Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study).

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP). METHODS: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP. DISCUSSION: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy. TRIAL REGISTRATION: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].

MRI with DWI improves detection of liver metastasis and selection of surgical candidates with pancreatic cancer: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to evaluate if magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) adds value compared to contrast-enhanced computed tomography (CECT) alone in the preoperative evaluation of pancreatic cancer. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched for relevant published studies through October 2022. Studies met eligibility criteria if they evaluated the per-patient diagnostic performance of MRI with DWI in the preoperative evaluation of newly diagnosed pancreatic cancer compared to CECT. Our primary outcome was the number needed to treat (NNT) to prevent one futile surgery using MRI with DWI, defined as those in which CECT was negative and MRI with DWI was positive for liver metastasis (i.e., surgical intervention in metastatic disease missed by CECT). The secondary outcomes were to determine the diagnostic performance and the NNT of MRI with DWI to change management in pancreatic cancer. RESULTS: Nine studies met the inclusion criteria with a total of 1121 patients, of whom 172 had liver metastasis (15.3%). The proportion of futile surgeries reduced by MRI with DWI was 6.0% (95% CI, 3.0-11.6%), yielding an NNT of 16.6. The proportion of cases that MRI with DWI changed management was 18.1% (95% CI, 9.9-30.7), corresponding to an NNT of 5.5. The per-patient sensitivity and specificity of MRI were 92.4% (95% CI, 87.4-95.6%) and 97.3% (95% CI, 96.0-98.1). CONCLUSION: MRI with DWI may prevent futile surgeries in pancreatic cancer by improving the detection of occult liver metastasis on preoperative CECT with an NNT of 16.6. CLINICAL RELEVANCE STATEMENT: MRI with DWI complements the standard preoperative CECT evaluation for liver metastasis in pancreatic cancer, improving the selection of surgical candidates and preventing unnecessary surgeries. KEY POINTS: • The NNT of MRI with DWI to prevent potential futile surgeries due to occult liver metastasis on CECT, defined as those in which CECT was negative and MRI with DWI was positive for liver metastasis, in patients with pancreatic cancer was 16.6. • The higher performance of MRI with DWI to detect liver metastasis occult on CECT can be attributed to an increased detection of subcentimeter liver metastasis.

Association between preoperative sarcopenia and prognosis of pancreatic cancer after curative-intent surgery: a updated systematic review and meta-analysis.

BACKGROUND: Sarcopenia is associated with poor outcomes in many malignancies. However, the relationship between sarcopenia and the prognosis of pancreatic cancer has not been well understood. The aim of this meta-analysis was to identify the prognostic value of preoperative sarcopenia in patients with pancreatic cancer after curative-intent surgery. METHODS: Database from PubMed, Embase, and Web of Science were searched from its inception to July 2023. The primary outcomes were overall survival (OS), progression-free survival (PFS), and the incidence of major complications. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CIs) were used to assess the relationship between preoperative sarcopenia and the prognosis of patients with pancreatic cancer. All statistical analyses were conducted by Review Manager 5.3 and STATA 17.0 software. RESULTS: A total of 23 retrospective studies involving 5888 patients were included in this meta-analysis. The pooled results demonstrated that sarcopenia was significantly associated with worse OS (HR = 1.53, P < 0.00001) and PFS (HR = 1.55, P < 0.00001). However, this association was not obvious in regard to the incidence of major complications (OR = 1.33, P = 0.11). CONCLUSION: Preoperative sarcopenia was preliminarily proved to be associated with the terrible prognosis of pancreatic cancer after surgery. However, this relationship needs to be further validated in more prospective studies.

Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with pathological features could help to elucidate the mechanism of physical abnormalities in cancer tissues. A total of 93 patients who underwent radical surgery for pancreatic and bile duct cancers at a single center hospital during a 28-month period were recruited for this study that aimed to estimate the stiffness of PDAC tissues compared to the other neoplasms and assess relationships between tumor stiffness and pathological features. Physical alterations and pathological features of PDAC, with or without preoperative therapy, were analyzed. The immunological tumor microenvironment was evaluated using multiplexed fluorescent immunohistochemistry. The stiffness of PDAC correlated with the ratio of Azan-Mallory staining, α-smooth muscle actin, and collagen I-positive areas of the tumors. Densities of CD8+ T cells and CD204+ macrophages were associated with tumor stiffness in cases without preoperative therapy. Pancreatic ductal adenocarcinoma treated with preoperative therapy was softer than that without, and the association between tumor stiffness and immune cell infiltration was not shown after preoperative therapy. We observed the relationship between tumor stiffness and immunological features in human PDAC for the first time. Immune cell densities in the tumor center were smaller in hard tumors than in soft tumors without preoperative therapies. Preoperative therapy could alter physical and immunological aspects, warranting further study. Understanding of the correlations between physical and immunological aspects could lead to the development of new therapies.

Diagnostic performance of endoscopic ultrasound elastography for differential diagnosis of solid pancreatic lesions: A propensity score-matched analysis.

BACKGROUND: Endoscopic ultrasound-elastography (EUS-EG) is a non-invasive complementary diagnostic method for differential diagnosis of solid pancreatic lesions (SPL). However, the optimal strain ratio (SR) value and diagnostic performance of EUS-EG have not yet been determined in pancreatic neuroendocrine neoplasm (PNEN), mass-forming pancreatitis (MFP), and pancreatic ductal adenocarcinoma (PDAC). We aimed to determine the optimal SR value in EUS-EG for differential diagnosis of SPLs. METHODS: Patients who underwent EUS-EG for SPL evaluation between July 2016 and June 2019 were retrospectively investigated. Patients were divided into three groups based on the final diagnosis (PNEN, MFP, or PDAC). Patient demographics, characteristics of SPL, and EUS-EG were compared. RESULTS: The mean (± standard deviation) SR value for each group were 11.85 ± 7.56 (PNEN, n = 10), 11.45 ± 5.97 (MFP, n = 37), and 22.50 ± 13.19 (PDAC, n = 87). Multinomial logistic regression analysis revealed that an increase of SR value was significantly associated with PDAC (PNEN versus PDAC, p = 0.0216; MFP versus PDAC, p = 0.0006). The optimal cut-off value for differential diagnosis was confirmed as 17.14 after propensity score matching. CONCLUSIONS: We provided the optimal cut-off SR values for differential diagnosis between MFP and PDAC. EUS-EG can be used as a supplementary diagnostic method in the diagnosis of SPLs. (Clinical trial registration number: https://cris.nih.go.kr/cris: KCT0002082).

Prediction of the characteristics of aggressiveness of pancreatic neuroendocrine neoplasms (PanNENs) based on CT radiomic features.

OBJECTIVES: To predict tumor grade (G1 vs. G2/3), presence of distant metastasis (M+), metastatic lymph nodes (N+), and microvascular invasion (VI) of pancreatic neuroendocrine neoplasms (PanNEN) based on preoperative CT radiomic features (RFs), by applying a machine learning approach aimed to limit overfit. METHODS: This retrospective study included 101 patients who underwent surgery for PanNEN; the entire population was split into training (n = 70) and validation cohort (n = 31). Based on a previously validated methodology, after tumor segmentation on contrast-enhanced CT, RFs were extracted from unenhanced CT images. In addition, conventional radiological and clinical features were combined with RFs into multivariate logistic regression models using minimum redundancy and a bootstrap-based machine learning approach. For each endpoint, models were trained and validated including only RFs (RF_model), and both (radiomic and clinicoradiological) features (COMB_model). RESULTS: Twenty-five patients had G2/G3 tumor, 37 N+, and 14 M+ and 38 were shown to have VI. From a total of 182 RFs initially extracted, few independent radiomic and clinicoradiological features were identified. For M+ and G, the resulting models showed moderate to high performances: areas under the curve (AUC) for training/validation cohorts were 0.85/0.77 (RF_model) and 0.81/0.81 (COMB_model) for M+ and 0.67/0.72 and 0.68/0.70 for G. Concerning N+ and VI, only the COMB_model could be built, with poorer performance for N+ (AUC = 0.72/0.61) compared to VI (0.82/0.75). For all endpoints, the negative predictive value was good (≥ 0.75). CONCLUSIONS: Combining few radiomic and clinicoradiological features resulted in presurgical prediction of histological characteristics of PanNENs. Despite the limited risk of overfit, external validations are warranted. KEY POINTS: • Histology is the only tool currently available allowing characterization of PanNEN biological characteristics important for prognostic assessment; significant limitations to this approach exist. • Based upon preoperative contrast-enhanced CT images, a machine learning approach optimized to favor models' generalizability was successfully applied to train predictive models for tumor grading (G1 vs. G2/3), microvascular invasion, metastatic lymph nodes, and distant metastatic spread. • Moderate to high discriminative models (AUC: 0.67-0.85) based on few parameters (≤ 3) showing high negative predictive value (0.75-0.98) were generated and then successfully validated.

