Introduction

Cholangiocarcinoma (CCA) prevalence is high in East and Southeast Asia, especially in northeast Thailand. The first line of treatment for unresectable CCA is systemic chemotherapy which a median OS of less than 1 year under palliative systemic therapy. Albumin-Bilirubin (ALBI) prognosis score is the new method for the evaluation of liver performance status and prediction of treatment outcome but there is a lack of data in CCA patients.

Aims & Methods

Aim: To study the association of overall survival and ALBI prognostic score in unresectable CCA patients who received systemic chemotherapy.
Methods: This retrospective cohort study was conducted in Maha Chakri Sirindhorn Medical Center, Thailand. Demographic data, Clinical information, Laboratory profile, and survival analysis were extensively reviewed in the patient who received systemic chemotherapy from 2012 - 2022. All patients were monitored for at least 1 year after initial treatment with chemotherapy or until death.

Results

​69 patients of Unresectable CCA received systemic chemotherapy enrolled in this study. Most of the patients were men (45/69, 65.22%) and Intrahepatic type CCA (55/69, 79.71%). 17 patients (24.6%) need Biliary drainage before systemic chemotherapy which median pre-drainage TB was 11.35 mg/dL (10.7 – 20.6). Most ALBI prognostic score were group 2 (37/69, 53.6%) and anemia was significantly in ALBI 2 group (81.08%, P <0.001). The median overall survival was 10.23 months and the median progression-free survival was 5.77 months. Significantly better overall survival of the ALBI 1 group compared with the ALBI 2 group (ALBI 1, 13.76 months; ALBI 2, 6.33 months; log-rank test, P <0.001). The estimated 6, 12, 18, and 24-month survival rates were 72.46%, 40.58%, 18.84%, and 8.70%, respectively, whereas the estimated progression-free survival rate at 6, 12, 18, and 24 months were 47.83% and 10.14%, respectively.

Conclusion

ALBI prognosis score may serve as a surrogate marker in predicting the overall survival and progression-free survival of CCA patients who received Systemic chemotherapy.

References

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Disclosure

There is no any conflict of interest in this study

Clinical Case Summary

A 70-year-old patient with diabetes mellitus and cholecystectomy performed six months earlier was admitted to the emergency department for generalized abdominal pain, hyporexia and weight loss.
An abdominal CT scan showed a solid-cystic pancreatic lesion suggestive of mucinous neoplasia, together with peritoneal nodules in the right paracolic gout. In view of the suspicion of malignancy, an echoendoscopy with fine needle aspiration puncture (EUS-FNA) was performed, identifying an irregular lesion with heterogeneous and hypovascular ultrastructure in the pancreatic neck-body and a discrete dilatation of the main pancreatic duct. Finally, the histological study didn´t show neoplastic cells.
Suddenly the patient experienced a clinical worsening with severe pain and high fever. Laboratory tests showed a progressive increase in C-reactive protein and leukocytosis with left shift. In a control CT scan, a reduction in the size of the pancreatic lesion is observed, together with an increase in the peritoneal lesions which present a polyglobulated contour, hypercapillary margins and rarefaction of the surrounding fat. These finding suggesting the presence of peritoneal abscesses secondary to dropped gallstones. After broad-spectrum antibiotic therapy, the intra-abdominal abscesses improved radiologically, but the collection persisted in the right posterior pararenal space which was drained under ultrasound control with subsequent disappearance of fever and normalization of analytical parameters.
Dropped gallstones occur in approximately 7% of cholecystectomies. The secondary granulomatous reaction in paucisymptomatic patients can simulate peritoneal tumor processes in imaging tests, being one of the adverse effects described in relation to this pathology. In our case, the concomitant presence of peritoneal lesions together the pancreatic lesion oriented the initial case as a malignant process; however, the patient's evolution were key to the final diagnosis.

Introduction

In patients with chronic pancreatitis (CP), pancreatic exocrine insufficiency (PEI) and poor nutritional intake may cause nutritional deficiencies. Guidelines advise monitoring key nutrients and supplementing is case of deficiency to prevent malnutrition-related complications. However, adherence remains low, possibly due to limited evidence on the clinical relevance of single nutrient deficiencies and the benefit of targeted supplementation. The aim of this study is to evaluate the prevalence of nutritional deficiencies in patients with CP and to identify predictors of those at highest risk. Secondary, we seek to explore association between nutritional deficiencies and malnutrition-related complications, and to provide insight into the natural course of nutritional deficiencies.

