Neoplasia mucinosa papilar intraductal del páncreas: características clínico-patológicas y supervivencia a largo plazo de pacientes sometidos a pancreatectomía / Intraductal papillary mucinous neoplasm of pancreas: clinicopathological features and long-term survival after surgical resection

Introducción La neoplasia mucinosa papilar intraductal (NMPI) del páncreas puede progresar de displasia de bajo grado a displasia de alto grado y carcinoma invasivo asociado. El objetivo de este trabajo fue describir las características clínico-patológicas y los resultados de seguimiento a largo plazo de pacientes con pancreatectomía por NMPI. Métodos En este estudio retrospectivo de un solo centro, se analizan los resultados de los pacientes sometidos a resección pancreática, con diagnóstico anatomopatológico de NMPI, desde enero del 2009 a diciembre del 2019. Resultados Un total de 31 pacientes tuvieron diagnóstico de NMPI. Nueve pacientes fueron varones y 22 mujeres. La edad media fue de 67 años. Veintisiete pacientes (87%) presentaron síntomas. Los estigmas de alto riesgo se encontraron en 20 pacientes (64,5%) y las características preocupantes («worrisome features») en 10 pacientes (32,2%). Siete pacientes tuvieron NMPI tipo conducto principal, 13 NMPI tipo rama y 11 NMPI tipo mixto. El carcinoma invasivo asociado estuvo presente en 13 pacientes (41,9%), la displasia de alto grado en 4 pacientes (12,9%) y la displasia de bajo grado en 14 pacientes (45,2%). El tiempo de seguimiento fue de 2 a 12 años. La supervivencia media de los pacientes con NMPI y carcinoma invasivo asociado fue de 45,8 meses y la supervivencia libre de enfermedad de estos pacientes fue de 40,8 meses. Conclusiones En nuestros pacientes operados, la NMPI tuvo mayor prevalencia en mujeres, fue predominantemente sintomática y tuvo una elevada incidencia de carcinoma invasivo asociado a las de tipo rama. La supervivencia a 5 años fue buena aun con carcinoma invasivo asociado. (AU)

Introduction Intraductal papillary mucinous neoplasm (IPMN) of pancreas can progress from low grade dysplasia to high grade dysplasia and invasive carcinoma. Methods in this single center retrospective series we analyze the clinicopathological features and long-term follow up of patients who underwent pancreatic resection for IPMN, from January 2009 to December 2019. Results 31 patients were diagnosed with IPMN. Nine males and 22 females. The mean age was 67 years. Twenty-seven patients (87%) were symptomatic. Seven patients had main duct IPMN, 11 branch type IPMN and 13 mixed type IPMN. High-risk stigmata were found in 20 patients (64.5%) and worrisome features in 10 patients (32.2%). Thirteen patients (41.9%) had an associated invasive carcinoma, 4 (12.9%) high-grade dysplasia and 14 (45.2%) low-grade dysplasia. The follow-up was from 2 to 12 years. Median survival for patients with IPMN and associated invasive carcinoma was 45.8 months and disease-free survival was 40.8 months. Conclusions IPMN had higher prevalence in females, mostly symptomatic and high incidence of associated invasive carcinoma with branch type. The 5-year survival was good even with associated invasive carcinoma. (AU)

Glucose Metabolism After Pancreatectomy: Opposite Extremes Between Pancreaticoduodenectomy and Distal Pancreatectomy.

CONTEXT: The rate of glucose metabolism changes drastically after partial pancreatectomy. OBJECTIVE: This work aims to analyze changes in patients' glucose metabolism and endocrine and exocrine function before and after partial pancreatectomy relative to different resection types (Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy: KIP-MEP study). METHODS: A series of 278 consecutive patients with scheduled pancreatectomy were enrolled into our prospective study. Of them, 109 individuals without diabetes, who underwent partial pancreatectomy, were investigated. Data were compared between patients with pancreaticoduodenectomy (PD, n = 73) and those with distal pancreatectomy (DP, n = 36). RESULTS: Blood glucose levels during the 75-g oral glucose tolerance test (75gOGTT) significantly decreased after pancreatectomy in the PD group (area under the curve [AUC] -9.3%, P < .01), and significantly increased in the DP population (AUC + 16.8%, P < .01). Insulin secretion rate during the 75gOGTT and glucagon stimulation test significantly decreased after pancreatectomy both in the PD and DP groups (P < .001). Both groups showed similar homeostasis model assessment of insulin resistance (HOMA-IR) values after pancreatectomy. Decrease in exocrine function quality after pancreatectomy was more marked in association with PD than DP (P < .01). Multiple regression analysis indicated that resection type and preoperative HOMA-IR independently influenced glucose tolerance-related postoperative outcomes. CONCLUSIONS: Blood glucose levels after the OGTT differed markedly between PD and DP populations. The observed differences between PD and DP suggest the importance of individualization in the management of metabolism and nutrition after partial pancreatectomy.

