Treatment of pancreatic pseudocysts.

According to the Atlanta classification an acute pseudocyst is a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a consequence of acute pancreatitis or pancreatic trauma, whereas a chronic pseudocyst is a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue, which arises as a consequence of chronic pancreatitis and lack an antecedent episode of acute pancreatitis. It is generally agreed that acute and chronic pseudocysts have a different natural history, though many reports do not differentiate between pseudocysts that complicate acute pancreatitis and those that complicate chronic disease. Observation--"conservative treatment"--of a patient with a pseudocyst is preponderantly based on the knowledge that spontaneous resolution can occur. It must, however, be admitted that there is substantial risk of complications or even death; first of all due to bleeding. There are no randomized studies for the management protocols for pancreatic pseudocysts. Therefore, today we have to rely on best clinical practice, but still certain advice may be given. First of all it is important to differentiate acute from chronic pseudocysts for management, but at the same time not miss cystic neoplasias. Conservative treatment should always be considered the first option (pseudocysts should not be treated just because they are there). However, if intervention is needed, a procedure that is well known should always be considered first. The results of percutaneous or endoscopic drainage are probably more dependent on the experience of the interventionist than the choice of procedure and if surgery is needed, an intern anastomosis can hold sutures not until several weeks (if possible 6 weeks).     

Minimally invasive approaches to the management of pancreatic pseudocysts: review of the literature

Although one third or more of pancreatic pseudocysts might resolve spontaneously, interventional therapy is required for most. Several minimally invasive management approaches are now available, including percutaneous drainage under radiologic control, endoscopic transpapillary or transmural drainage, and laparoscopic internal drainage. This paper reviews the methodology, applications, advantages, shortcomings, and results of these management approaches. A computerized search was made of the MEDLINE, PREMEDLINE, and EMBASE databases using the search words pancreatic and pseudocysts and all relevant articles in English Language or with English abstracts were retrieved. In addition, cross-references from the identified articles were reviewed. Percutaneous drainage is best applied to pseudocysts complicated with secondary infection and in critically ill patients or those unfit for surgery. Radiologic drainage, however, risks the introduction of secondary infection and the formation of an external pancreatic fistula, and is associated with high recurrence rates. Endoscopic transpapillary drainage is beneficial for pseudocysts that communicate with the pancreatic duct and when a dependent drainage could be established. Endoscopic transmural (transgastric or transduodenal) drainage offers good results in the management of suitably located pseudocysts that complicate chronic pancreatitis, but is associated with high rates of failure to drain, secondary infection, and recurrence when pseudocysts that complicate acute necrotizing pancreatitis are approached. Laparoscopic pseudocyst gastrostomy or pseudocyst jejunostomy achieves adequate internal drainage, facilitates concomitant debridement of necrotic tissue within acute pseudocysts, and achieves good results with minimal morbidity. A randomized controlled trial that compares laparoscopic and endoscopic drainage techniques of retrogastric pseudocysts of chronic pancreatitis is required.     

Timing of surgical drainage for pancreatic pseudocyst. Clinical and chemical criteria.

Traditional concepts of managing pancreatic pseudocysts have changed with the advent of computerized tomography (CT) and ultrasound scanning, but new misconceptions related to spontaneous resolution have replaced some old ones. This report shows a difference in natural history and treatment requirements when pseudocysts are associated with acute versus chronic pancreatitis. There were 42 consecutive patients with pseudocysts treated over 5 years. Thirty-one were known alcoholics, two had gallstone pancreatitis, and nine had idiopathic pancreatitis. An attack of acute pancreatitis was identifiable within 2 months preceding in 22 patients, but there were only chronic symptoms in 20. Spontaneous resolution of the pseudocyst occurred in three patients (7%), all of whom had recent acute idiopathic pancreatitis, normal serum amylase levels, and pancreatograms showing normal pancreatic ducts freely communicating with the pseudocyst. Factors associated with failure to resolve included known chronic pancreatitis, pancreatic duct changes of chronic pancreatitis, persistence greater than 6 weeks, and thick walls (when seen) on scan. Nearly all (18/19) patients with known chronic pancreatitis had successful internal drainage of the pseudocysts immediately upon admission, whereas 6/20 patients with antecedent acute pancreatitis were found to require external drainage at the time surgery was eventually elected. Isoamylase analysis, performed on serum from 19 patients by means of polyacrylamide gel electrophoresis, detected the abnormal pancreatic isoamylase pattern described as "old amylase" in 15. When old amylase was present in the serum, internal drainage was always possible (14/14). In four of five patients whose serum contained no detectable old amylase, internal drainage was not possible regardless of the length of prior observation. There were four nonfatal complications arising from an acute pseudocyst during the wait for maturity. It is concluded that prolonged waiting is expensive and unnecessary for pseudocysts in chronic pancreatitis when there has been no recent acute attack. However, pseudocysts developing after identifiable acute pancreatitis should be observed in the safety of a hospital for up to 6 weeks to allow for either spontaneous resolution or maturation of the cyst wall. The appearance of old amylase in the serum suggests that the pseudocyst wall has achieved sufficient maturity to allow safe internal anastomosis.     