Obesity Is Associated With Increased Risk for Adverse Postoperative Outcomes After Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Conflicting reports exist about the effect obesity has on adverse postoperative surgical outcomes after distal pancreatectomy (DP). The aim of this study is to explore the role of obesity in terms of morbidity and pancreas-specific complications following DP for pancreatic ductal adenocarcinoma (PDAC). METHODS: All patients who underwent DP at a single institution over 10 y were analyzed (2009-2020). Patients were categorized as nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2). Independent predictors of adverse postoperative outcomes were calculated using multivariate logistic regression models. Overall survival was assessed using Kaplan-Meier survival analysis. RESULTS: Of the 178 patients included, 58 (32.5%) were obese. Clinically relevant postoperative pancreatic fistula (CR-POPF) formation rate was significantly higher in the obese group (20.6% versus 7.5%, P value = 0.011). We did not identify any significant difference between obese and nonobese patients in median overall survival (30.2 mon versus 28.9 mon, P value = 0.811). On multivariate binary logistic regression analysis, BMI ≥ 30 was an independent predictor of morbidity (any complication) and CR-POPF formation after DP for PDAC. CONCLUSIONS: Obesity is associated with a significantly increased risk for CR-POPF in patients undergoing DP for PDAC. Obesity should be considered as a variable in fistula risk calculators for DP.

Long-term surveillance of branch-duct intraductal papillary mucinous neoplasms without worrisome or high-risk features.

INTRODUCTION: Long-term data evaluating clinical outcomes in patients with branch-duct Intraductal papillary mucinous neoplasms (BD-IPMN) without high-risk stigmata (HRS) or worrisome features (WF) remain limited. METHODS: This observational cohort study included all patients diagnosed with BD-IPMN without HRS or WF between 2003 and 2019 who were enrolled in a prospective surveillance program. Time-to-progression analysis was performed using a cumulative incidence function plot and survival analysis was conducted using Kaplan-Meier. RESULTS: The median follow-up time for the 267 patient cohort was 44.5 months (interquartile range [IQR]: 24.1-72.2). Radiographic cyst growth was observed in 123 (46.1%) patients; 65 (24.3%) patients progressed to WF/HRS. Twenty-six (9.7%) patients were selected for resection during surveillance: 21 (80.8%) WF, 4 (15.4%) HRS; 1 (3.9%) transformed to mixed-duct. Of all the patients who underwent resection, 5 (19.2%) had adenocarcinoma, and 1 (3.8%) had carcinoma-in-situ. The probability of any radiographic progression was 21.3% (5-year) and 51.3% (10-year). For the entire cohort, there was 1.1% mortality secondary to pancreatic adenocarcinoma and 8.2% all-cause mortality. The 5-year overall survival rate was 91.5%, and at 10 years, 81.5%. CONCLUSION: Approximately one in four patients with nonworrisome BD-IPMN have progression to WF/HRS stigmata during surveillance. However, the risk of malignant transformation remains low. Surveillance strategy remains prudent in this patient population.

The burden of pancreatic cancer and its attributable risk factors in the Middle East and North Africa region, 1990-2019.