International consensus statement on robotic pancreatic surgery

The robotic surgical system has been applied to various types of pancreatic surgery. However, controversies exist regarding a variety of factors including the safety, feasibility, efficacy, and cost-effectiveness of robotic surgery. This study aimed to evaluate the current status of robotic pancreatic surgery and put forth experts' consensus and recommendations to promote its development. Based on the WHO Handbook for Guideline Development, a Consensus Steering Group* and a Consensus Development Group were established to determine the topics, prepare evidence-based documents, and generate recommendations. The GRADE Grid method and Delphi vote were used to formulate the recommendations. A total of 19 topics were analyzed. The first 16 recommendations were generated by GRADE using an evidence-based method (EBM) and focused on the safety, feasibility, indication, techniques, certification of the robotic surgeon, and cost-effectiveness of robotic pancreatic surgery. The remaining three recommendations were based on literature review and expert panel opinion due to insufficient EBM results. Since the current amount of evidence was low/meager as evaluated by the GRADE method, further randomized controlled trials (RCTs) are needed in the future to validate these recommendations.

Active involvement of family members in postoperative care after esophageal or pancreatic resection: A feasibility study.

BACKGROUND: Active involvement of relatives has the potential to improve postoperative patient outcomes by prevention of complications sensitive to basic care and unplanned readmissions. The aim of this study was to assess the feasibility of a program in which relatives participated in postoperative care. METHODS: A pragmatic feasibility trial conducted at the surgical ward of a University hospital in the Netherlands. Patients undergoing esophageal or pancreatic resection with a relative who was willing and able to participate formed the intervention group (n = 20). A control group (n = 20) received usual postoperative care. The program consisted of the following: (1) information; (2) shared goal setting; (3) task-oriented training; (4) participation in basic care, focusing on mobilization, breathing exercises, cognitive activities and oral hygiene; (5) presence of relatives during ward rounds; and (6) rooming-in. Feasibility criteria were adherence to basic care, caregiver burden, and satisfaction of patients, family, and healthcare professionals. RESULTS: All participants completed the program. Patients in the intervention group mobilized more (estimated difference for walking 170 meters per day, P = .037, and for sitting 109 minutes per day, P < .001), and showed more adherence to breathing exercises (estimated difference per day 1.4, P = .003), oral hygiene (estimated difference 1.52, P = .001), and cognitive activities (estimated difference 2.6, P < .001). Relatives'Care-Related Quality of Life instrument score did not deteriorate over time (P = .64); 96% of relatives would recommend the program and 92% felt better prepared for discharge. Patients in the intervention group were more satisfied with hospital admission. Healthcare professionals valued the program positively. CONCLUSION: This program is feasible and is positively appreciated by patients, family, and healthcare professionals. Patients following the program showed more adherence to basic care activities.

Braden scale for pressure ulcer risk predicts rehabilitation placement after pancreatic resection.

BACKGROUND: Patients undergoing pancreatic resection frequently require rehabilitation facilities after hospital discharge. We evaluated the predictive role of validated markers of frailty on rehabilitation facility placement to identify patients who may require this service. METHODS: Single-center retrospective cohort study of patients who underwent pancreatic resection from 2010 to 2015. 90-day morbidity and mortality were calculated. Postoperative validated markers of frailty (Activities of Daily Living scale, Braden scale [assesses pressure ulcer risk, lower scores = higher risk] and Morse fall scale) were evaluated via multivariate regression to identify predictors of discharge to rehabilitation facility. RESULTS: 470 patients with complete data were included. Mean age was 62 and 49.2% were male. Postoperative median length of stay (LOS) was 8 (IQR 7-10). 92 (19.66%) patients were discharged to rehabilitation facilities and 138 (29.49%) patients were readmitted within 90 days. On multivariate analysis, age, sex, LOS > 8 days, inpatient Comprehensive Complication Index (CCI) and initial Braden scale were predictive of rehabilitation placement. CONCLUSION: A marker of frailty routinely collected daily by nursing staff, the Braden scale, is available to help surgeons predict the need for postoperative rehabilitation placement after pancreatic resection. Engaging discharge planning services for at-risk patients may help prevent delayed hospital discharge and should be further evaluated.