Pancreatic pseudocysts: a proposed classification and its management implications

Pancreatic pseudocysts in 83 patients were classified according to clinical and radiographic criteria. Group I (45 patients) had acute, 'post-necrotic' pseudocysts with normal pancreatic duct anatomy and rarely duct-pseudocyst communication. Percutaneous drainage was curative in all patients in whom it was used. Group II (26 patients) included 'post-necrotic' pseudocysts developing in patients already suffering from chronic pancreatitis. The pancreatic duct was diseased but not strictured, and duct-pseudocyst communication was often present. Percutaneous drainage is possible for such patients but it may have to be prolonged; surgical internal drainage was usually successful. Group III (12 patients) had chronic 'retention' pseudocysts. The pancreatic duct was grossly diseased and strictured and duct-pseudocyst communication was present in all cases. Percutaneous drainage is contraindicated and surgical internal drainage has a high recurrence rate. Operative procedures in this group should address the specific ductal pathology. An improved classification of pseudocysts could help the surgeon to choose the most appropriate form of treatment.     

Surgical Therapy of Pancreatic Pseudocysts

Background  Pancreatic pseudocysts are a common complication associated with acute and chronic pancreatitis. Fifteen percent and 40% of patients diagnosed with either acute or chronic pancreatitis, respectively, develop pseudocysts (Grace and Williamson, Br J Surg, 80:573–581, 1993). The treatment of pancreatic pseudocysts has evolved since the early 1980s, and changes in management have lead to an improved understanding of the pathophysiology of pseudocysts as well as necessary treatment paradigms. Conclusions  It has become evident that not all pseudocysts are equal. Pseudocysts arising in the setting of acute pancreatitis have a different pathophysiologic basis than those arising from chronic pancreatitis. Moreover, even those pseudocysts that arise in acute pancreatitis exhibit unique features. Pseudocysts that develop from a mild episode of pancreatitis, complicated by pancreatic duct disruption, differ significantly from those developed as a consequence of severe acute necrotizing pancreatitis with severe distortion of the pancreatic parenchyma or pancreatic duct. This review will focus on the surgical therapy of pancreatic pseudocysts in the context of the underlying pathophysiology and alternative nonoperative therapies.     

Pancreatic pseudocysts and fluid collections: percutaneous approaches

Radiological imaging and intervention play important roles in the management of pancreatic fluid collections and pseudocysts. Computed tomography evaluation of the severity of pancreatitis and assessment of its course are now routine. Percutaneous drainage of pancreatic pseudocysts and abscesses is commonly performed as an adjunct to surgical treatment and is frequently definitive therapy. Percutaneous débridement of pancreatic necrosis has recently emerged as a viable alternative to open surgical treatment.     

