Introduction

Despite the advancements in imaging modalities, diagnosis of biliary strictures remains challenging in some cases. Endoscopic retrograde cholangiopancreatography (ERCP) is the current gold standard for diagnosis. However, the pathological diagnosis via ERCP is limited due to the small specimen. Therefore, a novel device for the diagnosis of biliary stricture has been long-awaited. Although high sensitivity and specificity have been reported for probe-based confocal laser endomicroscopy (pCLE) for the diagnosis of biliary strictures using the Miami Classification, it remains uncertain whether confocal miniprobes can be properly applied to the target site with the use of pCLE under fluoroscopic guidance. The aim of the present study was to prospectively evaluate the clinical utility of pCLE under the direct view of peroral cholangioscopy (POCS) for the diagnosis of biliary strictures.

Aims & Methods

Consecutive patients with biliary strictures were included. All patients underwent imaging examination, such as computed tomography, magnetic resonance imaging, or endoscopic ultrasound, and were found to have biliary disorders. We investigated sensitivity, specificity, and accuracy to diagnose malignancy for: 1) ERCP alone, 2) POCS, 3) pCLE under the direct view of POCS, and 4) tissue sampling under the direct view of POCS. pCLE images were interpreted prospectively using the Miami Classification. We also evaluated other outcomes of pCLE under the direct view of POCS.

Results

A total of 30 patients (17 with malignant lesions) were prospectively enrolled.
1) ERCP alone showed 88.2% sensitive, 46.2% specific, and 70% (95% confidence interval [CI], 52.1%–83.3%) accurate.
2) POCS showed 100% sensitive, 76.9% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
3) pCLE under the direct view of POCS showed 94.1% sensitive, 92.3% specific, and 93.3% (95% CI, 78.7%–98.8%) accurate.
4) Tissue sampling under the direct view of POCS showed 82.4% sensitive, 100% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
The POCS could not pass the biliary stricture in four patients, and we could not complete successful observation of the target area. Therefore, the success rate of pCLE under the direct view of POCS was 88.2% (30/34). The median procedural time for pCLE under the direct view of POCS was 42 min (interquartile range [IQR], 31.3–48 min). Accurate diagnosis rate of common bile duct and accurate diagnosis rate of hilar and intrahepatic bile duct were 86.7% (13/15), 100% (15/15) respectively. There was no significant difference among stricture locations (P=0.48). Adverse events occurred in three patients (one with mild pancreatitis, and two with mild cholangitis).

Diagnosis modality (n=30)	Sensitivity n (%) 95% CI	Specificity n (%) 95% CI	NPV n (%) 95% CI	PPV n (%) 95% CI	Accuracy n (%) 95% CI
1) ERCP alone	15/17 (88.2) 65.7-97.9	6/13 (46.2) 23.3-70.9	6/8 (75) 40.9-95.6	15/22 (68.2) 47.3-83.6	21/30 (70) 52.1-83.3
2) POCS	17/17 (100) 81.6-100	10/13 (76.9) 49.7-91.8	10/10 (100) 72.2-100	17/20 (85) 64.0-94.8	27/30 (90) 74.4-96.5
3) pCLE under the direct view of POCS	16/17 (94.1) 73.0-99.7	12/13 (92.3) 66.7-99.6	12/13 (92.3) 66.7-99.6	16/17 (94.1) 73.0-99.7	28/30 (93.3) 78.7-98.8
4) Tissue sampling under the direct view of POCS	14/17 (82.4) 59.0-93.8	13/13 (100) 77.2-100	13/16 (81.3) 57.0-93.4	14/14 (100) 78.5-100	27/30 (90) 74.4-96.5
2) VS 3) P value	0.50	0.59			>0.99
3) VS 4) P value	0.60	>0.99			>0.99

Table 1. Summary of primary outcomes

Conclusion

pCLE under the direct view of POCS provided highly accurate and sensitive characterization of biliary strictures and showed the potential for more diagnostic reliability and reduction of delays in diagnosis.

