10 YEAR OUTCOMES OF SMOKING CESSATION ATTEMPTS IN REDUCING LOW BONE DENSITY DISEASE IN CHRONIC PANCREATITIS

Background Chronic pancreatitis (CP) may severely impact quality of life (QoL). Since CP is a chronic condition, multiple assessments of QoL are required to obtain a thorough understanding of its impact on patients. Such studies are currently lacking. Therefore, the aim of the present study is to gain insight into the course and predictors of both physical and mental QoL in patients with CP using prospective longitudinal data from a large cohort of patients.
Methods Post-hoc analysis of patients with CP registered in a prospective database between 2011 and 2019. Patient and disease characteristics, nutritional status, pain severity, medication usage, pancreatic function and pancreatic interventions were assessed from patients’ medical records and through standard follow-up questionnaires. The physical (PCS) and mental component summary (MCS) scales of the Short-Form 36 were used to assess QoL at baseline and during follow-up. The course of both physical and mental QoL and their associated factors were longitudinally assessed by using generalized linear mixed models (GLMM).
Results Overall, 1,165 patients with CP were included for this analysis. During 10-year follow-up, GLMM analyses revealed improvements in both PCS (41.6 to 45.1, p < .001) and MCS (45.8 to 48.5, P = 0.041). Older age, no alcohol consumption, unemployment, need for dietetic consultation, steatorrhea, higher Izbicki pain score and pain coping mechanism were negatively associated with physical QoL (P < .05). For mental QoL, a positive correlation was found between employment, non-alcoholic CP, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, pain coping mechanism and surgical treatment. No association was observed between disease duration and longitudinal QoL per patient.
Conclusions The present study provides insight into the dynamics of physical and mental QoL in patients with CP over time. Important and potentially influenceable factors to improve QoL in patients with CP are nutritional status, exocrine pancreatic function, employment status, and patients’ coping strategy.

Background: Central sensitization is a dimension of the pain experience in patients with painful chronic pancreatitis (CP) that has been identified by detection of specific patterns of hyperalgesia via pancreatic quantitative sensory testing (P-QST). Patients with hyperalgesia respond poorly to conventional therapy. Currently, there are no mechanism-based biomarker signatures for central sensitization. This pilot study hypothesized that specific biomarker profiles will associate with the presence of hyperalgesia in patients with painful CP.

Methods: Biomarkers (cytokines, chemokines, peptides, hormones) potentially associated with inflammation and metabolism were measured (all pg/mL) in serum samples from CP patients enrolled in the P-QST study. P-QST was used to classify patients based on the presence of hyperalgesia. Biomarker levels are reported as median and interquartile range. In cases where levels were below the level of detection (LOD), a binary variable (detectable v non-detectable) was created. P-values were calculated in the univariable analysis using the Wilcoxon rank-sum test, and Benjamini & Hochberg method for control of false discovery rate (FDR) was applied. Machine learning techniques including random forests and principal component analysis (PCA) were utilized to identify biomarker patterns (individual or groups) that correlate with presence of hyperalgesia.

Results: Of 39 patients, 22 (56%) had hyperalgesia on P-QST testing. Patients with hyperalgesia had significantly lower levels of Tumor Necrosis Factor-alpha (TNF-α) (1.6 [1.4: 2.4] v 3.2 [2.7: 4.9]; p = 0.0003), interleukin (IL) -17F (55.3 [0.0: 133.3] v 94.2 [54.9: 188.8]; p = 0.035), ghrelin (94.3 [34.4: 140.5] v 140.6 [121.4: 226.4]; p = 0.018), and IL - 27 (115.1 [80.5: 195.7] v 176.3 [114.4: 289.0]; p = 0.042). Using FDR-adjusted p-values, lower TNF-α was significantly associated with presence of hyperalgesia (p<0.01) and ghrelin was marginally significant (p=0.09). On random forests analysis, 56% of patients had TNF-α level <2.5, of those 86% had hyperalgesia; whereas among the 44% of patients whose TNF-α was ≥ 2.5, only 18% had hyperalgesia. On PCA analysis, 3 principal components were able to identify patients with hyperalgesia in increasingly higher proportions.