JPN Guidelines for the management of acute pancreatitis: surgical management

Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course to a rapidly progressive, severe illness. The mortality rate of severe acute pancreatitis exceeds 20%, and some patients diagnosed as mild to moderate acute pancreatitis at the onset of the disease may progress to a severe, life-threatening illness within 2–3 days. The Japanese (JPN) guidelines were designed to provide recommendations regarding the management of acute pancreatitis in patients having a diversity of clinical characteristics. This article sets forth the JPN guidelines for the surgical management of acute pancreatitis, excluding gallstone pancreatitis, by incorporating the latest evidence for the surgical management of severe pancreatitis in the Japanese-language version of the evidence-based Guidelines for the Management of Acute Pancreatitis published in 2003. Ten guidelines are proposed: (1) computed tomography-guided or ultrasound-guided fine-needle aspiration for bacteriology should be performed in patients suspected of having infected pancreatic necrosis; (2) infected pancreatic necrosis accompanied by signs of sepsis is an indication for surgical intervention; (3) patients with sterile pancreatic necrosis should be managed conservatively, and surgical intervention should be performed only in selected cases, such as those with persistent organ complications or severe clinical deterioration despite maximum intensive care; (4) early surgical intervention is not recommended for necrotizing pancreatitis; (5) necrosectomy is recommended as the surgical procedure for infected pancreatic necrosis; (6) simple drainage should be avoided after necrosectomy, and either continuous closed lavage or open drainage should be performed; (7) surgical or percutaneous drainage should be performed for pancreatic abscess; (8) pancreatic abscesses for which clinical findings are not improved by percutaneous drainage should be subjected to surgical drainage immediately; (9) pancreatic pseudocysts that produce symptoms and complications or the diameter of which increases should be drained percutaneously or endoscopically; and (10) pancreatic pseudocysts that do not tend to improve in response to percutaneous drainage or endoscopic drainage should be managed surgically.     

Preoperative endoscopic retrograde cholangiopancreatography (ERCP) in patients with pancreatic pseudocyst associated with resolving acute and chronic pancreatitis.

Experience with patients with pancreatic pseudocysts has led the authors to the hypothesis that preoperative evaluation of the pancreatic and bile ducts by ERCP will define those patients who may be inadequately treated by pseudocyst drainage alone without attention to associated pancreatic and biliary ductal abnormalities. In patients with certain ductal abnormalities, the pseudocyst operation was combined with a definitive operative drainage of the pancreatic duct and/or of the biliary tree where appropriate. A prospective evaluation of routine preoperative ERCP was undertaken over a 36-month period in all patients scheduled for operative treatment of pseudocyst of the pancreas. From an initial group of 44 patients with pseudocysts, three patients who had spontaneous regression of the pseudocyst were excluded. ERCP was successful in 39 of the remaining 41 patients. Among 41 operated patients, 24 were admitted with a diagnosis of pseudocyst that arose after an episode of acute pancreatitis, and 17 had chronic pancreatitis with pseudocyst. Nine patients, initially assumed to have acute pancreatitis, were recognized to have chronic pancreatitis on the basis of ERCP findings. Communication with the main pancreatic duct (MPD) was demonstrated in 18 of 41 pseudocysts, and the rate of communication was similar in patients with acute and chronic pancreatitis. Dilatation of the MPD was seen in 23 of 41 patients and was associated with chronic pancreatitis in 21. Dilatation of the common bile duct was found in 12 patients with chronic pancreatitis. The operative plan was altered by ERCP findings in 24 of 41 patients; 22 of the 24 patients had chronic pancreatitis. There were no complications of ERCP. These data suggest that ERCP should be performed in all patients with pseudocysts to establish correct diagnosis and to allow optimal choice of operation.     

Endoscopic Drainage of Pancreatic Pseudocysts

Pancreatic pseudocysts arise as a complication of acute and chronic pancreatitis, pancreatic trauma, or after surgery. Endoscopic treatment of pancreatic pseudocysts can be achieved using transpapillary and/or transmural (transgastric or transduodenal) approaches with acceptable success rates, complication rates, and recurrence rates. Advantages of endoscopic drainage is the avoidance of external pancreatic fistula.     

Controversies in the management of pancreatic pseudocysts

Review of the diagnosis and treatment of patients with pancreatic pseudocysts over the past 8 years has led us to three conclusions regarding controversial aspects of their treatment. We found that patients who present with chronic pseudocysts can be identified with the help of computerized axial tomography and promptly undergo successful internal drainage, whereas patients with acute peripancreatic fluid secondary to pancreatitis can be observed expectantly with a 43 percent frequency of spontaneous resolution. Patients with infected pancreatic pseudocysts can be safely drained internally. The most common cause of extrahepatic biliary obstruction in this group of patients with pancreatic pseudocysts was stricture due to pancreatitis and fibrosis, not extrinsic compression.     