Introduction

Colonoscopy is highly effective yet inefficient at colorectal cancer (CRC) prevention with a prevalence of target (advanced adenomas) of only about 8%. Thus, finding a modality to risk-stratify for colonoscopy would be of public health implications One approach is to leverage field carcinogenesis, the concept that the gene/environmental interaction that predispose to neoplastic lesions are diffuse and thus rectal mucosa can predict risk of proximal neoplasia (1). Given the diffuse molecular alterations, our group has focused on transcriptional assessment through chromatin nano-architecture. While epigenetics such as methylation, histone acetylation etc will be reflected in chromatin nano-architecture, microRNAs (mIRs) provide an independent impact on gene expression. We, therefore, wanted to test whether chromatin + miR markers from the rectum would predict concomitant adenomas.

Aims & Methods

Chromatin Nano-architecture: We used a novel nanoscale optics technology, partial wave spectroscopic microscopy (PWS) which enables us to go quantify chromatin heterogeneity through pixel-to-pixel variability in refractive indices (2). The calculated marker correlated with fractal dimension (D).
Human Studies: We recruited patients undergoing screening/surveillance colonoscopy with IRB consent. Following colonoscopy 6 biopsies of endoscopically normal rectum. We had 104 controls and 53 advanced adenoma patients for these studies. Advanced adenomas were defined as size >10mm, >25% villous features or high grade dysplasia. Controls were those without adenomas/carcinomas.
miR: We used RT-PCR with internal controls. We used literature to identify 4 candidates miRs and used the delta delta approach to compute fold change of miR expression (case versus control).

Results

We analyzed D from the rectal biopsies with PWS from our clinical dataset and observed excellent diagnostic performance of area under receiver operator characteristic curve (AUC) of = 0.85 for those with and without advanced adenomas sensitivity = 0.74, specificity = 0.83.
The potential of our biomarker is also evaluated via combining with epigenetic regulators microRNAs (miR) in an independent pilot study. Evaluating the 4 oncomiRs in 20 human rectal biopsies (10 control, 10 advanced adenoma) had increased expressions in patients harboring advanced adenomas (fold changes were miR137=3.4, miR92a=5.97, miR-135b-5p=174 and miR361-5p=2.01).
With our PWS marker, the elevation of miR-92a, miR-135b-5p, and D was synergistic for discriminating patients with vs. without advanced adenomas to 0.9 increase in AUC compared to D alone. AUC) = 0.90, sensitivity = 0.88, specificity = 0.85.

Conclusion

We demonstrate, for the first time, that the chromatin nano-architectural parameter, D had excellent performance for identifying patients screen relevant neoplasia elsewhere in the colon. Furthermore, adding several miR markers to provide a more comprehensive epigenetic profile was synergistic diagnostics with D. Future studies will employ more miRs and combine with artificial intelligence to further improve the already strong performance for potential clinical impact.

References

Rebello D, Rebello E, Custodio M, Xu X, Gandhi S, Roy HK. Field carcinogenesis for risk stratification of colorectal cancer. Adv Cancer Res. 2021;151:305-344. doi: 10.1016/bs.acr.2021.03.004. Epub 2021 Mar 31. PMID: 34148616.
Gladstein S, Damania D, Almassalha LM, Smith LT, Gupta V, Subramanian H, Rex DK, Roy HK, Backman V. Correlating colorectal cancer risk with field carcinogenesis progression using partial wave spectroscopic microscopy. Cancer Med. 2018 May;7(5):2109-2120. doi: 10.1002/cam4.1357. Epub 2018 Mar 23. PMID: 29573208; PMCID: PMC5943438.

Disclosure

Hemant Roy, Vadim Backman, and Hariharan Subramanian are co-founders, have equity stakes, own IP and are on the Board of Directors for Nanocytomics LLC, a biomedical company providing cancer risk-stratification tests based on their proprietary biophotonics technology platform, partial wave spectroscopic (PWS) microscopy which is being utilized in this research. Sravya Prabhala is also an employee of Nanocytomics LLC.

Introduction

The early diagnosis of pancreatic cancer has long been considered a major clinical challenge. Recently in Japan, imaging-based screening strategies focusing on indirect findings have ushered in a new era, enabling the detection of carcinoma in situ and high-grade pancreatic intraepithelial neoplasia (PanIN). This study aimed to elucidate the molecular evolutionary mechanisms of PanIN development and progression.