Conclusions: This pilot study suggests that distinct biochemical profiles may associate with presence of hyperalgesia in CP patients. Several cytokines and hormones with anti-nociceptive properties were higher in subjects that did not have hyperalgesia. Validation in larger populations and further work combining biomarker data with clinical characteristics will help in the development of precision medicine tools to optimize treatments for painful CP.

Introduction:
Pain in CP has multiple mechanisms including neural alterations. Understanding the pain type could guide administration of the appropriate treatment. It is often difficult to identify neuropathic pain in the clinic.
Pancreatic quantitative sensory testing (P-QST) in an evolving technique used to identify different types of neural sensitization. Since this is not routinely available, in this study we aimed to evaluate clinical surrogates that could identify sensitization patterns in CP.
Methods:
In this 3-center study, patients with CP of at least 3-yrs duration irrespective of the pain status were enrolled. Patients with acute exacerbation at presentation, malignancy, narcotic dependence, and antidepressant use were excluded. Included patients were subjected to through clinical evaluation including pain phenotyping (duration, intensity, frequency, patterns and triggers of pain, involvement of new areas, change in pain character), assessment of depression/anxiety (BDI II and HAD), quality of life (EORTC QLQc30), pancreatic morphology (duct size, calcification/calculi, atrophy).
P-QST was performed and the patients with pain were divided into those with segmental and widespread sensitization based on recently published criteria (PMID: 31787527)(Figure 1a). Principal component analysis (PCA) with analysis of similarity (ANOSIM) was performed to evaluate sensitization pattern. Logistic regression was employed to identify clinical surrogates for widespread sensitization. Data were expressed as odd’s ratio with 95% CI..
Results:
We included 424 patients (72 painless/347 painful) between October 2021 to October 2022. Overall, mean (SD) age was 35.01 (12.7)yrs and 276 (65.1%) were males. Patients with pain had significantly higher depression (HAD [p<0.0001]) and anxiety (HADS [p<0.0001]) scores, and, poorer global (p<0.0001), physical (p<0.0001), cognitive (p=0.04), emotional (p=0.04) and role (p=0.002) functions in the EORTC QLQc30 (Figure 1b-h).
P-QST was performed on 294 patients. While 57 (19.4%) patients did not have any sensitization, 74 (25.2%) and 163 (55.4%) had segmental and widespread sensitization respectively. There was significant clustering between the patients with and without widespread sensitization (Bonferroni corrected p =0.009 based on Bray Curtis Distance) (Figure 2a). Indicators of sensitization significantly positively correlated with anxiety and depression, while negatively with global, cognitive, and emotional functions (Figure 2b).
Logistic regression revealed the following surrogates for widespread sensitization: involvement of new areas of pain [OR(95%CI) 3.7 (1.79 to 8.70), p=0.03]; diabetes [OR(95%CI) 2.60(1.49-4.54), p=0.001]; and significant depression [OR(95%CI) 3.25(1.62-9.27); p=0.002].
Conclusion:
We identified clinical surrogates that can be used to suspect widespread sensitization, i.e., neuropathic pain in CP.