Imaging in pancreatic infection

The most common cause of infection involving the pancreas is complicated pancreatitis. Infected necrosis, pancreatic abscess, and infection of pancreatic pseudocysts are seen. Diagnostic imaging, in particular, contrast-enhanced computed tomography, plays a large role in the identification of the complications seen in acute pancreatitis. The imaging findings of the infectious complications of pancreatitis is reviewed. Diagnostic imaging also plays a role in the diagnosis of infected necrosis and in the percutaneous management of pancreatic abscesses and pseudocysts. The imaging findings of pancreatic necrosis are usually not sensitive to the presence of co-existent infection. Image-guided needle aspiration of the necrotic pancreas can be crucial in the diagnosis of infected necrosis. Image-guided placement of percutaneous drainage catheters is a nonsurgical alternative for the management of pancreatic abscesses and pseudocysts. Image-guided catheter placement and the management of these catheters is discussed.     

Differentiating pancreatic pseudocyst and pancreatic necrosis using computerized tomography.

Ten per cent of patients with acute pancreatitis will develop pancreatic complications. Differentiating pancreatic pseudocyst formation from pancreatic necrosis may be difficult based on clinical grounds. The purpose of this study was to evaluate the role of computerized tomography in differentiating these processes. A retrospective analysis was performed of 40 patients who developed pancreatic complications following an episode of acute pancreatitis and who subsequently underwent operation for drainage of their pancreatic fluid collections. All 40 patients had abdominal CT scans performed before surgery and the patients were then categorized on the basis of CT findings as having (1) a pseudocyst with a well-defined cyst wall, (2) peripancreatic fluid marked by the absence of a cyst wall, and (3) a combination of a pseudocyst as well as free peripancreatic fluid. Patients with pseudocysts had an average hospital stay of 14 +/- 2 days, a hospital morbidity rate of 16%, and a hospital mortality rate of 0%. In contrast, patients with peripancreatic fluid collections had an average hospital stay of 43 +/- 4 days (p less than 0.01) and hospital morbidity and mortality rates of 74% (p less than 0.01) and 22% (p less than 0.05), respectively. Patients with both pseudocysts and peripancreatic fluid collections behaved in a similar fashion to patients with peripancreatic fluid alone as characterized by a prolonged hospital stay and a high incidence (80%) of postoperative complications. At one year follow-up, 89% of the patients with pseudocysts were asymptomatic, whereas only 13% (p less than 0.01) of patients with peripancreatic fluid were symptom free. These data demonstrate that pseudocyst and peripancreatic fluid collections have markedly different biologic characteristics both in their short-term and long-term behavior. The results suggest that CT scanning can differentiate these processes and may help in directing the appropriate surgical therapy.     

The role of surgery in the management of acute pancreatitis.

Surgical intervention in acute pancreatitis may have varied goals. Early laparotomy may be required for diagnostic purposes. There is, however, no convincing evidence that attempts to reduce the morbidity of severe pancreatitis by early operative pancreatic drainage, early formal pancreatic resection, or early biliary procedures have been effective. In fact, they may be harmful. Peritoneal lavage by catheter induced under local anesthesia may ameliorate early cardiovascular and respiratory complications in some patients. Preliminary experience suggests that early operative debridement of devitalized pancreatic tissue with postoperative lavage may be helpful in selected patients. Patients with infections of devitalized pancreatic or peripancreatic tissue require operative debridement and drainage or packing. Other complications such as colonic necrosis or pseudocysts also require operative treatment. Rarely do patients require operation to relieve protracted pancreatitis. Patients with gallstone-associated pancreatitis should usually undergo surgical correction of their cholelithiasis as soon as their pancreatitis has subsided.     

Endoscopic versus laparoscopic drainage of pseudocyst and walled-off necrosis following acute pancreatitis: a randomized trial