Aims & Methods

We conducted detailed histopathological analysis and multi-regional genomic sequencing on 33 lesions obtained from a single patient with a family history of pancreatic cancer. The patient initially underwent distal pancreatectomy for a branch duct-type intraductal papillary mucinous neoplasm (IPMN) accompanied by adjacent main pancreatic duct (MPD) stenosis, followed by remnant pancreatectomy four years later due to newly detected ductal irregularities. The analyzed lesions included 15 low-grade PanINs, 14 high-grade PanINs, two low-grade IPMNs, and two concomitant pancreatic ductal adenocarcinoma components. Molecular analyses included KRAS and GNAS mutation detection using droplet digital PCR, targeted sequencing using a pancreatic cancer-related gene panel, and whole-exome sequencing. Tumor phenotypes were assessed by immunohistochemistry.

Results

Among numerous low-grade PanINs harboring various KRAS mutations, four distinct multicentric high-grade PanINs arose in the pancreatic body and tail. These included a laterally spreading high-grade PanIN within the stenotic MPD, characterized by KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54; and three discrete high-grade PanINs located in branch ducts, all harboring KRAS G12V accompanied respectively by TP53 Y107D; TP53 S241F and ARID1A Q386X and S2096X; and TP53 G245S and ARID1A Q1066X. A low-grade gastric-type IPMN harboring KRAS G12R was determined to be clonally independent from the adjacent high-grade PanINs. A low-grade PanIN with KRAS G12D was identified at the pancreatic cut margin, though it showed no evidence of malignancy. In the remnant pancreatic head, a high-grade PanIN harboring KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54—identical to the dominant clone in the pancreatic body—had extended along the MPD from the ductal stump to the ampulla. Two small invasive carcinoma foci were found to be continuous with this high-grade PanIN and shared identical KRAS, TP53, and GATA6 mutations, along with additional copy number variations affecting several genes. Another small high-grade PanIN with KRAS G12D and TP53 C275Y was identified in a neighboring branch duct. Furthermore, a germline CDKN2A H66R variant was detected, suggesting a potential hereditary predisposition to pancreatic tumorigenesis. The patient has remained recurrence-free for four years following the remnant pancreatectomy.

Conclusion

In high-risk individuals with a family history of pancreatic cancer or IPMN, PanINs may develop in large numbers, and multiple carcinomas in situ can arise simultaneously. Among these, clones exhibiting pronounced intraductal proliferation or progression toward invasion—thereby impacting clinical outcomes—may be selectively favored. This study provides novel insights into the clonal selection and molecular progression of multicentric high-grade PanINs. To our knowledge, this is the first report to comprehensively delineate the molecular trajectory of multifocal high-grade PanINs in a high-risk patient.

Introduction

The rise in obesity rates has triggered a surge in associated health issues, with metabolic syndrome (MS) affecting approximately 25% of populations in Western countries. Severe acute pancreatitis (AP) is associated with mortality rates as high as 50%. Prior research has linked components of MS to heightened complications and mortality in cases of AP.

Aims & Methods

This meta-analysis aims to elucidate potential risk factors and their combined effects on the outcomes of AP. We performed a systematic search of PubMed, Embase, and the Cochrane Library until November 1, 2023, identifying studies based on specified criteria. We investigated the influence of MS and its components (obesity, hypertension, diabetes mellitus, and hypertriglyceridemia) on AP outcomes, calculating pooled odds ratios (OR) with 95% confidence intervals (CIs). The study protocol was registered with PROSPERO under the identifier CRD42023471092.

Results

From an initial 15,904 records, 93 studies were included in the analysis. Overweight and obesity emerged as significant risk factors for complications (local OR: 2.677, 95%CI: 1.421-5.044; systemic OR: 2.404, 95%CI: 1.481-3.901) and the severity of AP (BMI≥30 kg/m², OR: 3.058, 95%CI: 1.369-6.829). Elevated triglyceride levels were linked to ICU admissions (OR: 2.546, 95%CI: 1.529-4.237) and severe AP (OR: 2.372, 95%CI: 1.275-4.413); hypertension correlated with increased mortality (OR: 2.135, 95%CI: 1.870-2.437), while diabetes was associated with higher odds of ICU admission (OR: 1.645, 95%CI: 1.358-1.992) and severe AP (OR: 1.49, 95%CI: 1.09-2.03). Our findings suggest that MS may elevate the likelihood of severe AP (OR=1.398, 95%CI: 0.918-2.129).