BACKGROUND AND AIM: Globally, pancreatic cancer is recognized as one of the most lethal types of cancers. We report the burden of pancreatic cancer and its attributable risk factors in the Middle East and North Africa (MENA) region, from 1990 to 2019, by age, sex, and socio-demographic index. METHODS: Publicly available data from the Global Burden of Disease 2019 study were used to report the incidence, deaths, and disability-adjusted life years (DALYs) attributable to pancreatic cancer, as counts and age-standardized rates with 95% uncertainty intervals. RESULTS: In 2019, pancreatic cancer had an age-standardized incidence rate of 5.3 and a death rate of 5.5 (per 100 000) in MENA, which have increased by 97.5% and 93.4%, respectively, since 1990. There were 563.6 thousand DALYs attributable to pancreatic cancer in 2019, with an age-standardized DALY rate of 123.0, which has increased by 84.9% since 1990. The highest number of incident cases was found in the 60-64 and 65-69 age groups, among male and female, respectively. In addition, the MENA/global DALY ratios were higher in all age groups for both sexes in 2019, than they were in 1990. There was a positive association between socio-demographic index and the burden of pancreatic cancer. Smoking, high fasting plasma glucose, and high body mass index were responsible for 19.2%, 9.3%, and 9.3% of the attributable DALYs in 2019, respectively. CONCLUSIONS: There was a clear and substantial increase in the burden of pancreatic cancer in the MENA region. Prevention programs should be implemented in the region that target these three risk factors.

Development of a predictive model for unplanned intensive care unit admission after pancreatic resection within an enhanced recovery pathway.

BACKGROUND: It is unclear whether routine postoperative admission to the intensive care unit (ICU) can improve outcomes for patients undergoing elective pancreatic surgery. Aim of the study was to determine preoperative and intraoperative predictors of unplanned ICU access in patients undergoing pancreatectomy treated within an established enhanced recovery pathway (ERP) and compare outcomes between direct and late ICU admission. METHODS: A retrospective observational study was conducted on adult patients who underwent pancreatic resection (2015-2019) within an ERP. Patients with preoperatively planned ICU admission were excluded from the study. Multiple multivariate logistic regression models were constructed to verify the association of preoperative and intraoperative variables with study outcomes. RESULTS: The study included 1486 consecutive patients (cancer diagnosis 60%, pancreaticoduodenectomy 60%; laparoscopic approach 20%; vascular resection 9%). Sixty-six (4.4%) patients had an unplanned ICU admission. Direct admission occurred in 22 (33%) patients and late ICU admission in 44 (67%) patients. Mortality was significantly lower in direct admission group (n = 3, 14%) compared to late admission (n = 25, 57%; p > 0.001). A comprehensive model including preoperative and intraoperative variables identified ASA score ≥ 3 (OR 5.59, p value < 0.001), history of hypertension (OR 2.29, p = 0.029), chronic obstructive pulmonary disease (OR 3.05, p = 0.026), proximal pancreatic resection (OR 2.79, p value 0.046), multivisceral resection (OR 8.86, p value < 0.001), high intraoperative blood loss (OR 1.01 per ml, p < 0.001), and increased serum lactate at the end of surgery (OR 1.25, p = 0.017) as independent factors associated with ICU admission. Area under the ROC curve was 0.891. CONCLUSION: Patient comorbidities, surgical complexity, and lactic acidosis at the end of surgery were associated with unplanned postoperative ICU admission. Late ICU admission had very high mortality rates compared to direct admission. Our findings suggest that patients with a combination of preoperative and intraoperative risk factors could benefit from upfront postoperative ICU admission to potentially improve postoperative outcomes.

Classification, risk factors, and management of lumen apposing metal stent dysfunction during follow-up of endoscopic ultrasound-guided choledochoduodenostomy: Multicenter evaluation from the Leuven-Amsterdam-Milan Study Group.