Background: Extracorporeal shock wave lithotripsy (ESWL) is a first-line treatment for large and painful pancreatic duct stones (PDS) in chronic pancreatitis (CP). The role of stone density on computer tomography (CT) scans in determining the efficacy of ESWL in renal stones has been well established. The aim of this study is to evaluate the role of CT-based assessment of PDS characteristics in determining the technical efficacy of ESWL.
Methods: We retrospectively evaluated patients with PDS secondary to CP who underwent ESWL for stone fragmentation at 3 academic centers in India and US. Successful fragmentation was defined as the breakdown of stones to < 3mm. Besides relevant demographic and clinical data, PDS-related CT features including number, location, size, and density in terms of the mean value of CT attenuation were noted. The Izbicki pain scores before and after fragmentation were recorded and their difference was calculated to determine the clinical success. Data were then analyzed to determine the relationship between PDS size, density and the number of required ESWL sessions for successful fragmentation.
Results: 187 subjects (Mean age 36.9±12.3 years, 61.5% male) underwent ESWL. The mean PDS size was 8.7±4.2 mm and the mean density measured by CT attenuation value was 940.3±328 HU (346-1800 HU). 143 (76.4%) had the PDS located in the head region while the remaining 44 (23.6%) had PDS in the body or tail. 96 (51.3%) needed a single session, 83 (44.4%) needed 2, and the remaining 8 (4.3%) needed 3 ESWL sessions for successful fragmentation. The clinical success rate measured by the difference in pain scores was 59.5±29.4% (Table 1). We found a significantly strong positive correlation between the mean PDS density and the number of ESWL sessions (r=0.746, CI 0.675-0.804, p-value <0.01). However, the correlation between PDS size and the number of ESWL sessions was moderate (r=0.551, CI 0.442-0.644, p-value <0.01). To adjust for size and difference in integer values of size and density, we combined the two variables into a single metric by dividing the product of size and density by 100 (size x density/100). This was found to have a significant relationship with the number of ESWL sessions (R² 0.47, r=0.685, 95% CI 67.98 to 92.73, p-value <0.01). The PDS density metric had an AUROC of 0.929 in predicting the number of ESWL sessions (p-value <0.01) and a density threshold of 895 HU could predict the need for multiple ESWL sessions with an accuracy of 89.1% (Figure 1).
Conclusion: The PDS size and density measured by the mean attenuation coefficient on CT are strong predictors of the technical efficacy of ESWL in terms of determining the number of sessions required for successful fragmentation. This information would help the provider in discussing the procedure plan with the patient and planning the logistics.

Background: Patients with chronic pancreatitis are at increased risk of low bone density, and tobacco smoking is an independent risk factor for the development of low bone density in this patient population. We aimed to determine if smoking cessation would lower the risk of low bone density in chronic pancreatitis patients.

Methods: We conducted a retrospective cohort study utilizing TriNetX, which is a global federated health research network of electronic medical records from 59 healthcare organizations from 2002 to 2022. Utilizing ICD-10 codes, we identified chronic pancreatitis patients with tobacco smoking history and divided them into two cohorts of smoking cessation and no smoking cessation. Smoking cessation was defined as a prescription for varenicline/bupropion or a smoking cessation counseling visit. Propensity score matching was performed for demographics and medications (pancreatic enzyme replacement, calcium, and vitamin D). We assessed 10-year outcomes for osteoporosis, osteopenia, fractures, malnutrition, calcium deficiency, vitamin D deficiency, and mortality.

Results: Of chronic pancreatitis patients with tobacco smoking history, we identified 9,142 patients with smoking cessation attempts (Cohort 1) and 52,679 patients with no smoking cessation attempts (Cohort 2). After propensity score matching, 9,085 patients were accounted for in each group (Table 1). Cohort 1 was more likely to be prescribed lipase (16.5% vs 6.7%, p<0.001), pancrelipase (7.1% vs 3.5%, p<0.001), vitamin D (13.6% vs 8.8%, p<0.001), and calcium supplements (28.0% vs 20.8%, p<0.001) when compared to Cohort 2. There was lower 10-year-mortality (OR: 0.85, 95% CI: 0.79-0.92, p<0.001) and malnutrition (OR: 0.77, 95% CI: 0.71-0.82, p<0.001) in Cohort 1 compared with Cohort 2. A sub-analysis, excluding patients on lipase, pancrelipase, vitamin D, and calcium supplementation, still noted patients who received smoking cessation therapy had lower 10-year-mortality (OR: 0.71, 95% CI: 0.58-0.86, p=0.001) and malnutrition (OR: 0.44, 95% CI: 0.34-0.55, p<0.001). No differences in 10-year development of osteoporosis, osteopenia, or fractures were noted between chronic pancreatitis patients with tobacco smoking history on chronic pancreatitis therapies, regardless of smoking cessation attempts (Table 2).

Conclusion: Smoking cessation in chronic pancreatitis patients with smoking history is associated with 10-year decreased risk of mortality and malnutrition. We did not find a difference in risk of osteoporosis, osteopenia, and fractures. Smoking cessation needs to be addressed in chronic pancreatitis patients to improve overall outcomes.