A severe but reversible reduction in insulin sensitivity is observed in patients with insulinoma.

BACKGROUND: Hypoglycemic manifestations are highly variable in patients with an insulinoma and largely independent of tumour size and severity of insulin hypersecretion. OBJECTIVES: We investigated the clinical, biological and tumoral characteristics of insulinomas in a large monocentric series of patients and we evaluated their insulin sensitivity before and after successful pancreatic surgery. PATIENTS AND METHODS: This was a retrospective analysis of 40 patients treated for an insulinoma between 1982 and 2012 in our academic hospital. Insulin sensitivity and beta cell function were evaluated by a HOMA test outside hypoglycaemic episodes in a large subset of these patients. RESULTS: The mean age at onset of symptoms was 48.8±20.1 years and the mean age at diagnosis was 50.7±19.9 years. Neuroglycopenic symptoms were observed in 90% of patients. The most effective preoperative imaging technique to localize the tumour was endoscopic ultrasound. Insulin sensitivity was greatly reduced in patients with insulinoma (38.9%±22.3%), while beta cells function was increased (359.0±171.5%), but to a variable extent (range: 110.6-678.6%). After complete resection of the tumour and remission of hypoglycemic episodes, insulin sensitivity increased in all evaluated subjects (72.8±36.7%) and normalized in the majority. CONCLUSION: Although neuroglycopenic symptoms are present in most patients, diagnosis of insulinoma is often delayed. Endoscopic ultrasound remains the most sensitive preoperative technique to localize the tumour. We also show that in response to chronic hyperinsulinemia, patients with insulinoma develop protective mechanisms responsible for a marked insulin resistance, which is reversible after complete resection of the tumour.

Selecting post-acute care settings after abdominal surgery: Are we getting it right?

BACKGROUND: We investigated whether variation in post-acute care (PAC) services could be explained by surgeons discharging clinically similar patients to different PAC destinations, including home health (HH), skilled nursing facilities (SNF), and inpatient rehabilitation (IR). METHODS: We studied patients having colectomy, pancreatectomy or hepatectomy in the 2008-2011 Nationwide Inpatient Sample. We used propensity matching to determine: 1. Proportion of patients discharged to SNF/IR who could be matched to clinically similar patients discharged with HH. 2. Potential cost savings from greater use of HH. RESULTS: 30,843 patients were discharged with HH and 23,172 to SNF or IR. 14,163 (61%) SNF/IR patients could be matched to similar patients discharged with HH. Potential cost savings from increasing use of HH as an alternative to SNF/IR ranged from $2.5-$438 million annually. CONCLUSIONS: There is considerable potential for reducing variation in PAC use and costs by better understanding how surgeons make decisions about PAC placement.

Manejo nutricional en la rehabilitación multimodal precoz en cirugía pancreática / Nutrition management in enhanced recovery after abdominal pancreatic surgery

Los programas de rehabilitación multimodal precoz son estrategias estandarizadas perioperatorias con el objetivo de mejorar la recuperación del paciente, disminuir las complicaciones, la estancia hospitalaria y el coste sanitario. El aspecto nutricional es un componente esencial de la rehabilitación multimodal precoz, recomendándose realizar un cribado nutricional previo al ingreso hospitalario, evitar el ayuno prequirúrgico mediante una sobrecarga oral de hidratos de carbono, e iniciar de manera precoz la ingesta oral posquirúrgica. Sin embargo, no existen protocolos estandarizados de progresión de dieta en cirugía pancreática. Se realiza una revisión de las diferentes estrategias nutricionales publicadas desde 2006 hasta 2016 en la rehabilitación multimodal precoz de este tipo de cirugía y sus posibles implicaciones en la evolución postoperatoria. Los estudios evaluados son muy heterogéneos por lo que no se pueden extraer resultados concluyentes sobre el protocolo de dieta a implementar, su influencia en variables clínicas ni la necesidad o no de nutrición artificial concomitante (AU)