Pancreatic fluid collections (PFC) may develop following acute pancreatitis (AP). Endoscopic and laparoscopic internal drainage are accepted modalities for drainage of PFCs but have not been compared in a randomized trial. Our objective was to compare endoscopic and laparoscopic internal drainage of pseudocyst/walled-off necrosis following AP. Patients with symptomatic pseudocysts or walled-off necrosis suitable for laparoscopic and endoscopic transmural internal drainage were randomized to either modality in a randomized controlled trial. Endoscopic drainage comprised of per-oral transluminal cystogastrostomy. Additionally, endoscopic lavage and necrosectomy were done following a step-up approach for infected collections. Surgical laparoscopic cystogastrostomy was done for drainage, lavage, and necrosectomy. Primary outcome was resolution of PFCs by the intended modality and secondary outcome was complications. Sixty patients were randomized, 30 each to laparoscopic and endoscopic drainage. Both groups were comparable for baseline characteristics. The initial success rate was 83.3% in the laparoscopic and 76.6% in the endoscopic group (p = 0.7) after the index intervention. The overall success rate of 93.3% (28/30) and 90% (27/30) in the laparoscopic and endoscopic groups respectively was also similar (p = 1.0). Two patients in the laparoscopic group required endoscopic cystogastrostomy for persistent collections. Similarly, two patients in the endoscopic group required laparoscopic drainage. Postoperative complications were comparable between the groups except for higher post-procedure infection in the endoscopic group (19 vs. 9; p = 0.01) requiring endoscopic re-intervention. Endoscopic and laparoscopic techniques have similar efficacy for internal drainage of suitable pancreatic fluid collections with < 30% debris. The choice of procedure should depend on available expertise and patient preference.     

Evaluation of therapeutic options for pancreatic pseudocysts

A review of 81 patients with pancreatic pseudocyst was conducted to assess the value of different treatment modalities. Resection was associated with 18% mortality (two of 11 patients) and 36% morbidity. In three of nine patients undergoing external drainage a recurrent pseudocyst developed, and in one additional patient, a pancreatic fistula persisted. Internal drainage by cystogastrostomy (21 patients) resulted in 9.5% mortality and 9.5% morbidity, whereas cystojejunostomy (33 patients) was associated with a 6% mortality and 6% morbidity. Endoscopic drainage through the posterior wall of the stomach was unsuccessful in the two patients in which it was used. Internal drainage into the stomach, duodenum, or jejunum is a safe and effective approach for most pseudocysts. Persistent symptoms following surgical treatment were primarily related to failure to recognize multiple cysts and/or pancreatic duct obstruction and dilation characteristic or chronic pancreatitis.     

Laparoscopic Roux-en-Y pancreatic cyst-jejunostomy

Background: The surgical management of pancreatic pseudocysts can be established through a variety of techniques. Internal drainage has consistently proven to be the treatment of choice for both acute and chronic pancreatic pseudocysts. With the growing popularity of minimally invasive surgery and improvements in surgical technique, laparoscopic internal drainage procedures for pancreatic pseudocysts are being attempted. While most authors have focused on laparoscopic cyst-gastrostomies, few have written about laparoscopic cyst-jejunostomies. Methods: In this article, we report our experience with eight laparoscopic Roux-en-Y cyst-jejunostomies. Of the eight patients, six had alcoholic pancreatitis, and two had gallstone pancreatitis. There were five men and three women with a mean age of 48 (range 35–71 years). Results: The mean operative time was 150 min, with a range of 100–215 min. We report a mean EBL of 78 cc, a minor complication rate of 20%, and no major complications or mortalities. Conclusions: These data compare favorably with both open and laparoscopic internal drainage procedures. Laparoscopic cyst-jejunostomy offers a feasible alternative in the minimally invasive management of pancreatic pseudocyst.     

The impact of technology on the management of pancreatic pseudocyst. Fifth annual Samuel Jason Mixter Lecture

The records of 299 patients with 357 admissions for pancreatic pseudocysts seen between 1960 and 1989 were studied; 233 patients underwent operation. The natural history of pancreatic pseudocysts has been clarified by newer technology, such as ultrasonography, computer tomography, amylase isoenzyme measurements, and endoscopic retrograde cholangiopancreatography. All have influenced diagnosis, nonoperative management, and surgical operation. Differences between pancreatic pseudocysts associated with acute pancreatitis in contrast with chronic pancreatitis, and the complications of obstruction, hemorrhage, rupture, pancreatic ascites, infection, and jaundice can now be more rationally treated. Pancreatic pseudocysts and pancreatic ductal changes are now revealed earlier, especially by endoscopic retrograde cholangiopancreatography. Paradoxically, this information has encouraged nonoperative conservative therapy and also larger operations, eg, resection and adjunctive pancreaticojejunostomy. Partial resection of the pancreas together with the pancreatic pseudocysts was performed in 58 (25%) of the 233 patients. Recent technology permits cautious exploration of selective pancreatic pseudocyst drainage percutaneously or transgastroduodenally avoiding laparotomy.     