Aims & Methods

We analyzed data from the COMBO-trial, a nationwide stepped-wedged cluster randomized trial to evaluate the effect of an evidence-based algorithm for the management of CP. Measurements of fat-soluble vitamins, minerals, and albumin conducted in the outpatient clinic during the 35-month study period were included. PEI was defined as fecal elastase-1 concentration <200 µg/g or the use of pancreatic enzyme replacement therapy (PERT). The Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q), designed to evaluate the severity of PEI symptoms, was administered at four distinct time points throughout the study. Supplement use was collected from health records and patient questionnaires. Multivariate logistic regression analysis was performed for the presence of multiple deficiencies. Potential predictors included patient and disease characteristics at baseline and the mean score of the PEI-Q during follow-up.

Results

In total 409 patients were included in this study. At baseline 327 (80.0%) had PEI and PERT was used by 297 (72.6%). Nutritional deficiencies were present in 195 patients (47.7%) of which 81 (19.8%) had multiple deficiencies. The prevalence of deficiencies included vitamin A in 13/172 (7.6%) patients, vitamin D 111/289 (38.4%), vitamin E 15/168 (8.9%), vitamin K 52/88 (59.1%), iron 44/137 (32.1%) calcium 4/198 (2.0%), magnesium 24/132 (18.2%) zinc 13/67 (19.4%), selenium 4/42 (9.5%), and albumin in 41/288 (14.2%) patients. No abnormal coagulation was observed in the 20 patients with vitamin K deficiency and available INR measurements. Osteopenia was diagnosed in 110/236 (46.6%) and osteoporosis in 56/236 (23.7%). Deficiencies in vitamin K and vitamin D, micronutrients critical to bone metabolism, were not associated with osteopenia or osteoporosis. Of 44 patients with an iron deficiency, 22 (50%) were anemic. Deficiency resolved without single nutrient supplementation in 71.4% (vitamin A), 75.0% (vitamin D), 50.0% (vitamin E) , 33.3% (vitamin K), 63.6% (iron), 100% (magnesium), 80.0% (zinc) of cases. Independent predictors for multiple deficiencies were more severe PEI symptoms (OR 1.86, 1.09 – 3.17) and daily alcohol consumption (OR 2.80, 1.27 – 6.18).

Conclusion

Nutritional deficiencies are present in approximately half of the patients with CP. Most nutritional deficiencies resolve without single nutrient supplementation. Predictors for multiple nutritional deficiencies were severity of PEI symptoms and daily alcohol consumption. Therefore, nutritional deficiencies should be considered a marker of malnutrition, with treatment focused on addressing the underlying cause rather than isolated correction through single nutrient supplementation.

Introduction

Despite advances with chemotherapy regimens, Pancreatic adenocarcinoma (PDAC) is becoming the 2^nd cause of cancer-related death. Personalized medicine will be the game changer, but molecular characterization of pancreatic neoplasms is yet extremely cumbersome and has been performed on surgical samples or few EUS-tissue acquisition (TA) cases, mostly for DNA analysis. Our aim was to evaluate DNA and RNA extracted for research purposes from pancreatic neoplasms employing Endoscopic Ultrasound (EUS) Fine needle aspiration (FNA) and biopsy (FNB) and adequacy to molecular analyses.

Aims & Methods

From Oct 2022, patients with solid pancreatic neoplasms suggestive of either PDAC or neuroendocrine neoplasm (NEN) undergoing diagnostic EUS-TA were considered for enrollment. Employed needles were either FNA, or Franseen, Fork-tip or Three-prong, either 22G or 25G based on operator’s preference, with Rapid on Site Evaluation and, in case of adequacy within the first 2 passes, 1 additional pass with the same needle was performed for molecular analyses. DNA and RNA were then extracted with a new technique and nucleic acids were quantified and evaluated for adequacy for molecular analysis. Mann-Whitney was employed for comparison of continuous variables, and Kruskal-Wallis test for comparison between multiple groups; Logistic regression was applied to determine factors associated with adequacy to molecular tests.

