Technical Perspective for Video Based Assessment of Surgeries in Low-Resource Settings.

OBJECTIVE: Scalable digital learning environments are essential to sustain surgical training programs worldwide. Detailed images of surgeries enriched with educational annotations are vital to train the eyes of the learners. Here, we report a low-cost method, deployed in a low-resource setting in West Africa, which may contribute to the growth of use in open-sourced digital surgical resources world-wide. DESIGN: This paper is based on the authors participatory and observational experiences creating surgical video content by way of recording surgical procedures and reflecting on field notes and video content. All surgeries were recorded between January and December 2018. SETTING: Masanga Hospital, a rural district hospital in Sierra Leone, West Africa. PARTICIPANTS: Thirty-five patients undergoing inguinal hernia repair, elective caesarian section, salpingectomy, bowel resection, hydrocele repair, or below-knee amputation consented for recording their surgical procedure and using the anonymized material for educational purposes. RESULTS: This manual for non-professional cinematographers provides chronological steps for shooting a surgical procedure in a low-resource setting. Recording a surgical procedure to explain surgical techniques, and perform quality assessment through error analysis and coaching requires more than just point-and-shoot. While taking into account local customs and possibilities, practical tips were provided to prepare for the set-up, and recording of a surgical procedure in a low-resourced setting. CONCLUSION: Commercially available digital video technology allows for filming high-quality surgical procedures for educational purposes at rural district hospitals in a low-resource setting.

Oncological Safety and Potential Cost Savings of Routine vs Selective Histopathological Examination After Appendectomy: Results of the Multicenter, Prospective, Cross-Sectional FANCY Study.

OBJECTIVE: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. BACKGROUND: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. METHODS: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. RESULTS: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients. CONCLUSIONS: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Predicting the outcome of closed-loop small bowel obstruction by preoperative characteristics.

BACKGROUND: Closed-loop small bowel obstruction (CL-SBO) can threaten the viability of the intestine by obstructing a bowel segment at two adjacent points. Prompt recognition and surgery are crucial. AIM: To analyze the outcomes of patients who underwent surgery for CL-SBO and to evaluate clinical predictors. METHODS: Patients who underwent surgery for suspected CL-BSO on computed tomography (CT) at a single center between 2013 and 2019 were evaluated retrospectively. Patients were divided into three groups by perioperative outcome, including viable bowel, reversible ischemia, and irreversible ischemia. Clinical and laboratorial variables at presentation were compared and postoperative outcomes were analyzed. RESULTS: Of 148 patients with CL-SBO, 28 (19%) had a perioperative viable small bowel, 86 (58%) had reversible ischemia, and 34 (23%) had irreversible ischemia. Patients with a higher age had higher risk for perioperative irreversible ischemia [odds ratio (OR): 1.03, 95% confidence interval (CI): 0.99-1.06]. Patients with American Society of Anaesthesiologists (ASA) classification ≥ 3 had higher risk of perioperative irreversible ischemia compared to lower ASA classifications (OR: 3.76, 95%CI: 1.31-10.81). Eighty-six patients (58%) did not have elevated C-reactive protein (> 10 mg/L), and between-group differences were insignificant. Postoperative in-hospital stay was significantly longer for patients with irreversible ischemia (median 8 d, P = 0.001) than for those with reversible ischemia (median 6 d) or a viable bowel (median 5 d). Postoperative morbidity was significantly higher in patients with perioperative irreversible ischemia (45%, P = 0.043) compared with reversible ischemia (20%) and viable bowel (4%). CONCLUSION: Older patients or those with higher ASA classification had an increased risk of irreversible ischemia in case of CL-SBO. After irreversible ischemia, postoperative morbidity was increased.

Safety and economic analysis of selective histopathology following cholecystectomy: multicentre, prospective, cross-sectional FANCY study.