OBJECTIVES: Long-term outcomes of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) performed with lumen apposing metal stents (LAMS) have been poorly evaluated in small or retrospective series, leading to an underestimation of LAMS dysfunction. METHODS: All consecutive EUS-CDS performed in three academic referral centers were included in prospectively maintained databases. Technical/clinical success, adverse events (AEs), and dysfunction during follow-up were retrospectively analyzed. Kaplan-Meier analysis was used to estimate dysfunction-free survival (DFS), with Cox proportional hazard regression to evaluate independent predictors of dysfunction. RESULTS: Ninety-three patients were included (male 56%; mean age, 70 years [95% confidence interval (CI) 68-72]; pancreatic cancer 81%, metastatic disease 47%). In 67% of procedures, 6 mm LAMS were used. Technical and clinical success were achieved in 97.8% and 93.4% of patients, respectively, with AEs occurring in 9.7% (78% mild/moderate). Dysfunction occurred in 31.8% of patients after a mean of 166 days (95% CI 91-241), with an estimated 6 month and 12 month DFS of 75% and 52%, respectively; mean DFS of 394 (95% CI 307-482) days. Almost all dysfunctions (96%) were successfully managed by endoscopic reintervention. Duodenal invasion (hazard ratio 2.7 [95% CI 1.1-6.8]) was the only independent predictor of dysfunction. CONCLUSIONS: Endoscopic ultrasound-guided choledochoduodenostomy shows excellent initial efficacy and safety, although stent dysfunctions occurs frequently during long-term follow-up. Almost all stent dysfunctions can be managed successfully by endoscopic reinterventions. We propose a comprehensive classification of the different types of dysfunction that may be encountered and rescue procedures that may be employed under these circumstances. Duodenal invasion seems to increase the risk of developing EUS-CDS dysfunction, potentially representing a relative contraindication for this technique.

CT classification model of pancreatic serous cystic neoplasm and mucinous cystic neoplasm based on deep transfer learning.

BACKGROUND: Pancreatic cancer is a highly lethal disease. The preoperative distinction between pancreatic serous cystic neoplasm (SCN) and mucinous cystic neoplasm (MCN) remains a clinical challenge. OBJECTIVE: The goal of this study is to provide clinicians with supportive advice and avoid overtreatment by constructing a convolutional neural network (CNN) classifier to automatically identify pancreatic cancer using computed tomography (CT) images. METHODS: We construct a CNN model using a dataset of 6,173 CT images obtained from 107 pathologically confirmed pancreatic cancer patients at Shanghai Changhai Hospital from January 2017 to February 2022. We divide CT slices into three categories namely, SCN, MCN, and no tumor, to train the DenseNet201-based CNN model with multi-head spatial attention mechanism (MSAM-DenseNet201). The attention module enhances the network's attention to local features and effectively improves the network performance. The trained model is applied to process all CT image slices and finally realize the two categories classification of MCN and SCN patients through a joint voting strategy. RESULTS: Using a 10-fold cross validation method, this new MSAM-DenseNet201 model achieves a classification accuracy of 92.52%, a precision of 92.16%, a sensitivity of 92.16%, and a specificity of 92.86%, respectively. CONCLUSIONS: This study demonstrates the feasibility of using a deep learning network or classification model to help diagnose MCN and SCN cases. This, the new method has great potential for developing new computer-aided diagnosis systems and applying in future clinical practice.

KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer.

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; ptrend <0.001) and 1.31 (95% CI, 1.16-1.48; ptrend <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.

Preoperative Radiomics Approach to Evaluating Tumor-Infiltrating CD8+ T Cells in Patients With Pancreatic Ductal Adenocarcinoma Using Noncontrast Magnetic Resonance Imaging.

BACKGROUND: CD8+ T cell in pancreatic ductal adenocarcinoma (PDAC) is closely related to the prognosis and treatment response of patients. Accurate preoperative CD8+ T-cell expression can better identify the population benefitting from immunotherapy. PURPOSE: To develop and validate a machine learning classifier based on noncontrast magnetic resonance imaging (MRI) for the preoperative prediction of CD8+ T-cell expression in patients with PDAC. STUDY TYPE: Retrospective cohort study. POPULATION: Overall, 114 patients with PDAC undergoing MR scan and surgical resection; 97 and 47 patients in the training and validation cohorts. FIELD STRENGTH/SEQUENCE/3 T: Breath-hold single-shot fast-spin echo T2-weighted sequence and noncontrast T1-weighted fat-suppressed sequences. ASSESSMENT: CD8+ T-cell expression was quantified using immunohistochemistry. For each patient, 2232 radiomics features were extracted from noncontrast T1- and T2-weighted images and reduced using the Wilcoxon rank-sum test and least absolute shrinkage and selection operator method. Linear discriminative analysis was used to construct radiomics and mixed models. Model performance was determined by its discriminative ability, calibration, and clinical utility. STATISTICAL TESTS: Kaplan-Meier estimates, Student's t-test, the Kruskal-Wallis H test, and the chi-square test, receiver operating characteristic curve, and decision curve analysis. RESULTS: A log-rank test showed that the survival duration in the CD8-high group (25.51 months) was significantly longer than that in the CD8-low group (22.92 months). The mixed model included all MRI characteristics and 13 selected radiomics features, and the area under the curve (AUC) was 0.89 (95% confidence interval [CI], 0.77-0.92) and 0.69 (95% CI, 0.53-0.82) in the training and validation cohorts. The radiomics model included 13 radiomics features, which showed good discrimination in the training cohort (AUC, 0.85; 95% CI, 0.77-0.92) and the validation cohort (AUC, 0.76; 95% CI, 0.61-0.87). DATA CONCLUSIONS: This study developed a noncontrast MRI-based radiomics model that can preoperatively determine CD8+ T-cell expression in patients with PDAC and potentially immunotherapy planning. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 2.