Results

351 patients underwent sampling for molecular analyses, 309 with a definitive diagnosis of PDAC and 42 with NEN. 92,9% of patients were sampled with 25G FNA needles. Median quantity of DNA extracted was significantly lower in PDAC 2048 ng (95%CI: 1470 -3651) compared to NEN 6752 ng (95%CI: 3502-9655)(p<0.0144). Mean quantity of RNA extracted was similar, 312 ng for PDAC, and 444 ng for NEN (p=0.07), with a higher median RIN of 6,4 (95%CI:6,2-6,5) for PDAC versus 4,7 (95%CI:3,9-5) for NEN (p<0.0001). In terms of needle type, concerning DNA extraction, 25G FNA needles retrieved a median of 3384 ng, 25G Franseen needles (4312 ng), 22G Franseen (73864 ng), 25G Fork-tip or Three-prong (3104 ng), with no significant difference. In terms of needle type, concerning RNA extraction, 25G FNA needles retrieved a median of 310 ng (RIN 6,3), 25G Franseen needles 460 ng (RIN 5,5), 22G Franseen 884 ng (RIN 5,9), 25G Fork-tip or Three-prong 301 ng (RIN 5,15), with no significant difference. 295 (95,5%) of PDAC samples and 34 (80,9%) of NEN samples were considered adequate for sequencing. The only factor associated to adequacy for molecular analysis was tumor type, with PDAC having an OR of 5,44 (95%CI 2,06-14,37)(p=0.0006), while the type of employed needle was not

Conclusion

Molecular analysis on EUS-acquired tissue of pancreatic neoplasms will be the mainstay of personalized therapies but how to best perform tissue acquisition and sample handling for this specific purpose is yet to be defined. This is the largest study ever performed on DNA and RNA extraction from EUS-acquired samples, demonstrating superior adequacy for molecular analysis in PDAC compared to NEN. All needle types result similar in terms of performance despite the low number of needles other than 25G FNA needles.

Introduction

Besides stage, age and CA19-9 there is limited knowledge on “patient-related factors” associated with chemotherapy response for Pancreatic Ductal Adenocarcinoma (PDAC) patients. Smoking worsens chemotherapy response in other tumours and seems to promote tumor progression in PDAC preclinical models, but data in human PDAC are scanty.

Aims & Methods

PDAC patients were prospectively enrolled at diagnosis with exposome and clinical data registered, and tumors sampled for research purpose during Endoscopic Ultrasound (EUS). Patients were then followed-up to register chemotherapy treatment [whether Folfirinox (F), Abraxane-gemcitabine (AG) or a combination of cisplatin, abraxane, capecitabine and gemcitabine (PAXG)] and evaluate disease control rate (DCR) at 6-months (DCR-6), Progression-Free-Survival (PFS) and Overall-Survival (OS). We also explored transcriptomic signatures associated with smoking on a subset of EUS-acquired PDAC samples undergoing RNA-sequencing, with differential gene expression (DGE) analysis and pathways analysis performed. Furthermore, in vitro analyses with PDAC cell lines CAPAN-1 were treated with Folfirinox or gemcitabine with/without the nicotine compound 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone to evaluate in vitro effects.

Results

326 patients treated with chemotherapy of interest were analyzed. Median age was 65, with 51.5% being males. Disease’s resectability at diagnosis was 10.4% resectable, 37.7% borderline-resectable, 26.9.% locally-advanced, 24.8% metastatic. AG was used in 42.3% of patients, PAXG in 25.7%, Folfirinox in 31.9%. DCR-6 was 57.9% in current smokers vs 70.4% in never-/ex-smokers (p=0.05). Current smoking was associated with a lack of DCR-6 at adjusted multivariable analysis (OR=1.99; 95%CI:1.1-3.5; p=0.01). At subgroup analysis, this was confirmed only for Folfirinox patients, with DCR-6 being 46.2% for current smokers vs 75.6% for non-current smokers(p=0.007). Current smokers had a significantly shorter PFS (5 vs 13 months; HR:1.79; 95%CI:1.13-3.21; p=0.01) and OS (24 vs 34; HR 1.93; 95%CI: 1-3.67; p=0.04) compared to non-smokers at adjusted multivariable analysis.
At transcriptomic analysis on a subset of 84 patients, current smokers were more prevalent in patients developing the more aggressive basal-like subtype (50% vs 15%; p=0.03), had lower expression of the classical marker GATA6 (3.27 vs 3.92; p=0.03) as also different activated pathways such as activated MAPK signalling, Axon guidance, Hypoxia and epithelial-mesenchymal-transition signalling among the others.
At in vitro experiments, for cell survival analysis, CAPAN-1 PDAC cells showed a significant reduced response to Folfirinox treatment when treated in combination with nicotin compounds, which was not observed for gemcitabine alone or in combination.