Laparoscopic endogastric pseudocyst gastrostomy: a report of three cases

The transgastric pseudocyst-gastrostomy is the standard approach for internal drainage of persistent and large retrogastric pancreatic pseudocysts that complicate acute necrotizing pancreatitis. We report on the application of a laparoscopic endogastric approach for drainage of pancreatic pseudocysts and discuss the merits of this technique as well as of the other previously described minimally invasive approaches for the management of pancreatic pseudocysts. Between January 2001 and August 2001, three female patients presented with large symptomatic pseudocysts 3-10 months after an episode of acute necrotizing pancreatitis. Internal drainage was effected by a laparoscopic endogastric pseudocyst gastrostomy, and the necrotic pancreas was debrided. There were no conversions and no postoperative complications. The median postoperative hospital stay was 4 days (range, 3-5). All patients remain asymptomatic, and resolution of the pseudocyst was radiologically evident at a median follow-up of 6 months (range, 4-11). The laparoscopic endogastric pseudocyst gastrostomy appears to be a safe and effective minimally invasive approach for internal drainage of large retrogastric pancreatic pseudocysts and facilitates debridement of the necrotic pancreas.     

Complications of chronic pancreatitis

The most common complication of chronic pancreatitis is pain, which in many cases seems related to pancreatic ductal obstruction with ductal hypertension. Longitudinal pancreaticojejunostomy is indicated in patients with a dilated (larger than 7 mm) duct and pain that requires narcotic analgesics for relief. Chronic pseudocysts may be corrected surgically without the usual 6-week wait, and asymptomatic pseudocysts less than 4 cm in diameter may not require surgery at all. The relative efficacy and risks of percutaneous drainage of pseudocysts versus the standard surgical approaches need to be studied. Pancreatic fistulas may be external or internal, where pancreatic ascites or hydrothorax can be the clinical manifestation. The pharmacologic suppression of pancreatic secretion (e.g., with somatostatin) may be useful in their management, but surgery may be required. Pancreatic resection or internal drainage is usually effective. Persistent jaundice should be relieved surgically by choledochoduodenostomy to avoid the development of secondary biliary cirrhosis. Obstruction at various levels of the gastrointestinal tract (duodenum, small bowel, colon) may require bypass (gastrojejunostomy) or resection. Hemorrhage from major arteries is an infrequent but often lethal complication of chronic pancreatitis, especially associated with pseudocysts. Angiography is invaluable for diagnosis and occasionally for treatment (embolization). Surgery is preferred in good-risk patients, with suture ligation (resection) of the bleeding source. Chronic pancreatitis is the most common cause of splenic vein thrombosis. The resultant hemorrhage from gastric varices is managed effectively by splenectomy.     

Management of pancreatic pseudocysts

BACKGROUND: This review analyses the outcome for patients with acute and chronic pancreatic pseudocysts managed in two major referral centres. PATIENTS AND METHODS: From 1987 to 1997, 33 patients were treated with either acute (n = 19) or chronic (n = 14) pseudocysts. Procedures performed included cystgastrostomy (64%), cystduodenostomy (6%), cystjejunostomy (3%), distal pancreatectomy with resection of pseudocyst (12%), laparotomy with external drainage (9%), endoscopic transpapillary stenting (3%) and endoscopic pancreatic duct sphincterotomy with percutaneous drainage of the pseudocyst (3%). RESULTS: All patients had resolution of their pseudocyst and no patient developed recurrence. There were no deaths in this series. There was a 9% incidence of major complications and a 21% incidence of minor complications. Outcome was excellent in 63% and good in 27% of patients. Two patients (6%) had persistent chronic pain and one patient (3%) had evidence of exocrine pancreatic insufficiency with malabsorption. CONCLUSIONS: Surgical internal drainage of pancreatic pseudocysts can be performed safely with low morbidity and mortality provided patients are carefully selected and their medical management is optimized. Although minimally invasive techniques now offer a variety of treatment options, open surgical drainage is still indicated for a significant number of cases.