Minimally invasive total pancreatectomy with islet autotransplantation for chronic pancreatitis: the robotic approach.

INTRODUCTION: Total pancreatectomy with islet autotransplantation (TPIAT) treats refractory pain in chronic pancreatitis, prevents episodes of acute exacerbation, and mitigates postoperative brittle diabetes. The minimally invasive (MIS) approach offers a decreased surgical access trauma and enhanced recovery. Having established a laparoscopic TPIAT program, we adopted a robotic approach (R-TPIAT) and studied patient outcomes compared to open TPIAT. METHODS: Between 2013 and 2021, 61 adult patients underwent TPIAT after a comprehensive evaluation (97% chronic pancreatitis). Pancreatic islets were isolated on-site during the procedure. We analyzed and compared intraoperative surgical and islet characteristics, postoperative morbidity and mortality, and 1-year glycemic outcomes. RESULTS: MIS-TPIAT was performed in 41 patients (67%, 15 robotic and 26 laparoscopic), and was associated with a shorter mean length of intensive care unit stay compared to open TPIAT (2.9 vs 4.5 days, p = 0.002). R-TPIAT replaced laparoscopic TPIAT in 2017 as the MIS approach of choice and demonstrated decreased blood loss compared to open TPIAT (324 vs 843 mL, p = 0.004), similar operative time (609 vs 562 min), 30-day readmission rate (7% vs 15%), and 90-day complication rate (13% vs 20%). The glycemic outcomes including C-peptide detection at 1-year (73% vs 88%) and insulin dependence at 1-year (75% vs 92%) did not differ. The mean length of hospital stay after R-TPIAT was 8.6 days, shorter than for laparoscopic (11.5 days, p = 0.031) and open TPIAT (12.6 days, p = 0.017). Both MIS approaches had a 1-year mortality rate of 0%. CONCLUSIONS: R-TPIAT was associated with a 33% reduction in length of hospital stay (4-day benefit) compared to open TPIAT. R-TPIAT was similar to open TPIAT on measures of feasibility, safety, pain control, and 1-year glycemic outcomes. Our data suggest that robotic technology, a new component in the multidisciplinary therapy of TPIAT, is poised to develop into the primary surgical approach for experienced pancreatic surgeons.

Pancreatic duct pressure: A review of technical aspects and clinical significance.

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP.

Overlap and cumulative effects of pancreatic duct obstruction, abnormal pain processing and psychological distress on patient-reported outcomes in chronic pancreatitis.

OBJECTIVE: Several factors have been suggested to mediate pain in patients with chronic pancreatitis. However, it is unknown whether these factors are overlapping and if they have cumulative effects on patient-reported outcomes (PROs). DESIGN: We performed a multicentre cross-sectional study of 201 prospectively enrolled subjects with definitive chronic pancreatitis. All subjects underwent evaluation for pancreatic duct obstruction, abnormalities in pain processing using quantitative sensory testing, and screening for psychological distress (anxiety, depression and pain catastrophising) based on validated questionnaires. Abnormality was defined by normal reference values. PROs included pain symptom severity (Brief Pain Inventory short form) and quality of life (EORTC-QLQ-C30 questionnaire). Associations between pain-related factors and PROs were investigated by linear trend analyses, multiple regression models and mediation analyses. RESULTS: Clinical evaluation suggestive of pancreatic duct obstruction was observed in 29%, abnormal pain processing in 23%, anxiety in 47%, depression in 39% and pain catastrophising in 28%; each of these factors was associated with severity of at least one PRO. Two or more factors were present in 51% of subjects. With an increasing number of factors, there was an increase in pain severity scores (p<0.001) and pain interference scores (p<0.001), and a reduction in quality of life (p<0.001). All factors had independent and direct effects on PROs, with the strongest effect size observed for psychological distress. CONCLUSION: Pain-related factors in chronic pancreatitis are often present in an overlapping manner and have a cumulative detrimental effect on PROs. These findings support a multidisciplinary strategy for pain management. TRIAL REGISTRATION NUMBER: The study was registered with ClinicalTrials.gov (NCT03434392).

Pancreatic QST Differentiates Chronic Pancreatitis Patients into Distinct Pain Phenotypes Independent of Psychiatric Comorbidities.