BACKGROUND: There is ongoing debate concerning the necessity of routine histopathological examination following cholecystectomy. In order to reduce the pathology workload and save costs, a selective approach has been suggested, but evidence regarding its oncological safety is lacking. METHODS: In this multicentre, prospective, cross-sectional study, all gallbladders removed for gallstone disease or cholecystitis were systematically examined by the surgeon for macroscopic abnormalities indicative of malignancy. Before sending all specimens to the pathologist, the surgeon judged whether histopathological examination was indicated. The main outcomes were the number of patients with hypothetically missed malignancy with clinical consequences (upper limit two-sided 95 per cent c.i. below 3:1000 considered oncologically safe) and potential cost savings of selective histopathological examination. RESULTS: Twenty-two (2.19:1000) of 10 041 specimens exhibited malignancy with clinical consequences. In case of a selective policy, surgeons would have held back 7846 of 10041 (78.1 per cent) gallbladders from histopathological examination. Malignancy with clinical consequences would have been missed in seven of 7846 patients (0.89:1000, upper limit 95% c.i. 1.40:1000). No patient benefitted from the clinical consequences, while two were harmed (futile additional surgery). Of 15 patients in whom malignancy with clinical consequences would have been diagnosed, one benefitted (residual disease radically removed), two potentially benefitted (palliative systemic therapy), and four experienced harm (futile additional surgery). Estimated cost savings established by replacing routine for selective histopathological examination were €703 500 per 10 000 patients. CONCLUSION: Selective histopathological examination following cholecystectomy is oncologically safe and could reduce pathology workload, costs, and futile re-resections.

Does livestreaming surgical education have the future? Development and participant evaluation of a national COVID-19 livestreaming initiative.

BACKGROUNDS: COVID-19 related reduction of surgical procedures jeopardizes learning on the job of surgical residents. Many educators resorted to digital resources in the search for alternatives. However, these resources are often limited to the extent they offer resident-surgeon interaction like a joint surgical performance does. Here we present a roadmap of livestreaming surgical procedures, and evaluate how surgical livestreams on human cadavers address the unmet educational needs of surgical residents in our Dutch nationwide initiative. METHODS: Technical and organizational feasibility, and definition of outcome deliverables for the livestream series and per livestream were essential in livestream development. Faculty selected interventions, lecture contents, and participant preparations. Appropriate location, technical setup, and support were imperative for a stable, high-quality stream with integrated interaction, while maintaining digital privacy. A survey was sent to livestream participants to evaluate each livestream, and allow for constant improvement during the broadcasting of the series. Only surveys which were completed by surgical residents were included in the analysis of this study. RESULTS: Each livestream attracted 139-347 unique viewers and a total of 307 surveys were completed by participants (response rate of 23-38% per livestream). Sixty percent of surveys (n = 185) were completed by surgical residents. Livestreams were highly valued (appreciation 7.7 ± 1.1 and recommendation 8.6 ± 1.1), especially the live procedures combined with interaction and theoretical backgrounds. Criticized were technical difficulties and timing of the livestreams between 5 and 7 pm, which interfered with clinical duties. CONCLUSION: Livestreaming surgical procedures on human cadavers is a valid and valued solution to augment resident education. Digital privacy and a stable, high-quality interactive stream are essential, as are appropriate moderation and relevant lectures. While livestreaming cannot replace hands-on training in the operating room, it enables surgeon-resident interaction which is key in education-and missed in pre-recorded surgical procedures which are currently available online.

Correlation of CT findings with intra-operative outcome in closed-loop small bowel obstruction (CL-SBO).