How to approach pancreatic cancer after neoadjuvant treatment: assessment of resectability using multidetector CT and tumor markers.

OBJECTIVES: To investigate clinical and CT factors associated with local resectability in patients with nonmetastatic pancreatic cancers after neoadjuvant chemotherapy ± radiation therapy (CRT). METHODS: This retrospective study included consecutive patients with nonmetastatic pancreatic cancers who underwent neoadjuvant CRT between June 2009 and June 2019. Tumor size, tumor-vascular contact with artery/vein, and local resectability categories (resectable, borderline resectable, or locally advanced) were assessed at baseline and post-CRT CT. Baseline and post-CRT carbohydrate antigen (CA) 19-9 levels were also assessed. Clinical or imaging features related to R0 resection were determined using logistic regression analysis. RESULTS: A total of 179 patients (mean age, 62.4 ± 9.3 years; 92 men) were included. After neoadjuvant CRT, 105 (58.7%) patients received R0 resection, while 74 (41.3%) did not. R0 resection rates were significantly different according to post-CRT CT resectability categories (p < 0.001): 82.8% (48/58), 70.1% (47/67), and 18.5% (10/54) for resectable, borderline resectable, and locally advanced disease, respectively. For post-CRT borderline resectable disease, ≥ 50% decrease in CA 19-9 was significantly associated with R0 resection (odds ratio (OR), 3.160; p = 0.02). For post-CRT locally advanced disease, small post-CRT tumor size ≤ 2 cm (OR, 9.668; p = 0.026) and decreased tumor-arterial contact (OR, 24.213; p = 0.022) were significantly associated with R0 resection. CONCLUSION: Post-CRT CT resectability categorization may be useful for the assessment of R0 resectability in patients with pancreatic cancer following neoadjuvant CRT. Additionally, ≥ 50% decrease in CA 19-9 was associated with R0 resection in post-CRT borderline resectable disease, while small post-CRT tumor size and decreased tumor-arterial contact were with locally advanced disease. KEY POINTS: • R0 resection rates following neoadjuvant chemotherapy ± radiation therapy (CRT) were 82.8%, 70.1%, and 18.5% in resectable, borderline resectable, and locally advanced disease, respectively, at post-CRT CT (p < 0.001). • For post-CRT borderline resectable disease, ≥ 50% decrease in carbohydrate antigen (CA) 19-9 was significantly associated with R0 resection. • For post-CRT locally advanced disease, small post-CRT tumor size ≤ 2 cm and decreased tumor-arterial contact were significantly associated with R0 resection.

Time to Neoadjuvant Chemotherapy Initiation Is not Associated With Survival in Pancreatic Cancer.