Multimodal rehabilitation programs are perioperative standardized strategies with the objective of improving patient recovery, and decreasing morbidity, hospital stay and health cost. The nutritional aspect is an essential component of multimodal rehabilitation programs and therefore nutritional screening is recommended prior to hospital admission, avoiding pre-surgical fasting, with oral carbohydrate overload and early initiation of oral intake after surgery. However, there are no standardized protocols of diet progression after pancreatic surgery. A systematic review was been performed of papers published between 2006 and 2016, describing different nutritional strategies after pancreatic surgery and its possible implications in postoperative outcome. The studies evaluated are very heterogeneous, so conclusive results could not be drawn on the diet protocol to be implemented, its influence on clinical variables, or the need for concomitant artificial nutrition (AU)

Nutrition management in enhanced recovery after abdominal pancreatic surgery. / Manejo nutricional en la rehabilitación multimodal precoz en cirugía pancreática.

Multimodal rehabilitation programs are perioperative standardized strategies with the objective of improving patient recovery, and decreasing morbidity, hospital stay and health cost. The nutritional aspect is an essential component of multimodal rehabilitation programs and therefore nutritional screening is recommended prior to hospital admission, avoiding pre-surgical fasting, with oral carbohydrate overload and early initiation of oral intake after surgery. However, there are no standardized protocols of diet progression after pancreatic surgery. A systematic review was been performed of papers published between 2006 and 2016, describing different nutritional strategies after pancreatic surgery and its possible implications in postoperative outcome. The studies evaluated are very heterogeneous, so conclusive results could not be drawn on the diet protocol to be implemented, its influence on clinical variables, or the need for concomitant artificial nutrition.

Involvement of Pancreatic Stellate Cells in Regeneration of Remnant Pancreas after Partial Pancreatectomy.

BACKGROUND AND OBJECTIVES: Mechanism of regeneration of remnant pancreas after partial pancreatectomy (PX) is still unknown. In this study, effect of siRNA against the collagen specific chaperone, HSP47, which inhibits collagen secretion from activated pancreas stellate cells (aPSCs), and induces their apoptosis, on regeneration of remnant pancreas was determined. METHODS: Pancreatectomy was performed according to established methods. Proliferation of cells was assessed by BrdU incorporation. Immunostaining of HSP47 was employed to identify PSCs. Progenitor cells were identified by SOX9 staining. Acinar cells were immunostained for amylase. Co-culture of acinar cells with aPSCs were carried out in a double chamber with a cell culture insert. siRNA HSP47 encapsulated in vitamin A-coupled liposome (VA-lip siRNA HSP47) was delivered to aPSCs by iv injection. RESULTS: In remnant pancreas of 90% PX rat, new areas of foci were located separately from duodenal areas with normal pancreatic features. After PX, BrdU uptake of acinar cells and islet cells significantly increased, but was suppressed by treatment with VA-lip siRNA HSP47. BrdU uptake by acinar cells was augmented by co-culturing with aPSCs and the augmentation was nullified by siRNA HSP47. BrdU uptake by progenitor cells in foci area was slightly enhanced by the same treatment. New area which exhibited intermediate features between those of duodenal and area of foci, emerged after the treatment. CONCLUSION: aPSCs play a crucial role in regeneration of remnant pancreas, proliferation of acinar and islet cells after PX through the activity of secreted collagen. Characterization of new area emerged by siRNA HSP47 treatment as to its origin is a future task.

Progressive postresection program (pPRP) after pancreatic resection: study protocol for a randomized controlled trial.