PURPOSE: To correlate CT-findings in patients with closed-loop small bowel obstruction (CL-SBO) with perioperative findings, to identify patients who require immediate surgical intervention. Secondary purpose was to substantiate the role of radiologists in predicting perioperative outcome. METHODS: Data were retrospectively obtained from patients with surgically confirmed CL-SBO, between September 2013 and September 2019. Three radiologists reviewed CTs to assess defined CT features and predict patient outcome for bowel wall ischemia and necrosis using a likelihood score. Univariate statistical analyses were performed and diagnostic performance parameters and interobserver agreement were assessed for each feature. RESULTS: Of 148 included patients, 28 (19%) intraoperatively had viable bowel and 120 (81%) had bowel wall ischemia or necrosis. Most CT characteristics, as well as the likelihood of ischemia and necrosis, found fair or moderate multirater agreement. Increased attenuation of bowel wall and mesenteric vessels on non-contrast-enhanced CT had a specificity for bowel ischemia or necrosis of 100% (sensitivity respectively 48% (p < 0.001) and 21% (p = 0.09)). Mesenteric edema had high sensitivity for ischemia or necrosis (90%), but specificity of only 26% (p < 0.001). For mesenteric fluid, sensitivity was 60% and specificity 57% (p = 0.004). Decreased enhancement of bowel wall in both arterial and PV-phase showed significant correlation, respectively a sensitivity of 58% and 42%, and specificity of 88% and 79% (both p < 0.001). Likelihood of both ischemia and necrosis were significantly correlated with perioperative outcome (p < 0.001). CONCLUSION: CT findings concerning mesenteric and bowel wall changes, as well as radiologists' judgement of likelihood of ischemia and necrosis are significantly correlated with perioperative outcome of bowel wall ischemia and necrosis in patients with CL-SBO.

[Transpapillary gallbladder drainage with 'pigtail' stent]. / Transpapillaire galblaasdrainage met 'pigtail'-stent.

The transpapillary double 'pigtail' stent is placed endoscopically to drain the gallbladder after remission of a (recurrent) acute cholecystitis in patients with increased surgical risk. Technical success rate (placement of stent) is 83-88% and clinical success rate (remission of symptoms) is 80-93%. Although the procedure is effective, the stent is not commonly implemented. Possibly due to the challenging procedure or the introduction of the transgastric or transduodenic drainage with the Lumen Apposing Metal Stent (LAMS). This technique has a technical and clinical success rate of 94-95% and 90-97% respectively, significantly higher than the transpapillary stent. The LAMS can be placed during an acute cholecystitis. However, a cholecystectomy is contraindicated afterwards. Although the two procedures are complementary, future studies will tell if these two procedures will both continue to be used.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

[Pigtail stent for gallbladder drainage]. / 'Pigtail'-stent voor inwendige galblaasdrainage.

Endoscopic transpapillary gallbladder drainage is a new, relatively non-invasive treatment for patients with symptomatic gallbladder disease and a high surgery risk. Placement of an internal pigtail stent is an alternative treatment for percutaneous gallbladder drainage. This procedure can be performed in patients with a temporary contra-indication - in preparatory process to a cholecystectomy - as well as in patients with a prolonged contra-indication where the pigtail stent can remain in situ for a longer period of time. This technique appears to be an effective and safe procedure for patients with acute cholecystitis or symptomatic gallbladder disease and a high surgery risk.

Alternative specimen extraction techniques after laparoscopic emergency colectomy in inflammatory bowel disease.

BACKGROUND: Omitting the extraction site incision potentially further decreases the abdominal wall trauma in laparoscopic surgery. The purpose of this study was to report the results of alternative specimen extraction techniques after laparoscopic emergency colectomy in patients with inflammatory bowel disease (IBD). METHODS: Ten consecutive patients with IBD underwent (sub)acute emergency colectomy for refractory disease from October 2009 until December 2010. The specimen was retrieved via the stoma site in three and transrectally in seven patients. Patient data were prospectively collected. In case of later completion proctectomy and pouch procedure, adhesions were systematically scored. RESULTS: The extraction techniques were all feasible. Median operative time was 219 (interquartile range (IQR), 197-232) min. The pain scores and morphine requirement in patients decreased quickly after surgery. No infectious complications occurred. In five patients, a completion proctectomy was performed at a median time of 7 (IQR, 3.8-9.3) months after colectomy. All patients showed absence of any adhesions in the pelvis. In two patients, limited adhesions of the cut side of the mesentery were present. CONCLUSIONS: Specimen extraction via the rectum or stoma site is a safe, alternative way to extract the specimen after laparoscopic colectomy. No infectious complications were observed postoperatively and no pelvic adhesions were found during completion proctectomy.