INTRODUCTION: Not all patients with pancreatic adenocarcinoma (PDAC) tolerate multiagent neoadjuvant chemotherapy (NAC). We utilized institutional data and the National Cancer Database (NCDB) to investigate if time from diagnosis to NAC initiation is associated with survival. METHODS: Patients who received NAC and underwent pancreatectomy at our institution (2010-2021) or within the NCDB (2010-2016) were identified. Time from diagnosis to NAC was grouped: <21, 21-35, and >35 d. Recurrence-free (RFS) and overall survival (OS) was compared. RESULTS: At our institution, 122 patients received NAC before pancreatectomy (<21 d: n = 36; 21-35 d: n = 61; >35 d: n = 25). Demographics, performance status, and anatomic resectability were similar. There was no difference in RFS (13.3 versus 12.4 versus 11.9 mo) or OS (26.7 versus 25.8 versus 26.1 mo) based on NAC timing. Patients who received FOLFIRINOX had an improvement in RFS (14.4 versus 12.2 versus 6.8 mo, P = 0.05) and OS (39.2 versus 21.4 versus 17.3 mo, P = 0.01) compared to gemcitabine with nab-paclitaxel or other regimens. Within the NCDB, 6713 patients were included (<21 d: n = 2087; 21-35 d: n = 2656; >35 d: n = 1970). There was no difference in OS (21.6 versus 20.9 versus 22.2 mo). Multiagent NAC was associated with improved OS compared to single-agent (22.6 versus 18.8 mo, P < 0.001). CONCLUSIONS: Delay in NAC initiation for PDAC is not associated with survival. Patient optimization could be considered with the goal of improving tolerance of multiagent chemotherapy.

Risk of pancreatic ductal adenocarcinoma associated with carriage of BRCA1 and/or BRCA2 mutation: A systematic review and meta-analysis.

Germline BRCA1/2 mutations lead to malfunction of DNA damage repair pathways and predispose to pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to synthesise the available research on this topic. Four studies reporting risk ratio (RR) were included in the final meta-analysis to minimise misrepresenting our results by combining separate risk estimates. Our meta-analysis revealed a statistically significant increased risk of PDAC in BRCA carriers overall (RR: 2.65, 95% confidence interval: 1.43-4.91, p = 0.002).

Exosomal miR-19a decreases insulin production by targeting Neurod1 in pancreatic cancer associated diabetes.

BACKGROUND: New onset diabetes mellitus demonstrates a roughly correlation with pancreatic cancer (PaC), which is unique in PaC and was named as PaC-induced DM, but the inner mechanism remains unclear. Exosomes mediate intercellular communication and bearing microRNAs might be direct constituent of effect in target cells. METHODS AND RESULTS: The isolated exosomes from PaC cells were used to treat pancreatic ß cells or the primary mice islets, and the glucose stimulated insulin secretions were measured. We validated the exosomal miR-19a from PaC cells to be an important mediator in the down regulation of insulin secretion by targeting Neurod1, the validated gene involved in insulin secretion, by using the quantitative real-time PCR, western blot, and promoter luciferase activity. The relative insulin, cAMP and Ca2+ expressions were also assayed to verify the inverse correlation between cancerous miR-19a and pancreatic islets Neurod1. CONCLUSIONS: Our study indicated that signal changes between cancer cells and ß cells via exosomes might be important in the pathogenesis of PaC-induced DM and supplemented the pathogenesis of PaC-induced DM and provide a possible access of PaC screening strategy.

A scoring system for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: a multicenter EUROPEAN validation.

PURPOSE: A preoperative estimate of the risk of malignancy for intraductal papillary mucinous neoplasms (IPMN) is important. The present study carries out an external validation of the Shin score in a European multicenter cohort. METHODS: An observational multicenter European study from 2010 to 2015. All consecutive patients undergoing surgery for IPMN at 35 hospitals with histological-confirmed IPMN were included. RESULTS: A total of 567 patients were included. The score was significantly associated with the presence of malignancy (p < 0.001). In all, 64% of the patients with benign IPMN had a Shin score < 3 and 57% of those with a diagnosis of malignancy had a score ≥ 3. The relative risk (RR) with a Shin score of 3 was 1.37 (95% CI: 1.07-1.77), with a sensitivity of 57.1% and specificity of 64.4%. CONCLUSION: Patients with a Shin score ≤ 1 should undergo surveillance, while patients with a score ≥ 4 should undergo surgery. Treatment of patients with Shin scores of 2 or 3 should be individualized because these scores cannot accurately predict malignancy of IPMNs. This score should not be the only criterion and should be applied in accordance with agreed clinical guidelines.