Conclusion

The individual components of metabolic syndrome are significant risk factors for complications, severity, and mortality related to acute pancreatitis. It is imperative to prioritize lifestyle counseling, education, and effective management for patients dealing with obesity.

Introduction

The PAN-PROMISE symptom score is the first patient-reported outcome (PROM) in acute pancreatitis (AP), and it was developed and validated in a prospective cohort of patients to be used as an endpoint in research. The aim of this study was to assess the performance of the score in a large randomized controlled trial (RCT) and its association with well-established AP endpoints.

Aims & Methods

This is an ancillary study of the WATERFALL trial, where PAN-PROMISE was evaluated at baseline, 24, 48 and 72 hours. The study examined the association between PAN-PROMISE with stablished endpoints in AP: severity, pancreatic and/or peripancreatic fat necrosis (necrosis), infected necrosis, intensive care unit (ICU) admission, persistent organ failure (POF), prolonged hospital stay and mortality. Areas under the ROC curve (AUC) were calculated and used to compare baseline PAN-PROMISE and baseline Bedside Index for Severity in AP (BISAP) for the prediction of these endpoints.

Results

248 patients from the WATERFALL trial were included. A statistically significant association was found between PAN-PROMISE and severity, necrosis, POF, ICU admission, and prolonged hospital stay at all checkpoints (p<0.05). Higher scores were also significantly associated with infected pancreatic necrosis at 24, 48, and 72h and death at baseline and 24 hours. PAN-PROMISE baseline score had a higher AUC than BISAP for severity and necrosis, but the results were not statistically significant.

Conclusion

In the context of a RCT, the PAN-PROMISE score, a patient-centered measure, has been validated with established AP outcomes and as an endpoint for future clinical trials.

Introduction

The impact of underweight and obesity on clinical outcomes for intestinal Behçet’s disease (BD) is unknown. We aimed to identify the association between body mass index (BMI) and clinical outcomes in patients with intestinal BD.

Aims & Methods

We categorized 760 patients with intestinal BD according to the BMI at diagnosis into four groups (underweight, normal, overweight, obese) at Severance Hospital, Seoul, Korea between 1997 and 2021.We performed a Cox proportional hazard analysis to investigate the predictive capability of BMI for clinical outcomes such as biologics use, surgery, hospitalization and emergency room visit.

Results

Of the 760 patients, 130 patients were classified into underweight group (BMI<18.5), 384 patients into normal group (BMI 18.5~22.9), 152 patients into overweight group (BMI 23~24.9), and 94 patients into obese group (BMI≥25). Patients with a higher BMI group showed significantly lower cumulative rates of biologics use (p trend = 0.001), surgery (p trend = 0.008), hospitalization (p trend = 0.002), and emergency room visits (p trend = 0.003) than those with a lower BMI group. In a multivariate analysis, normal BMI group (HR: 0.667, 95% CI 0.483-0.992, p =0.014), overweight group (HR: 0.589, 95% CI 0.394-0.879, p=0.010), and obese group (HR: 0.515, 95% CI 0.321-0.828, p=0.006) were negatively associated with future hospitalization compared to underweight group. Overweight group (HR: 0.490, 95% CI 0.241-0.996, p =0.049) and obese group (HR: 0.312, 95% CI 0.116-0.840, p =0.021) were negatively associated with future biologics use compared to the underweight group. Normal BMI group (HR: 0.706, 95% CI 0.484-1.029, p=0.070) and obese group (HR : 0.556, 95% CI 0.303-1.020, p=0.058) were negatively associated with future surgery compared to the underweight group. Normal BMI group (HR: 0.711, 95% CI 0.513-0.985, p=0.041) and obese group (HR: 0.602, 95% CI 0.376-0.963, p=0.034) were negatively associated with future emergency room visit compared to the underweight group.