[Acute abdomen in cystic fibrosis]. / Acute buik bij cystische fibrose.

A 44-year-old man with cystic fibrosis with an acute abdomen was hospitalized via the emergency care unit. Additional investigations revealed ileus of the small intestine and an enlarged appendix which suggested acute appendicitis. However, the clinical picture did not fit the diagnosis of appendicitis and therefore the patient was provisionally diagnosed as having a 'distal intestinal obstruction syndrome'. The patient was conservatively treated on this basis and recovered, being discharged in good condition from hospital after four days. An enlarged appendix occurs frequently in patients with cystic fibrosis, so that the appearance of this part of the intestine contributes little to the diagnosis.

Experimental acute biliary pancreatitis induced by retrograde infusion of bile acids into the mouse pancreatic duct.

Mechanistic studies of acute pancreatitis require animal models because clinical material is generally not available during the early phases of the disease. Here we describe a protocol to induce biliary pancreatitis by retrogradely infusing bile acids into the pancreatic duct of anesthetized mice. The resulting model replicates events believed to be responsible for the onset of clinical biliary (i.e., gallstone) pancreatitis and creates highly reproducible pancreatitis with a severity that depends on the concentration of infused bile acid. Pancreatitis reaches its maximal level of severity within 24 h of induction, and it resolves over the subsequent week. This protocol enables the investigator to use genetically modified strains of mice, and it requires only relatively simple and easily learned techniques of small animal surgery. With practice and gentle technique, the surgery (from induction of anesthesia to completion of the infusion) can be completed within 25 min per animal.

[Chest drains in trauma patients]. / Thoraxdrains bij traumapatiënten.

Adequate training for the insertion of chest drains in a trauma setting reduces the occurrence of procedure-related complications. Prophylactic antibiotics reduce the risk of infectious complications and empyema. For drainage of a traumatic pneumo- or haemothorax a large drain (28-36 French) is advised. The preferential insertion site is the 5th intercostal space in the midaxillary line. Drainage systems consist of a collection bottle, water seal and a suction control. Suction applied at 15-20 cm H2O is recommended for adequate drainage. Conversion to thoracotomy is determined by the drain production. Occult air leaks before removal of the drain can be detected by a temporary water seal or by clamping the drain followed by a chest X-ray. Removal of a chest drain at end-inspiration is as secure as end-expiration. Attention must be paid to potential complications of chest drains.

Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis.

Protease-activated receptor-2 (PAR2) is a 7-transmembrane G-protein-coupled tethered ligand receptor that is expressed by pancreatic acinar and ductal cells. It can be physiologically activated by trypsin. Previously reported studies (Namkung, W., Han, W., Luo, X., Muallem, S., Cho, K. H., Kim, K. H., and Lee, M. G. (2004) Gastroenterology 126, 1844-1859; Sharma, A., Tao, X., Gopal, A., Ligon, B., Andrade-Gordon, P., Steer, M. L., and Perides, G. (2005) Am. J. Physiol. 288, G388-G395) have shown that PAR2 activation exerts a protective effect on the experimental model of pancreatitis induced by supramaximal secretagogue (caerulein) stimulation. We now show that PAR2 exerts a worsening effect on a different model of experimental pancreatitis, i.e. one induced by retrograde pancreatic ductal infusion of bile salts. In vitro studies using freshly prepared pancreatic acini show that genetic deletion of PAR2 reduces bile salt-induced pathological calcium transients, acinar cell injury, and activation of c-Jun N-terminal kinase, whereas genetic deletion of PAR2 has the opposite or no effect on these pancreatitis-related events when they are elicited, in vitro, by caerulein stimulation. Studies employing a combination of trypsin inhibition and activation of PAR2 with the activating peptide SLIGRL show that all these differences indeed depend on the activation of PAR2. These studies are the first to report that a single perturbation can have model-specific and opposite effects on pancreatitis, and they underscore the importance of performing mechanistic pancreatitis studies using two dissimilar models of the disease to detect idiosyncratic, model-specific events. We suggest PAR2 activation exerts a worsening effect on the severity of clinical pancreatitis and that interventions interfering with PAR2 activation may be of benefit in the treatment of patients with severe pancreatitis.

Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis.

Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2(-/-) mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2(-/-) chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.

A mouse model of acute biliary pancreatitis induced by retrograde pancreatic duct infusion of Na-taurocholate.

OBJECTIVE: Most mechanistic studies of pancreatitis in mice employ the secretagogue-induced model. The currently reported studies were designed to develop an alternative, and possibly more clinically relevant, mouse model of pancreatitis. DESIGN: Na-taurocholate (10-50 microl, 1-5%) in saline, or saline alone, was retrogradely infused into the mouse pancreatic duct. The animals were killed 6-24 hours later and the severity of pancreatitis in the pancreatic head and tail was examined by quantitating hyperamylasemia, pancreatic edema, acinar cell necrosis, and pancreatic inflammation. In addition, intrapancreatic activation of trypsinogen, generation of IL-6, intrapulmonary sequestration of neutrophils, and alterations in lung compliance were evaluated. The effects of Na-taurocholate on in-vitro acinar cell calcium transients, viability, and trypsinogen activation were examined. RESULTS: Little or no evidence of pancreatitis was observed in mice infused with saline alone or in the tail of pancreata removed from animals infused with Na-taurocholate. In the head of the pancreas, evidence of pancreatitis was observed 12-24 hours after infusion of 20-50 microl 2-5% Na-taurocholate and the earliest morphological changes involved terminal duct and acinar cells. Intrapancreatic trypsin activity was transiently elevated within 5 minutes of Na-taurocholate infusion and pancreatic IL-6 levels were elevated 24 hours later. Under in-vitro conditions, Na-taurocholate triggered pathological acinar cell calcium transients, cell death, and calcium-dependent trypsinogen activation. CONCLUSION: This clinically relevant model of acute biliary pancreatitis yields reproducible results and its severity can be easily manipulated. It is ideally suited for use in mechanistic studies employing genetically modified mouse strains.

Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis.

We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.

Co-localization hypothesis: a mechanism for the intrapancreatic activation of digestive enzymes during the early phases of acute pancreatitis.

Acute pancreatitis is generally believed to be a disease in which the pancreas is injured by digestive enzymes that it normally produces. Most of the potentially harmful digestive enzymes produced by pancreatic acinar cells are synthesized and secreted as inactive zymogens which are normally activated only upon entry into the duodenum but, during the early stages of acute pancreatitis, those zymogens become prematurely activated within the pancreas and, presumably, that activation occurs within pancreatic acinar cells. The mechanisms responsible for intracellular activation of digestive enzyme zymogens have not been elucidated with certainty but, according to one widely recognized theory (the "co-localization hypothesis"), digestive enzyme zymogens are activated by lysosomal hydrolases when the two types of enzymes become co-localized within the same intracellular compartment. This review focuses on the evidence supporting the validity of the co-localization hypothesis as an explanation for digestive enzyme activation during the early stages of pancreatitis. The findings, summarized in this review, support the conclusion that co-localization of lysosomal hydrolases with digestive enzyme zymogens plays a critical role in permitting the intracellular activation of digestive enzymes that leads to acinar cell injury and pancreatitis.

Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity.

Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, and Steer ML. Gastroenterology 113: 304-310, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in vivo conditions, in two models of pancreatitis by using another highly soluble cell permeant cathepsin B inhibitor, L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-L-isoleucyl-L-proline methyl ester (CA-074me). Intravenous administration of CA-074me (10 mg/kg) before induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions that inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.