cofactor of the nonoxidative transketolase PPP reaction, or treating cancer patients with antithiamine analogues.

Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation.

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.

Detection of aerosolized cells during carbon dioxide laparoscopy.

Laparoscopic surgery for malignancy has been complicated by port-site recurrences. The exact mechanism has yet to be defined. In vitro studies suggest that carbon dioxide-induced tumor cell aerosolization may play a role. We have attempted to document this in a human model. Patients scheduled for elective laparoscopy underwent port placement and abdominal insufflation with carbon dioxide. A suction trap was then filled with 40 cc of normal saline solution and attached to an insufflation site on the port. The carbon dioxide effluent was directed through the saline. The specimen was concentrated, resuspended, and transferred to a slide. A Papanicolaou stain was used. Thirty-five specimens were obtained. Fifteen patients (37%) had malignant disease, which was metastatic in eight. Five patients had carcinomatosis. In two of those with carcinomatosis, staining revealed a large number of malignant cells. Malignant cells were not found in any other patients. In two patients, however, aerosolized mesothelial cells were identified. Follow-up ranged from 2 to 7 months. One patient who displayed cellular aerosolization developed a port-site recurrence. We conclude that malignant cells are aerosolized but only during laparoscopy in the presence of carcinomatosis. It is unlikely that tumor cell aerosolization contributes significantly to port-site metastasis.

Dehydroepiandrosterone-sulfate inhibits pancreatic carcinoma cell proliferation in vitro and in vivo.

BACKGROUND: Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo. METHODS: In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment. RESULTS: In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones. CONCLUSIONS: DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.

Photodynamic therapy for esophageal malignancy: a prospective twelve-year study.

BACKGROUND: We wanted to determine factors affecting survival rates of benefits to, and complications in patients with esophageal cancer treated with photodynamic therapy. METHODS: From 1982 to January 1994, we used photodynamic therapy to treat 77 patients with esophageal carcinoma and evaluated survival to July 1994. All patients had failed, refused, or were ineligible for surgical intervention, ionizing radiation therapy, or chemotherapy. RESULTS: The only significant variable affecting survival was clinical stage. Median survival after photodynamic therapy was as follows: all patients, 6.3 months (mean survival, 9.2 months); stage I, not reached; stage II, 12 months; stage III, 6.2 months; and stage IV, 3.5 months. For stages III and IV, a Karnofsky performance status of 70 or higher had a significant effect. For stage III, the median survival was 6.3 months when the Karnofsky performance status was equal to or greater than 70 and 3.5 months when it was less than 70. For stage IV, the median survival was 5.5 months when the Karnofsky performance status was equal to or greater than 70 and 2.5 months when it was lower than 70. Seven stage I patients with no treatment prior to photodynamic therapy had an estimated 5-year survival rate of 62%. Three patients with stage I invasive adenocarcinoma and Barrett's mucosa diagnosed when they underwent endoscopy for dysphagia were alive with no evidence of disease 17, 44, and 59 months after photodynamic therapy. CONCLUSIONS: Photodynamic therapy for esophageal carcinoma caused minimal complications and no procedure-related deaths. Photodynamic therapy can be considered an alternative treatment for patients with Barrett's esophagus with severe dysplasia or patients with stage I carcinoma who are under consideration for operation but are high surgical risks. The length of palliation for patients having "noncurative" treatment was equal to or better than that reported historically for most other treatment regimens.

Laparoscopic skills enhancement.

BACKGROUND: Laparoscopy requires a unique subset of surgical skills that, for the inexperienced, can significantly delay the development of basic operative skills. We hypothesized that learning laparoscopic suturing and knot tying would improve laparoscopic skills. METHODS: A laparoscopic training seminar for junior surgical residents was established to test this hypothesis. Emphasis was placed on laparoscopic knot tying and suturing. Skills were assessed at the beginning and the end of the course. RESULTS: All residents showed significant improvement. Dominant and nondominant hand skills improved by 30.2% and 26.9%, respectively. Two-handed skills improved by 58.6% and 30.1%. Overall scores improved by 28.9%. CONCLUSIONS: A structured laparoscopic skills course stressing knot tying and suturing is an effective way to develop dexterity and significantly improve the performance of laparoscopic tasks. These improvements can be accomplished in a cost-effective curriculum that should enhance the surgical education of residents and speed the acquisition of competent operative skills.

Pancreatic pseudocysts following acute pancreatitis.

BACKGROUND: Pancreatic pseudocysts (PP) following acute pancreatitis have traditionally been approached by observation to allow cyst maturation. However, recent evidence suggests a selective approach toward management is indicated. METHODS: We retrospectively reviewed the presentation, operative management, and outcome of patients developing PP following acute pancreatitis since 1988. PP related to chronic pancreatitis were excluded. RESULTS: Twenty-seven patients were identified, 17 with giant PP (> 10 cm) and 10 with PP less than 10 cm. Groups were not different with respect to age and etiology of pancreatitis, predominantly biliary. Patients with giant PP had a significantly greater number of Ranson criteria at presentation and underwent drainage procedures earlier following their initial presentation. With respect to giant PP, 7 patients underwent internal drainage all via cystogastrostomy with 5 complications. Nine of 10 patients underwent urgent operation via external drainage. There were 3 pancreatic fistulas in this group. The morbidity and mortality rates for giant PP were 65% and 18% respectively. With respect to smaller PP, 8 underwent internal drainage with 1 death (mortality rate 10%). External drainage was performed in 2 patients with 1 pancreatic fistula (morbidity 10%). CONCLUSIONS: Patients with PP and a high Ranson score following acute pancreatitis are at significant risk for giant PP formation. Expectant management of giant PP is associated with higher morbidity and mortality than small PP suggesting that earlier external drainage, before clinical deterioration, may be beneficial. To be accurate, comparisons of outcomes for various treatment modalities must take into consideration PP size.