BACKGROUND: At the time of initial diagnosis, only 15-20% of patients with pancreatic cancer present with a resectable disease. Patients with pancreatic cancer face a poor prognosis. Progression-free survival and overall survival rates are very limited, so it is important to develop concepts to improve the quality of life for their remaining lives. METHODS/DESIGN: The proposed trial is a randomized controlled intervention study. After pancreatic resection, the intervention group (cohort A, n = 30 patients) will take part in an intensified physiotherapy program consisting of endurance and muscle force exercises. The control group (cohort B, n = 30 patients) will take part in standard physiotherapy. Both groups will receive dietary counseling and, if necessary, substitution for endocrine/exocrine pancreatic insufficiency. Quality of life will be evaluated using the Short Form-8 Health Survey and the European Organization for Research and Treatment of Cancer QLQ-C30/QLQ-PAN26 questionnaires. DISCUSSION: The aim of this study is to investigate whether intensive physiotherapy improves the quality of life of patients after pancreatic resection. If the results for the intervention group are positive, a multicenter study should be performed with appropriate statistical power. The progressive postresection program includes a structured follow-up after pancreatic resection. In this study, all patients will undergo abdominal computed tomography for follow-up 6 and 12 months postoperatively. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006786. Date of registration 1 October 2014.

Fast-track recovery after major liver and pancreatic resection from the nursing point of view.

Postoperative fast-track recovery protocols combine various methods to support immediate care of patients who undergo major surgery. These protocols include control of postoperative pain and early beginning of oral diet and mobilization. The combination of these approaches may reduce the rate of postoperative complications and facilitate hospital discharge. The aim of this study was to evaluate progress and parameters of fast-track recovery after major liver and pancreatic resection. A descriptive bibliographical review from 2001 to 2012 via electronic databases such as MEDLINE, PubMed, and Google Scholar was undertaken. Articles that focused on a fast-track protocol were studied. Reports focusing on the implementation of a fast-track protocol in the postoperative recovery of patients after major hepatectomy or pancreatectomy were selected. Fast-track protocols may be applicable to patients recovering after major liver or pancreatic resection. Future research should be focused on particular parameters of the fast-track protocol separately.

[Novelties in surgery in 2013?]. / Quoi de neuf en chirurgie?

Multidisciplinary management of colorectal liver metastases allows an increase of about 20% in the resection rate of liver metastases. It includes chemotherapy, interventional radiology and surgery. In 2013, the preliminary results of the in-situ split of the liver associated with portal vein ligation (ALLPS) are promising with unprecedented mean hypertrophy up to 70% at day 9. However, the related morbidity of this procedure is about 40% and hence should be performed in the setting of study protocol only. For pancreatic cancer, the future belongs to the use of adjuvant and neo adjuvant therapies in order to increase the resection rate. Laparoscopic and robot-assisted surgery is still in evolution with significant benefits in the reduction of cost, hospital stay, and postoperative morbidity. Finally, enhanced recovery pathways (ERAS) have been validated for colorectal surgery and are currently assessed in other fields of surgery like HPB and upper GI surgery.

Evaluation of the quality of life after surgical treatment of chronic pancreatitis.

OBJECTIVE: Pain is the main symptom of chronic pancreatitis. However, in addition to an improvement in pain symptoms, an increase in the quality of life also influences therapeutic success. The present paper evaluates the influence of surgery on chronic pancreatitis, and the early and late postoperative quality of life. PATIENTS: From March 2000 until April 2005, 51 patients underwent surgical treatment for chronic pancreatitis at our institution. INTERVENTION: Thirty-nine (76.5%) patients were operated on according to the Frey procedure and, in 12 (23.5%) patients, a Whipple procedure was performed. STUDY DESIGN: Patient data were documented throughout the duration of the hospital stay. Postoperative follow-up data were recorded retrospectively. MAIN OUTCOME MEASURES: Postoperative follow-up with postoperative pain scores and quality of life were carried out using a standardized questionnaire. RESULTS: During a median follow-up period of 50 months, an improvement in pain scores was observed in 92.3% of the patients in the Frey group and in 66.7% in the Whipple group. The indices for global quality of life and for physical and emotional status increased in both surgical groups. CONCLUSION: For patients with chronic pancreatitis, the decisive factor is the quality of life, particularly concerning pain and metabolic changes. The Frey procedure seems to offer advantages with respect to long-term freedom of pain and low risk of surgery-induced pancreatic insufficiency.

Systematic review and meta-analysis: islet autotransplantation after pancreatectomy for minimizing diabetes.