Conclusion

Collectively, our results consistently point towards a deleterious effect of smoking on response to Folfirinox regimen. Clinical data show that current smoking is a predictive factor for lower DCR-6, shorter PFS and OS; transcriptomic analyses show different gene expressions between smokers and non-smokers, with a transition toward reduced expression of classical phenotype and activation of inflammatory and pro-mesenchimal pathways. In vitro experiments support the negative effect of smoking on the response to Folfirinox. Smoking should be considered as a covariate to be investigated when choosing chemotherapy regimens in patients with PDAC, and patients should be discouraged to continue smoking.

Introduction

Computer Aided Detection (CADe) systems may improve detection of (pre-)malignant lesions by endoscopists. Most CADe systems are developed using homogeneous datasets collected by experts, which do not represent the heterogeneous imaging conditions of daily clinical practice. Such heterogeneity is caused by endoscopist-dependent variation (e.g. skill and experience) as well as endoscopist-independent variation (e.g. endoscopy equipment). Recently, we presented a CADe system for Barrett’s neoplasia¹. However, all training and test data originated from expert centers.

Aims & Methods

We aimed to develop an updated CADe system (CADe 2.0) demonstrating more robustness to the varied imaging conditions found in routine patient care.
Our previously published CADe system (CADe 1.0) was trained and internally validated on a high-quality dataset originating from 15 expert centers. The dataset included 6.337 neoplastic (1.362 patients) and 7.695 non-dysplastic images (1.139 patients).
The updated CADe system (CADe 2.0) underwent four improvements. First, we included more heterogeneous training data from our training set patient population. We extracted video frames from videos comprising various quality artefacts (e.g. blurred lenses or insufficient mucosal cleaning). Second, we applied advanced data augmentation methods to address the diversity of post-processing enhancement settings used by modern endoscopy systems. Third, we updated the CADe system with a Vision Transformer architecture², which has shown to improve performance on lower quality endoscopic images³. Finally, we transitioned our pretraining approach from semi-supervised to a self-supervised learning framework⁴.
Both CADe systems were evaluated using three prospectively collected, independent test sets. The first test set represented the true diversity and complexity encountered in daily clinical practice. This dataset comprised all videos captured from all included patients in five referral centers between April 2022 and January 2024 (431 ten-second BE videos from 115 patients). The second test set focused on endoscopist-dependent variation. It included three paired subsets with high, moderate and low-quality images from 122 patients. Quality was determined by factors such as esophageal expansion and mucosal cleaning. The third test set addressed endoscopist-independent variation. It contained 16 paired subsets of 396 images (122 patients). Every subset was based on a different post-processing enhancement setting of the endoscopy system.

Results

For test set 1, CADe 1.0 reached a sensitivity and specificity of 84% and 73%. CADe 2.0 scored 93% and 76%. For test set 2, CADe 2.0 reached higher sensitivity and specificity scores on high-quality images compared to CADe 1.0. In addition, CADe 2.0 performance loss on moderate and low-quality images was smaller. On test set 3 CADe 1.0 scores substantially varied depending on the test sets enhancement setting (82-94% sensitivity, 52-83% specificity). Variation of CADe 2.0 was limited to 91-95% and 81-88%.

Table 1. Results of CADe 1.0 and CADe 2.0

Conclusion

The updated CADe system displayed improved performance for detection of Barrett’s neoplasia in videos. More importantly, this CADe system also displayed less performance loss when exposed to lower image quality and less performance variability when confronted with differing post-processing enhancement settings.

References

1. Fockens N, Jong MR, Jukema JB, Pouw RE, Duits LC, Van Munster SN, et al. A deep learning system for detection of early Barrett's neoplasia: a model development and validation study. The Lancet Digit Health. 2023;5:905-21.
2. Yu W, Si C, Zhou P, Luo M, Zhou Y, Feng J, et al. MetaFormer Baselines for Vision2022 October 01, 2022:[arXiv:2210.13452 p.]. Available from: https://ui.adsabs.harvard.edu/abs/2022arXiv221013452Y.
3. Kusters CHJ, Boers TGW, Jaspers TJM, Jukema JB, Jong MR, Fockens KN, et al., editors. CNNs vs. Transformers: Performance and Robustness in Endoscopic Image Analysis. Applications of Medical Artificial Intelligence; 2024 2024//; Cham: Springer Nature Switzerland.
4. Caron M, Touvron H, Misra I, Jégou H, Mairal J, Bojanowski P, et al. Emerging Properties in Self-Supervised Vision Transformers2021 April 01, 2021:[arXiv:2104.14294 p.]. Available from: https://ui.adsabs.harvard.edu/abs/2021arXiv210414294C.