Frederic E. Eckhauser

Phase I Trial of Radiation Dose Escalation With Concurrent Weekly Full-Dose Gemcitabine in Patients With Advanced Pancreatic Cancer

PURPOSE The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest. RESULTS Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management. CONCLUSION The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.

Microgastrinomas of the duodenum: a cause of failed operations for the Zollinger-Ellison syndrome

Gastrinomas are now being detected at an earlier stage than was formerly the case. Furthermore, with the ability to control acid secretion, emphasis has been placed on identifying gastrinoma patients who are potentially curable by tumor resection rather than by palliative gastrectomy. Despites estimates suggesting that 20-40% of sporadic gastrinoma patients can be successfully resected for cure, as many as 40% of such patients have occult tumors that elude detection. In an effort to better localize gastrinomas, we have used percutaneous transhepatic venous (THVS) gastrin sampling over the past 10 years. From 1978 to 1988, THVS was used in 46 patients in whom there was no other evidence of metastatic gastrinoma by conventional studies. Gastrinomas were found at operation in all but one patient. The purpose of this report is to emphasize that occult tumors are most often found in the duodenal wall, and frequently they may be no greater than 2 mm in diameter. Five recent cases illustrate that these small tumors or microgastrinomas may be the sole source of hypergastrinemia and can be cured by local excision. These recent cases emphasize that microgastrinomas are not usually palpable through the duodenal wall. They may be detected only after duodenotomy and meticulous evaluation of the mucosa by eversion and direct palpation. Duodenotomy and intraluminal exploration should be considered an essential component of the operation for patients with extrapancreatic gastrinomas.

Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas

The combination of gemcitabine with concurrent radiation therapy (Gem/RT) is a promising new approach that is being investigated in patients with unresectable pancreatic cancer. However, substantial toxicity with this combination has also been observed. This review was conducted to determine whether Gem/RT could be safely delivered in the neoadjuvant setting, based on our experience with this combined therapy in a cohort of patients with previously unresectable pancreatic cancer, who subsequently underwent surgical resection. Between July 1996 and June 2001, a total of 67 patients with locally unresectable pancreatic cancer, without distant metastatic disease, received Gem/RT at our institution. Seventeen patients (25%) underwent exploratory surgery following Gem/RT, and nine underwent standard Whipple resection. Thus 9 (52%) of 17 patients who had exploratory operations or 9 (13%) of 67 patients, underwent surgical resection. Thirty-day mortality after resection was 0%, and there were no major surgical complications. Median length of hospital stay was 14 days (range 11 to 19 days). With a median follow-up of 32 months, median survival for the resected patients was 17.6 months (95% confidence interval 12.6 to 37.3 months). Median survival for the remaining 58 patients was 11.9 months (95% confidence interval 9.6 to 14.7 months, P = 0.013). We conclude that surgical resection may be safely performed after Gem/RT in a select group of patients initially considered to have unresectable pancreatic cancer. The use of Gem/RT in a neoadjuvant setting is currently being investigated in a multi-institutional phase II trial.

Somatostatin analogue (SMS 201-995) in the management of gastroenteropancreatic tumors and diarrhea syndromes

SMS 201-995 (Sandostatin) was studied using low doses (50 to 100 micrograms) administered subcutaneously every 12 hours. A single 50-micrograms dose of SMS 201-995 effectively controlled gastric acid and blood gastrin levels for 12 hours in three patients with benign gastrinomas and was useful in their perioperative management. Higher doses of the agent (500 to 800 micrograms per day) had no effect on metastases in one of two patients with metastatic gastrinoma. In the other patient, one tumor shrank but the other continued to grow after three months of treatment while serum gastrin levels did not change. Cultured metastatic tumor tissue from this patient released different forms of gastrin; growth rates varied, independent of uptake of SMS 201-995, and gastrin release increased. A neonate with nesidioblastosis maintained normal blood glucose levels while receiving SMS 201-995 therapy following a 95 percent pancreatic resection. In two elderly patients with organic hypoglycemia--one with a single benign adenoma and one with multiple adenomatosis--the somatostatin analogue did not prolong the hypoglycemia-free interval. In nine patients with carcinoid syndrome, flushing was uniformly controlled with 50 micrograms of SMS 201-995 administered every eight to 12 hours. One of the nine required exocrine pancreatic replacement. After six months of treatment, three of the nine had no change in tumor size and one had remission of symptoms and stopped treatment. In two patients with vipoma, SMS 201-995 controlled diarrhea and reduced levels of vasoactive intestinal peptide; tumor necrosis occurred in one patient. In a patient with diabetic diarrhea unresponsive to all treatments, SMS 201-995 therapy controlled the diarrhea but did not interfere with control of the diabetes.