BACKGROUND & AIMS: Quantitative sensory testing (QST) has been previously used to study pain in chronic pancreatitis (CP) but included methods that are not suitable for clinical purposes. The aims of this study were to determine if pancreatic QST (P-QST) can differentiate patients into distinct pain phenotypes and to determine the association of these with their clinical pain and psychiatric comorbidities. METHODS: A multicenter cross-sectional study was conducted where patients completed validated questionnaires assessing quality of life (QoL), depression and anxiety scores as well as clinical pain symptoms followed by P-QST which included a cold pressor test, repetitive pinprick stimuli and pressure stimulation of the upper abdominal (T10) and control dermatomes. P-QST categorized patients into pain phenotypes based on a previously established nomogram. QoL, clinical pain and psychiatric assessment scores were compared across these groups. RESULTS: A total of 179 patients were enrolled with a mean age of 54.1±13.6 years among whom 59% were males and 42% had an alcoholic etiology. P-QST showed no hyperalgesia in 91 (51%), segmental hyperalgesia in 50 (28%) and widespread hyperalgesia in 38 (21%) patients. Patients with widespread hyperalgesia had significantly higher pain intensity scores (P = .03) and rates of constant pain (P = .002) as well as decreased QoL (P < .001) and physical functioning (P =.03) in comparison with the other two pain phenotypes. In contrast, psychiatric comorbidities were similar across all groups. CONCLUSIONS: P-QST may serve as a novel unbiased pain assessment tool in CP as it categorizes patients into distinct pain phenotypes independent of their psychiatric comorbidities.

Development of the Comprehensive Pain Assessment Tool Short Form for Chronic Pancreatitis: Validity and Reliability Testing.

BACKGROUND & AIMS: Pain is the foremost complication to chronic pancreatitis (CP), but no validated questionnaires for assessment exist. The COMPAT questionnaire includes all relevant pain dimensions in CP, but a short form is needed to make it usable in clinical practice. METHODS: The full COMPAT questionnaire was completed by 91 patients and systematically reduced to 6 questions. Pain severity and analgesic use were merged, leaving 5 pain dimensions. The pain dimension ratings were normalized to a 0-100 scale, and the weighted total score was calculated, where 3 dimensions were weighted double. Reliability of the short form was tested in a test-retest study in 76 patients, and concurrent validity tested against the Brief Pain Inventory and Izbicki pain questionnaire. Convergent validity was verified using confirmatory factor analysis, and criterion validity tested against quality-of-life and hospitalization rates. RESULTS: The COMPAT-SF questionnaire consisted of the following pain dimensions: a) pain severity, b) pain pattern, c) factors provoking pain, d) widespread pain, and e) a qualitative pain-describing dimension. Quality of life correlated with the total score and all pain dimensions (P <.05). The total score, pain severity, pain pattern, and factors provoking pain were correlated with hospitalization rates (P <.05). The total score correlated with the Izbicki and Brief Pain Inventory scores (P <.0001). The reliability of the questionnaire in patients in a stable phase was good with an interclass correlation coefficient of 0.89. CONCLUSION: The COMPAT-SF questionnaire includes the most relevant aspects of pain in CP and is a feasible, reliable, and valid pain assessment instrument recommended to be used in future trials.

Prevalence of primary painless chronic pancreatitis: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: While pain is the predominant symptom of chronic pancreatitis (CP), a subset of patients may experience a painless course. This systematic review aimed to determine the prevalence of primary painless CP. METHODS: MEDLINE (PubMed), EMBASE and Web of Science Core Collection databases were searched for published studies through September 15, 2020 that included at least 10 consecutive patients with CP and which reported the number with painless CP. The presence of a history of recurrent acute pancreatitis (RAP), exocrine pancreatic insufficiency (EPI), diabetes mellitus (DM) and pancreatic adenocarcinoma (PA) in the painless CP patients was also recorded. A random effects model was used to determine pooled prevalence estimates with 95% confidence intervals (95% CI). RESULTS: Among the 5057 studies identified and screened, 42 full-text articles were included in the final analysis. There were a total of 14,277 patients with CP among whom 1569 had painless CP. The pooled prevalence of painless CP was 12% (95% CI 10-15%). Among a subset of studies that reported on calcifications (n = 11), DM (n = 12), EPI (n = 8) and history of RAP (n = 14), the pooled prevalence estimates were 96% (95% CI 73-100%), 51% (95% CI 32-70%), and 47% (95% CI 15-81%), respectively. Alcohol, idiopathic/genetic and other etiologies were attributed to be the cause of painless CP in 32.4%, 56.9% and 8.9% patients, respectively. CONCLUSION: Approximately one in ten patients with CP have primary painless disease with the majority being attributable to an idiopathic/genetic etiology. Further research is needed to determine the optimal management of these patients.

Impact of genetic testing and smoking on the distribution of risk factors in patients with recurrent acute and chronic pancreatitis.

