Ingemar Ihse

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial

ObjectiveTo assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Summary Background DataPancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. MethodsESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. ResultsOf 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. ConclusionsResection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease

Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis

In a double-blind study on 19 patients with the diagnosis of chronic pancreatitis, the effects of treatment with a granulated pancreatic enzyme preparation (Pankreon) were compared with those of placebo administration. One week of treatment with each preparation was preceded by one week without any medication. The patients kept daidy records of their symptoms, plotting the severity of pain on an analog scale. Weekly assessments of the mean pain level were also made by an examiner questioning the patients. Recordings of body weights and pancreas and liver laboratory tests were done weekly. Fifteen of 19 patients noted less pain during the week of treatment with pancreatic enzymes as compared to that of placebo treatment (P<0.05). The average reduction of pain, as calculated for all patients, was 30% as evaluated by both patients (P<0.01) and the examiner (P<0.05). No differences were found in other parameters examined. A possible explanation of the findings could be an effect on the intraductal pressure by intraluminal trypsin.

Feedback Regulation of Pancreatic Enzyme Secretion by Intestinal Trypsin in Man

In a patient a papilla Vateri tumor completely prevented the bile-pancreatic flow into the intestine although the pancreatic juice was secreted into the bile duct via a common channel. Consequently, the bile-pancreatic juice was possible to sample via a percutaneous transhepatic cholangiography (PTC) catheter. This made it possible to study the effect of duodenal infusion of different substances on the bile-pancreatic secretion. In repeated experiments a suppression of the secretion was observed by intraduodenal trypsin as well as the patients own bile-pancreatic juice. In the presence the bile-pancreatic juice intraduodenal trypsin inhibitor infusion caused a marked stimulation of the secretion. The results are in accordance with the hypothesis that trypsin in the upper part of the intestine exerts a negative feedback regulation of the pancreatic secretion in man.

Total Pancreatectomy for Cancer of the Pancreas: Is It Appropriate?

Abstract. During the late 1960s total pancreatectomy was advocated on theoretic grounds as an operation superior to subtotal (Whipple) resection in patients with pancreatic cancer. There are, however, no prospective randomized studies and only few institutional comparisons between the two operations. The aim of the present paper was to report the clinical outcome of total and subtotal pancreatectomy, respectively, in a consecutive series of patients with exocrine pancreatic cancer. The short- and long-term results of 89 consecutive patients who underwent total pancreatectomy (1959–1984) for pancreatic cancer were retrospectively compared with a similar group of 36 patients who had a subtotal pancreatectomy (1985–1992) for the same diagnosis. The clinical characteristics were on the whole similar in the two groups. Postoperative mortality and morbidity, the amount of intraoperative bleeding, operation time, reoperation rate, postoperative days in the intensive care unit, and duration of hospital stay were statistically significantly increased after total pancreatectomy. The 5-year survival rate was lower after total pancreatectomy when hospital deaths were included in the analysis. At multivariate analysis total pancreatectomy adversely influenced long-term survival compared to subtotal resection, as did positive lymph nodes and poor histologic differentiation. Better early and long-term results were found after subtotal than after total pancreatectomy in patients with exocrine pancreatic cancer. Although the two operations were done during different time periods, we believe the results suggest that total pancreatectomy cannot be recommended as a routine treatment for this patient group.

Evaluation of aggressive surgery for carcinoma of the extrahepatic bile ducts.

The records of 80 consecutive patients with extrahepatic bile duct cancer, 45 women and 35 men, median age 70 years (33-89 years), were reviewed. The histologic diagnoses were adenocarcinoma in 45 patients, 34 cholangiocarcinoma and one squamous cell carcinoma. In 34 patients the tumor was located to the confluence, the right or left hepatic duct, in 16 to the middle and in four to the distal portion of the bile duct. In the remaining 26 patients the tumor comprised more than one of these locations (mixed location). Twenty-seven of the 80 patients (34%) were operated on with resection of the tumor. Among patients 70 years of age and younger the resectability rate was 57%. In nine patients the main surgical procedure was bile duct resection, in 15 patients bile duct resection and liver lobe resection, in 2 patients total pancreatectomy and in one local excision were performed. The resection of the tumor was regarded as radical in 12 patients and palliative in 15. The mortality rate was 11% after resection as compared to 30% in patients with nonresectable tumors. The most common postoperative complication was insufficiency of the anastomosis which occurred in seven patients. Three of these patients required reoperation. The median survival time in patients operated on with radical resection was 20 months, palliative resection 7(1/2) months and in patients with nonresectable tumors 2(1/2) months. The quality of life was estimated according to a special schedule and was found to be improved after resection as compared to nonresection. Patients operated with radical resection spent significantly less of their remaining life at hospital as compared to palliatively resected patients or patients with nonresectable tumors.