Total pancreatectomy for pancreatic adenocarcinoma: Evaluation of morbidity and long-term Survival

Objective:To analyze relative perioperative and long-term outcomes of patients undergoing total pancreatectomy versus pancreaticoduodenectomy. Background:The role of total pancreatectomy has historically been limited due to concerns over increased morbidity, mortality, and perceived worse long-term outcome. Methods:Between 1970 and 2007, patients who underwent total pancreatectomy (n = 100) or pancreaticoduodenectomy (n = 1286) for adenocarcinoma were identified. Clinicopathologic, morbidity, and survival data were collected and analyzed. Results:Total pancreatectomy patients had larger median tumor size (4 cm vs. 3 cm; P < 0.001) but similar rates of vascular (50.0% vs. 54.7%) and perineural invasion (90.7% vs. 91.8%) (total pancreatectomy vs. pancreaticoduodenectomy, respectively, both P > 0.05). A similar proportion of total pancreatectomy (74.7%) and pancreaticoduodenectomy (78.3%) patients had N1 disease (P = 0.45). Total pancreatectomy patients had more lymph nodes harvested (27 vs. 16) and were less likely to have positive resection margins (22.2% vs. 43.7%) (total pancreatectomy vs. pancreaticoduodenectomy, respectively, both P < 0.0001). Total pancreatectomy was increasingly used over time (1970–1989, n = 10, 1990–1999, n = 37, 2000–2007, n = 53). Total pancreatectomy was associated with higher 30-day mortality compared with pancreaticoduodenectomy (8.0% vs. 1.5%, respectively; P = 0.0007). However, total pancreatectomy operative mortality decreased over time (1970–1989, 40%; 1990–1999, 8%; 2000–2007, 2%; P = 0.0002). While operative morbidity was higher following total pancreatectomy (69.0% vs. 38.6% for pancreaticoduodenectomy; P < 0.0001), most complications were minor (Clavien Grade 1–2) (59%). Total pancreatectomy and pancreaticoduodenectomy patients had comparable 5-year survival (18.9% vs. 18.5%, respectively, P = 0.32). Conclusions:Total pancreatectomy perioperative mortality dramatically decreased over time. Long-term survival following total pancreatectomy versus pancreaticoduodenectomy was equivalent. Total pancreatectomy should be performed when oncologically appropriate.

Therapeutic and diagnostic colonoscopy in nonobstructive colonic dilatation

Cecal perforation has been well established as a consequence of mechanical obstruction of the distal colon and has been estimated to occur in 1.5% to 7% of patients with colon obstruction. Perforation of the cecum also occurs in cases of nonobstructive colonic dilatation (NCD). Although the incidence is unknown, the mortality rate is nearly 50%. Over an eight-year period, 44 patients (mean age 59 years) underwent 52 colonoscopic examinations for presumed NCD. Twelve patients (27%) developed NCD while convalescing from a recent operation and 29 patients (66%) had major systemic disorders that preceded the development of NCD. Medical treatment for an average of 2.6 days was uniformly unsuccessful. Mean cecal diameter prior to colonoscopy was 12.8 cm (range 9.5 to 17 cm). Based on radiographic or clinical criteria, 38 patients (86%) were successfully decompressed on the initial colonoscopic examination; mean cecal diameter decreased to 8.7 cm (p less than 0.01). Perforation of the cecum during colonsocopy occurred in one patient (2%) who survived. Fourteen patients died; six deaths were attributed solely to the patients who underwent operation. In summary, colonoscopy is a safe and effective therapeutic and diagnostic tool in cases of massive cecal dilatation. It should be considered before cecostomy in patients without radiographic evidence of pneumoperitoneum or clinical signs of peritoneal irritation.