Variables		BMI
		<18.5 (n=130) Underweight	18.5~22.9 (n=384) Normal	23~24.9 (n=152) Overweight	≥25 (n=94) Obese	p value for trend
Biologics use	Event	34 (26.2%)	50 (13.1%)	21 (13.8%)	9 (9.6%)	0.001
	Multivariable-adjusteda	Reference	0.619 (0.366-1.047)*	0.490 (0.241-0.966)**	0.312 (0.116-0.840)**
Surgery	Event	45 (34.6%)	87 (22.7%)	35 (23%)	15 (16%)	0.008
	Multivariable-adjusteda	Reference	0.706 (0.484-1.029)*	0.669 (0.411-1.088)	0.556 (0.303-1.020)*
Hospitalization	Event	87 (66.9%)	194 (50.8%)	69 (45.4%)	46 (48.9%)	0.002
	Multivariable-adjusteda	Reference	0.667 (0.483-0.922)**	0.589 (0.394-0.879)**	0.515 (0.321-0.828)**
Emergency room visit	Event	71 (55%)	144 (37.6%)	61 (40.1%)	32 (34%)	0.003
	Multivariable-adjusteda	Reference	0.711 (0.513-0.985)**	0.775 (0.523-1.149)	0.602 (0.376-0.963)**

*p <0.10
**p <0.05
^aMultivariate Cox proportional hazard analysis, including the confounders such as, age, gender, medical aid, smoking, appendectomy history, family history of BD, marriage status, DAIBD score, extraintestinal manifestation, systemic BD, number of ulcers, shape of ulcers, depth of ulcers, type of ulcers, laboratory findings.

Conclusion

Underweight could affect poor outcomes in intestinal Behçet’s disease. Physicians should pay attention to the patients with underweight and make an effort to improve nutritional status.

Introduction

Advanced pancreatic cancer (PC) continues to be associated with a poor prognosis, where the occurrence of pancreatic exocrine insufficiency frequently leads to malnutrition and deteriorating nutritional status. Traditional laboratory markers, such as lymphocyte count and serum albumin levels, are commonly employed to assess nutritional status; however, integrated nutritional indices like the Prognostic Nutritional Index (PNI) have emerged as significant prognostic indicators in various malignancies. Notably, a low PNI has been identified as a predictor of postoperative complications following the Whipple procedure in pancreatic cancer patients and significantly correlates with overall survival among individuals with advanced PC. While the Nutritional Risk Index (NRI) has been evaluated in other cancer types, its application in advanced pancreatic cancer remains underexplored.

Aims & Methods

This study aims to evaluate the prognostic value of PNI and NRI in patients with advanced pancreatic cancer.
A retrospective analysis was conducted on electronic medical records of 158 patients diagnosed with advanced pancreatic cancer who were initiating chemotherapy. PNI and NRI were computed using standard parameters, and baseline levels were compared between patients with proximal and distal tumor locations. Among 125 patients commencing FOLFIRINOX chemotherapy, baseline PNI and NRI were analyzed in relation to outcomes at the 12-week follow-up, categorizing patients into groups based on mortality (n=21), disease progression (n=51), and disease stabilization (n=53). Statistical differences between high and low nutritional index groups were assessed using the log-rank test, and both univariate and multivariable analyses were conducted to identify risk factors associated with mortality within three months post-chemotherapy initiation.

Results

The analysis revealed that patients with tumors located in the pancreatic head exhibited significantly lower PNI (40.11 vs. 42.01, p=0.002) and NRI (104.30 vs. 110.06, p=0.004) compared to those with distal tumors. In the FOLFIRINOX subgroup, a significant decrease in PNI (39.51 vs. 41.51 and 41.82, p=0.044) was observed among those who deceased by the first follow-up, while NRI did not show similar significance. Univariate analysis identified a PNI cut-off of 40.25 (HR 2.514; 95% CI: 1.025-6.169, p=0.044) and an NRI threshold below 105.6 (HR 2.75; 95% CI: 1.039-7.277, p=0.042) as independent prognostic factors. However, in multivariable analysis, the presence of two or more metastatic sites beyond the primary tumor was the only factor significantly related to mortality risk by the follow-up (HR 7.21; 95% CI: 2.02-25.738, p=0.002).

Conclusion

Our findings underscore the relationship between PNI and NRI with nutritional status, asserting their utility as predictive tools for survival in patients with advanced pancreatic cancer initiating chemotherapy.