OBJECTIVE: The aim of the present study is to assess the impact of smoking dose and duration on the distribution of risk factor(s) in patients with RAP and CP, and the impact of genetic testing on the distribution of risk factor(s) in patients with idiopathic RAP and CP. METHODS: All adult patients with RAP and CP referred to a multidisciplinary pancreatitis clinic between 2010 and 2017 were evaluated. Risk factors included alcohol and smoking, hypertriglyceridemia, biliary, and other etiologies. Genetic testing was only pursued in patients with idiopathic RAP or CP. RESULTS: Among the 1770 patients evaluated, 167 had RAP and 303 had CP. After genetic testing and smoking, the most common risk factors for RAP and CP were pathogenic variant(s) (23%) and the combination of alcohol and smoking (23%), respectively. Genetic testing and smoking assessment decreased the proportion of patients with alcoholic RAP from 17% to 5%, alcoholic CP from 33% to 10%, idiopathic RAP from 49% to 12%, and idiopathic CP from 54% to 14%. Pathogenic CFTR variants were the most common variant in patients with RAP (51%) and CP (43%). Among the 68 patients with pancreas divisum, other risk factor(s) were identified in 72%. CONCLUSION: Genetic testing and a detailed assessment of smoking dose and duration reduce the proportion of patients with alcoholic and idiopathic pancreatitis. Other risk factor(s) for pancreatitis are found in the majority of patients with pancreas divisum further questioning its role as an independent risk factor.1. What is the current knowledge?Approximately 30% of patients with pancreatitis have no clear risk factor(s) and are categorized as having an idiopathic etiology.Pathogenic variant(s) as well as smoking dose and duration are well-established risk factors for recurrent acute and chronic pancreatitis but are not widely recognized or incorporated into clinical practice.2. What is new here?Genetic testing and a detailed assessment of smoking dose and duration reduced the proportion of patients with alcoholic and idiopathic acute recurrent and chronic pancreatitis.Approximately three-fourths of patients with pancreas divisum have a risk factor for pancreatitis.

Morphologic Severity of Acute Pancreatitis on Imaging Is Independently Associated with Opioid Dose Requirements in Hospitalized Patients.

BACKGROUND: Prior studies have evaluated clinical characteristics associated with opioid dose requirements in hospitalized patients with acute pancreatitis (AP) but did not incorporate morphologic findings on CT imaging. AIMS: We sought to determine whether morphologic severity on imaging is independently associated with opioid dose requirements in AP. METHODS: Adult inpatients with a diagnosis of AP from 2006 to 2017 were reviewed. The highest modified CT severity index (MCTSI) score and the daily oral morphine equivalent (OME) for each patient over the first 7 days of hospitalization were used to grade the morphologic severity of AP and calculate mean OME per day(s) of treatment (MOME), respectively. Multiple regression analysis was used to evaluate the association of MOME with MCSTI. RESULTS: There were 249 patients with AP, of whom 196 underwent contrast-enhanced CT. The mean age was 46 ± 13.6 years, 57.9% were male, and 60% were black. The mean MOME for the patient cohort was 60 ± 52.8 mg/day. MCTSI (ß = 3.5 [95% CI 0.3, 6.7], p = 0.03), early hemoconcentration (ß = 21 [95% CI 4.6, 39], p = 0.01) and first episode of AP (ß = - 17 [95% CI - 32, - 2.7], p = 0.027) were independently associated with MOME. Among the 19 patients undergoing ≥ 2 CT scans, no significant differences in MOME were seen between those whose MCTSI score increased (n = 12) versus decreased/remained the same (n = 7). CONCLUSION: The morphologic severity of AP positively correlated with opioid dose requirements. No difference in opioid dose requirements were seen between those who did versus those who did not experience changes in their morphologic severity.

Psychiatric Disease Susceptibility and Pain in Chronic Pancreatitis: Association or Causation?

ABSTRACT: Pain perception in chronic pancreatitis (CP) is governed by the transmission of nociceptive inputs into the pain processing centers of the brain. These regions of the brain overlap with those that regulate and process emotions and cognition. Disorders in these regions also result in psychiatric conditions such as depression, anxiety, and posttraumatic stress disorder. The present study by Dunbar et al. evaluated 24 single nucleotide polymorphisms associated with anxiety and/or posttraumatic stress disorder and found correlations with constant and severe pain phenotypes in CP patients from a large cross-sectional cohort study. Although causation cannot be proven, the findings suggest that there may be a role for neuromodulator drugs for the treatment of pain in CP based on individual genetic susceptibility.