Pancreaticoduodenectomy and celiac occlusive disease.

Pancreaticoduodenectomy is currently associated with an average perioperative mortality rate of 25%. Breakdown of the pancreaticojejunal anastomosis accounts for the greatest morbidity and usually results from technical complications. The potential contribution of unsuspected celiac occlusive disease to anastomotic dehiscence remains unclear. Two patients with biopsy-proven carcinoma of the head of the pancreas, in addition to arteriographic evidence of hemodynamically significant stenosis or occlusion of the celiac artery, recently underwent potentially curative pancreaticoduodenal resection and simultaneous celiac revascularization using a splenic to superior mesenteric artery reimplantation technique. Neither patient experienced postoperative complications. Inadvertent sacriiice during pancreaticoduodenectomy of celiacomesenteric collateral pathways which have developed in response to chronic celiac artery insufficiency may predispose to ischemia of the upper abdominal viscera and thus contribute to postoperative complications such as liver failure and anastomotic breakdown. Selective celiac and superior mesenteric arteriography is recommended prior to pancreaticoduodenectomy. If high grade ostial stenosis or occlusion of the celiac axis is demonstrated by preoperative arteriography, strong consideration should be given at the time of pancreaticoduodenal resection to simultaneous celiac revascularization.

Adenocarcinoma of the ampulla of Vater. Diagnosis and treatment.

Fifty-one patients underwent operation for adenocarcinoma of the ampulla of Vater. Seven patients underwent palliative bypass, with an operative mortality of 28.6%; 44 additional patients underwent potentially curative pancreaticoduodenal resection (PDR), with an operative mortality of 15.9%. Postoperative complications occurred in 63% of patients. Postoperative gastrointestinal bleeding was observed in 11 of 44 patients who underwent PDR (25%). Although anastomotic ulcers (AU) were directly implicated in five cases (45%), the 12% incidence of AU-related bleeding among 33 patients who underwent PDR without truncal vagotomy (TV) was not significantly different from the 9% incidence observed in 11 patients who underwent PDR plus TV. However, performance of TV appeared to result in a higher incidence of postoperative pulmonary complications. Five patients who underwent curative resection survived for five years (11%). Only one of seven patients who underwent palliative bypass survived three years (14%), and none survived to five years. Acceptable survival rates following resectional therapy warrant an aggressive approach to this tumor. Further, our experience suggests that TV may increase postoperative patient morbidity without actually providing any protection from anastomotic ulceration.

Dual-phase helical CT of nonfunctioning islet cell tumors

PURPOSE The aim of this study was to evaluate the utility of dual-phase imaging in the assessment of nonfunctioning islet cell tumors (NFITs). METHOD Six patients with histologically and biochemically proven NFIT were evaluated by arterial and portal venous dual-phase helical CT. Scan delay was 20 s for the arterial phase and 70 s for the portal phase. Each phase was assessed by consensus reading and specifically evaluated for tumor conspicuity, hepatic metastases, vascular encasement by tumor, and presence of lymphadenopathy. RESULTS Overall, tumor conspicuity was greater in the arterial phase (5/6) than in the portal venous phase (1/6) with a mean tumor/normal pancreas attenuation difference of 31.8 HU in the arterial phase compared with 19.2 HU in the portal venous phase. The arterial phase detected a total of 17 liver metastases compared with 9 seen in the portal phase. Lymph node enlargement was noted in three patients, which, although visible in both phases, was more easily discernible in the arterial phase. Venous encasement by tumor was better evaluated on the delayed portal venous phase than the arterial phase. CONCLUSION Dual-phase helical CT scanning leads to improvement in the detection and staging of NFITs.

Renal Artery Embolism: Therapy With Intra-arterial Streptokinase Infusion

AbstractIntra-arterial infusion of streptokinase was used successfully to dissolve a 7-day-old main renal artery embolus in a 49-year-old woman. Renal artery patency was documented after 18 hours of thrombolytic therapy and secondary hypertension was ameliorated. Selective, intra-arterial fibrinolytic therapy may obviate the need for surgical embolectomy in poor risk patients in whom operative mortality rates appear unacceptably high.