OBJECTIVE: Islet autotransplantation (IAT) may decrease the morbidity and mortality of postpancreatectomy diabetes mellitus. The current systematic review and meta-analysis examined the rate of insulin independence (II) and mortality after IAT post-total (TP) or partial pancreatectomy (PP). METHODS: Ovid MEDLINE, EMBASE, Web of Science, SCOPUS and reference lists were searched until 31 January 2011. Eligible studies enrolled adult patients with IAT post-TP or PP, regardless of study design, sample size and language. Two investigators identified eligible studies and extracted data independently. From each study, 95% confidence intervals (CIs) were estimated and pooled using random effects meta-analysis. RESULTS: Fifteen observational studies were eligible (11 IAT post-TP, two post-PP and two including both). The II rates for IAT post-TP at last follow-up and transiently during the study were 4·62 per 100 person-years (95% CI: 1·53-7·72) and 8·34 per 100 person-years (95% CI: 3·32-13·37), respectively. In the later group, patients achieved transient II lasting 15·57 months (95% CI: 10·35-20·79). The II rate at last follow-up for IAT post-PP was 24·28 per 100 person-years (95% CI: 0·00-48·96). Whereas the 30-day mortality for IAT post-TP and post-PP was 5% (95% CI: 2-10%) and 0, respectively, the long-term mortality was 1·38 per 100 person-years (95% CI: 0·66-2·11) and 0·70 per 100 person-years (95% CI: 0·00-1·80) respectively. CONCLUSIONS: IAT postpancreatectomy offers some patients a chance for insulin independence. Better data reporting are essential to establish the risks and benefits of IAT after pancreatic surgery.

Idiopathic hyperammonemia in a patient with total pancreatectomy and islet cell transplantation.

CONTEXT: Idiopathic hyperammonemia is characterized by elevated serum ammonia associated with neurological deterioration of no other obvious etiology associated with relatively normal liver function tests and normal amino-acid levels. CASE REPORT: We report a case of a 32-year-old woman who presented with acute mental status changes with a pelvic abscess approximately a year following her total pancreatectomy and islet cell transplant surgery. Her ammonia level was elevated to 425 µg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Metabolic, pharmacologic, microbial, and autoimmune causes for hyperammonemia were excluded. The patient ultimately required continuous veno-venous hemofiltration to decrease her ammonia. Ammonia levels decreased following continuous veno-venous hemofiltration and the patient's mental status gradually returned to baseline. CONCLUSION: Idiopathic hyperammonemia in the setting of total pancreatectomy and islet cell transplantation has not been reported before. We propose that malnutrition following total pancreatectomy resulting in repressed urea cycle enzyme synthesis may have predisposed for this hyperammonemia.

Impact of pancreatic gland volume on fistula formation after pancreatic tail resection.

CONTEXT: Resection of the body and tail of the pancreas (distal pancreatectomy) is associated with high postoperative morbidity, most of which is due to leakage from the pancreatic transection surface. OBJECTIVE: The aim of the current study was to analyze factors which may affect the risk of pancreatic fistula formation. PATIENTS: All consecutive distal pancreatectomies prospectively registered in our hospital database from 1999 to 2007 were included. Clinically relevant pancreatic fistula grades B and C, defined according to the International Study Group on Pancreatic Fistula (ISGPF) definition were assessed. MAIN OUTCOME MEASURES: The impact of patient, tumor, surgery, and radiology-related factors on the risk of pancreatic fistula formation were assessed by univariate and multivariate analyses. RESULTS: A distal pancreatectomy was performed in 51 patients (median age: 59 years; range: 26-76 years), 22 of whom had malignant and 29 benign or premalignant disease. Pancreatic fistulas were diagnosed in 17 (33.3%) of the patients. An additional three patients had a local abscess without apparent but assumed pancreatic leakage. Multivariate analysis showed that pancreatic fistulas occurred more frequently after hand suturing of the transection area versus the use of a stapler (69.2% vs. 21.1%; OR: 40.4, 95% CI: 3.36-486; P=0.004) and a large volume of the pancreatic remnant (greater, or equal to, 34 cm3) increased the subsequent risk of pancreatic fistula (57.1% vs. 20.8%; OR: 6.14, 95% CI: 1.14-39.0; P=0.035). CONCLUSIONS: Development of pancreatic fistula after distal pancreatectomy remains a challenge. The volume of the remaining pancreas and the technique of closure of the transected pancreas were found to affect this risk, thus allowing future preventive measures to be explored and evaluated in clinical trials.