Psychiatric Comorbidity in Patients With Chronic Pancreatitis Associates With Pain and Reduced Quality of Life.

INTRODUCTION: Abdominal pain, frequent in patients with chronic pancreatitis (CP), has a negative impact on quality of life (QOL). Psychiatric comorbidities including anxiety and depression are associated with pain, but their prevalence and effects on QOL in CP have not been quantified. We studied the prevalence of anxiety and depression in patients with CP and their associated patient and disease characteristics and impact on QOL. METHODS: This was a cross-sectional, multicenter prospective study. Patients were screened with the Hospital Anxiety and Depression Scale questionnaire. A Hospital Anxiety and Depression Scale score >7 on the respective anxiety or depression subscales indicated the presence of anxiety or depression and was used as a surrogate for the diagnosis of psychiatric comorbidities. Patient demographics, disease characteristics, QOL (EORTC-QLQ-C30), and pain symptoms (Brief Pain Inventory Short Form) were compared between patients with and without psychiatric comorbidities. RESULTS: One hundred seventy-one patients with CP (mean age 53.8 ± 13.7 years, 60% men) were included. Anxiety and depression were present in 80 (46.8%) and 66 (38.6%) patients, with overlap in 50 (29%). Patients with anxiety or depression reported higher pain prevalence, pain severity, and pain interference scores (all P < 0.001). Psychiatric comorbidities also associated with reduced global health scores and functional subscales (all P < 0.001) and higher symptom burden (P ≤ 0.03). An independent association was noted between global health status and depression (P < 0.001). DISCUSSION: Psychiatric comorbidities are prevalent in patients with CP and associated with pain and QOL. Where the effect of anxiety on QOL may be mediated via pain, depression is independently related to QOL. These findings warrant consideration in the management of patients with CP.

A clinically feasible method for the assessment and characterization of pain in patients with chronic pancreatitis.

BACKGROUND AND AIMS: Pain is the primary symptom of chronic pancreatitis (CP), but methods for sensory testing and pain characterization have not previously been validated for clinical use. We present a clinically feasible method for the assessment and characterization of pain mechanisms in patients with CP based on quantitative sensory testing (QST). METHODS: This was a cross-sectional, multicenter study of 122 control subjects without pancreatic disease and another 60 patients with painful CP. All subjects underwent standardized QST assessments including a cold pressor test, a conditioned pain modulation paradigm, repetitive pin-prick stimuli (temporal summation) and pressure stimulation of the upper abdominal (pancreatic) and control dermatomes. The effects of age and gender on QST assessment parameters were investigated and normative reference values based on quartile regression were derived and implemented in algorithms to categorize patients according to their patterns of central pain processing (normal vs. segmental sensitization vs. widespread sensitization). RESULTS: Absolute pressure thresholds were subject to clinically relevant gender effects (all p < 0.001), while the remainder of QST parameters were unaffected by age and gender. The algorithm with the best discriminatory capacity showed good separation between patients and controls (p < 0.001); 50% of patients had normal central pain processing, 23% had evidence of segmental sensitization and 27% had evidence of widespread sensitization. CONCLUSION: We show normative reference values for a clinically feasible method for assessment and characterization of pain mechanisms in patients with CP. Application of this method streamlines the evaluation of pancreatic pain and may be used to inform treatment. CLINICALTRIALS. GOV ID: NCT03434392.

Pancreatic volume does not correlate with histologic fibrosis in adult patients with recurrent acute and chronic pancreatitis.

OBJECTIVES: Reduced pancreatic volume, often referred to as atrophy, is a commonly reported imaging feature of chronic pancreatitis (CP). This study evaluated whether there is an association between pancreatic volume and fibrosis, the criterion standard of CP, in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for recurrent acute pancreatitis (RAP) and CP. METHODS: All adult patients who underwent TPIAT between 2010 and 2019 were categorized into 3 groups: RAP, definite CP and indeterminate CP. Pancreatic volume was calculated by summing up the areas from each thin section of the pancreas on 3D CT imaging. Excisional biopsies of the pancreatic head as well as body/tail region were obtained at the time of TPIAT. Two different fibrosis scores were used for histologic assessment. RESULTS: A total of 16, 29 and 15 patients underwent TPIAT for RAP, definite CP and indeterminate CP, respectively. The mean pancreatic volumes for patients with RAP, definite CP and indeterminate CP were 65.7 ± 28.5 cc, 54.9 ± 22.9 cc and 61.8 ± 23.6 cc, respectively (p = 0.3). The mean fibrosis scores were significantly higher in patients with definite CP compared to RAP (p < 0.001) and indeterminate CP (p < 0.001). Pancreatic volume was not associated with either fibrosis score after adjusting for age, gender, duration of disease, BMI and diabetes in the multivariable analysis. CONCLUSIONS: While the fibrosis scores were higher in definite CP compared to both RAP and indeterminate CP, there was no correlation between pancreatic volume and fibrosis. This suggests that atrophy alone cannot be used to diagnose CP.

Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis.

BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history. METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period. RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ±â€¯13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ±â€¯21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up. CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.

Persistent SIRS and acute fluid collections are associated with increased CT scanning in acute interstitial pancreatitis.

BACKGROUND: The use of computed tomography (CT) in acute pancreatitis (AP) continues to increase in parallel with the increasing use of diagnostic imaging in clinical medicine. AIM: To determine the factors associated with obtaining >1 CT scan in acute interstitial pancreatitis (AIP). METHODS: Demographic and clinical data of all adult patients admitted between 1/2010 and 1/2015 with AP (AP) were evaluated. Only patients with a CT severity index (CTSI) ≤ 3 on a CT obtained within 48 h of presentation were included. RESULTS: A total of 229 patients were included, of whom 206 (90%) had a single CT and 23 (10%) had >1 CT during the first week of hospitalization. Patients undergoing >1 CT had significantly higher rates of acute fluid collection (AFC), persistent SIRS, opioid use ≥4 days, and persistent organ failure compared to those undergoing 1 CT (p < .05 for all). On multivariable analysis, only persistent SIRS (OR = 3.6, 95% CI 1.4-9.6, p = .01) and an AFC on initial CT (OR = 3.5, 95% CI 1.4-9, p = .009) were independently associated with obtaining >1 CT. CONCLUSION: An AFC on initial CT and persistent SIRS are associated with increased CT imaging in AIP patients. However, these additional CT scans did not change clinical management.

Total pancreatectomy for recurrent acute and chronic pancreatitis: a critical review of patient selection criteria.

PURPOSE OF REVIEW: Critical review of the indications for total pancreatectomy and highlight limitations in current diagnostic criteria for chronic pancreatitis. RECENT FINDINGS: The diagnosis of noncalcific chronic pancreatitis remains controversial because of an overreliance on nonspecific imaging and laboratories findings. Endoscopic ultrasound, s-magnetic resonance cholangiopancreatography, and/or endoscopic pancreatic function testing are often used to diagnose noncalcific chronic pancreatitis despite the fact that there is no gold standard for this condition. Abdominal pain is not specific for chronic pancreatitis and is more likely to be encountered in patients with functional gastrointestinal disorders based on the high incidence of these conditions. The duration of pain and opioid analgesic use results in central sensitization that adversely affects pain outcomes after total pancreatectomy. An alcoholic cause is associated with poorer pain outcomes after total pancreatectomy. SUMMARY: The lack of a gold standard for noncalcific chronic pancreatitis limits the diagnostic accuracy of imaging and laboratory tests. The pain of chronic pancreatitis is nonspecific and is affected by duration, preoperative opioid use, and cause. These factors will need to be considered in the development of future selection criteria for this morbid surgery.

Hospital admission volume does not impact the in-hospital mortality of acute pancreatitis.

BACKGROUND: Multiple factors influence mortality in Acute Pancreatitis (AP). METHODS: To evaluate the association of demographic, clinical, and hospital factors with the in-hospital mortality of AP using a population-based administrative database. The Maryland HSCRC database was queried for adult (≥18 years) admissions with primary diagnosis of AP between 1/94-12/10. Organ failure (OF), interventions, hospital characteristics and referral status were evaluated. RESULTS: There were 72,601 AP admissions across 48 hospitals in Maryland with 885 (1.2%) deaths. A total of 1657 (2.3%) were transfer patients, of whom 101 (6.1%) died. Multisystem OF was present in 1078 (1.5%), of whom 306 (28.4%) died. On univariable analysis, age, male gender, transfer status, comorbidity, OF, all interventions, and all hospital characteristics were significantly associated with mortality; however, only age, transfer status, OF, interventions, and large hospital size were significant in the adjusted analysis. Patients with commercial health insurance had significantly less mortality than those with other forms of insurance (OR 0.65, 95% CI: 0.52, 0.82, p = 0.0002). CONCLUSION: OF is the strongest predictor of mortality in AP after adjusting for demographic, clinical, and hospital characteristics. Admission to HV or teaching hospital has no survival benefit in AP after adjusting for OF and transfer status.