Total pancreatectomy for cancer. An appraisal of 65 cases.

Sixty-five patients operated with total pancreatectomy were reviewed with respect to factors influencing operative mortality and morbidity, long-term survival, and metabolic sequelae. The diagnoses were pancreatic cancer in 58 patients, periampullary cancer in three, cancer of the bile duct in two and leiomyosarcoma of the duodenum and cystadeno-carcinoma of the pancreas in one patient, respectively. In nine of the 58 cases with cancer of the caput, the histological examination revealed multicentricity of the tumor. In 44%, there were signs of degeneration and fibrosis in the distal part of the gland. Hospital mortality was 23% for the entire series. After 1970 the hospital mortality was 17%, and among patients operated by senior surgeons especially trained in pancreatic surgery, the hospital mortality was 12% during the whole period. The peroperative bilirubin levels seemed to influence survival time. Among 24 patients operated before 1975 in whom the operating surgeon judged the operation as radical, a five year survival of 21% was recorded. In patients without detectable lymph node metastases, the mean survival time was 25 months. The postoperative exocrine insufficiency and diabetes were possible to control. A blood sugar level above 10 micromol/1 was found to significantly decrease the frequency of hypoglycemic attacks. Total pancreatectomy appears to be the surgical procedure preferred when radical treatment is selected.

Factors influencing survival after total pancreatectomy in patients with pancreatic cancer.

A retrospective analysis of factors influencing short-term and long-term survival after total pancreatectomy for pancreatic cancer was done in 86 patients. Among the 41 factors studied, hospital mortality was significantly affected by age over 70 years, preoperative diabetes, pain as presenting symptom, S-bilimbin, preoperative bile drainage, prophylactic antibiotic treatment, stage of the tumor, and experience of the surgeon. The only factors which had a statistically significant influence on long-term survival were stage of the tumor and sex of the patient. It is concluded that improvement of long-term survival can mainly be achieved by earlier identification and removal of the tumors and by introduction of more efficient adjuvant therapy. Whereas these goals probably will require a long time to be reached, the majority of factors associated with worsening of hospital mortality may be avoided by a strict selection of the patient, the tumor and the surgeon.

Pancreatitis after sphincter of Oddi manometry.

The nature, frequency, severity, and possible causes of complications after 207 sphincter of Oddi manometry measurements were studied in 146 patients. Acute pancreatitis was diagnosed in 6% (12 of 207) of the investigations and in 8% (12 of 146) of the patients examined. The pancreatitis was mild in all patients. After cannulation of the pancreatic duct, acute pancreatitis occurred in 10 of 95 (11%) patients compared with one of 93 (1%) when the manometry catheter entered the bile duct only (p less than 0.02). Seven (58%) of the patients who developed acute pancreatitis, however, were found to be suffering from chronic pancreatitis. Some 26% of all sphincter of Oddi manometry measurements on patients with this diagnosis were complicated by an acute attack of pancreatitis compared with 3% (p less than 0.001) in patients without signs of chronic pancreatitis. In all patients the pancreatitis developed within three hours of manometry. We conclude that pancreatitis may occasionally follow sphincter of Oddi manometry measurement, even in patients without pancreaticobiliary disease, and that underlying chronic pancreatitis constitutes a definite risk. Sphincter of Oddi manometry measurement in control subjects should therefore be performed only in centres where the safety of the procedure has been established, and the presence of chronic pancreatitis should be excluded beforehand. Cannulation of the pancreatic duct should be avoided. Manometry can be safely performed, however, as an outpatient procedure.

Trypsin as a Regulator of Pancreatic Secretion in the Rat

The effect of intraduodenally administered trypsin on pancreatic exocrine secretion was investigated in conscious rats surgically prepared with bile--pancreatic fistulae. Introduction of NaHCO3 into the duodenum did not influence pancreatic secretion. Reintroduction of bile--pancreatic juice into the duodenum, however, suppressed pancreatic protein output, mainly because of changes in protein concentration. Infusion of trypsin into the duodenum in the absence of intraluminal pancreatic juice significantly suppressed the secretory volume and pancreatic enzyme output; addition of trypsin inhibitor to the trypsin infusion resulted in an immediate increase of pancreatic secretion. Trypsin inhibitor per se, however, was without effect. Bile--pancreatic juice affected amylase, kipase, and trypsinogen output in a parallel fashion; after addition of trypsin inhibitor to the infusion the inhibitory effects on pancreatic enzyme output was reversed in a parallel manner. The results support the hypothesis that pancreatic exocrine secretion is regulated by a feedback mechanism exerted--at least partly--by intraluminal trypsin.