Emerging Trends in Gastrointestinal Cancer Targeted Therapies: Harnessing Tumor Microenvironment, Immune Factors, and Metabolomics Insights.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence demonstrated that tumor cell functions are modulated by its microenvironment, compromising fibroblasts, ECMs, microbiome, immune cells, and the enteric nervous system. Along with the TME components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment (TME) and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and cell-extrinsic during tumor progression is critical for developing new therapeutic strategies.

Colorectal cancer murine models: Initiation to metastasis.

Despite significant advancements in prevention and treatment, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths. Animal models, including xenografts, syngeneic, and genetically engineered, have emerged as indispensable tools in cancer research. These models offer a valuable platform to address critical questions regarding molecular pathogenesis and test therapeutic interventions before moving on to clinical trials. Advancements in CRC animal models have also facilitated the advent of personalized and precision medicine. Patient-derived xenografts and genetically engineered mice that mirror features of human tumors allow for tailoring treatments to specific CRC subtypes, improving treatment outcomes and quality of life. To overcome the limitations of individual model systems, recent studies have employed a multi-modal approach, combining different animal models, 3D organoids, and in vitro studies. This integrative approach provides a comprehensive understanding of CRC biology, including the tumor microenvironment and therapeutic responses, driving the development of more effective and personalized therapeutic interventions. This review discusses the animal models used for CRC research, including recent advancements and limitations of these animal models.

Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Pancreatic Cyst Size Measurement on Magnetic Resonance Imaging Compared to Pathology.

BACKGROUND: While multiple cyst features are evaluated for stratifying pancreatic intraductal papillary mucinous neoplasms (IPMN), cyst size is an important factor that can influence treatment strategies. When magnetic resonance imaging (MRI) is used to evaluate IPMNs, no universally accepted sequence provides optimal size measurements. T2-weighted coronal/axial have been suggested as primary measurement sequences; however, it remains unknown how well these and maximum all-sequence diameter measurements correlate with pathology size. This study aims to compare agreement and bias between IPMN long-axis measurements on seven commonly obtained MRI sequences with pathologic size measurements. METHODS: This retrospective cohort included surgically resected IPMN cases with preoperative MRI exams. Long-axis diameter tumor measurements and the presence of worrisome features and/orhigh-risk stigmata were noted on all seven MRI sequences. MRI size and pathology agreement and MRI inter-observer agreement involved concordance correlation coefficient (CCC) and intraclass correlation coefficient (ICC), respectively. The presence of worrisome features and high-risk stigmata were compared to the tumor grade using kappa analysis. The Bland-Altman analysis assessed the systematic bias between MRI-size and pathology. RESULTS: In 52 patients (age 68 ± 13 years, 22 males), MRI sequences produced mean long-axis tumor measurements from 2.45-2.65 cm. The maximum MRI lesion size had a strong agreement with pathology (CCC = 0.82 (95% CI: 0.71-0.89)). The maximum IPMN size was typically observed on the axial T1 arterial post-contrast and MRCP coronal series and overestimated size versus pathology with bias +0.34 cm. The radiologist interobserver agreement reached ICCs 0.74 to 0.91 on the MRI sequences. CONCLUSION: The maximum MRI IPMN size strongly correlated with but tended to overestimate the length compared to the pathology, potentially related to formalin tissue shrinkage during tissue processing.

RNA Expression-based Analysis to Predict Response in Patients with Metastatic Mismatch Repair Proficient Colorectal Cancer Treated with Regorafenib and Nivolumab.

Introduction We previously conducted a phase I/Ib study (NCT03712943) with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the role of Xerna™ TME Panel in predicting the treatment response. Methods 22 archival pretreatment tumor samples were subjected to the Xerna™ TME Panel, a machine learning-based RNA-sequencing biomarker assay. The Xerna TME subtypes were evaluated for correlation with overall survival (OS), progression free survival (PFS), disease control rate (DCR), and other biomarkers including KRAS, PD-L1, CD8 expression, and Treg cells in tumor microenvironment. Results Based on Xerna™ TME Panel, four patients with immune active (IA) subtype and six patients with immune suppressed (IS) subtype were classified as biomarker-positive, and five with angiogenic (A) subtype and seven with immune desert (ID) subtype were biomarker-negative. While not reaching statistical significance, Xerna TME biomarker-positive patients seemed to have longer median PFS (7.9 vs. 4.1 months, P=0.254), median OS (15.75 vs. 11.9 months, P=0.378), and higher DCR (70% vs. 58%, P=0.675). The IA subtype in our cohort had higher levels of CD4+ FOXP3+ Treg cells, whereas the A subtype showed lower levels of Treg cells. Conclusion Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab might be of value for predictive clinical benefit. Further studies are needed to evaluate the predictive role of Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC.

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

p21 Protein Outperforms Clinico-pathological Criteria in Predicting Liver Metastases in Pancreatic Endocrine Tumors.

BACKGROUND/AIM: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases. MATERIALS AND METHODS: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases. RESULTS: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values. CONCLUSION: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.

Real time ex vivo chemosensitivity assay for pancreatic adenocarcinoma.

BACKGROUND: Patient-derived organoids (PDOs) and xenografts (PDXs) have been extensively studied for drug-screening. However, their usage is limited due to lengthy establishment time, high engraftment failure rates and different tumor microenvironment from original tumors. To overcome the limitations, we developed real time-live tissue sensitivity assay (RT-LTSA) using fresh tumor samples. METHODS: Tissue slices from resected pancreatic cancer samples were placed in 96-well plates, and the slices were treated with chemotherapeutic agents. The correlation between the chemo-sensitivity of tissue slices and each patient's clinical outcome was analyzed. RESULTS: The viability and tumor microenvironment of the tissue slices are well-preserved over 5 days. The drug sensitivity assay results are available within 5 days after tissue collection. While all 4 patients who received RT-LTSA sensitive adjuvant regimens did not develop recurrence, 7 of 8 patients who received resistant adjuvant regimens developed recurrence. We observed significantly improved disease-free survival in the patients who received RT-LTSA sensitive adjuvant regimens (median: not reached versus 10.6 months, P = 0.02) compared with the patient who received resistant regimens. A significant negative correlation between RT-LTSA value and relapse-free survival was observed (Somer's D: -0.58; P = 0.016). CONCLUSIONS: RT-LTSA which maintains the tumor microenvironment and architecture as found in patients may reflect clinical outcome and could be used as a personalized strategy for pancreatic adenocarcinoma. Further, studies are warranted to verify the findings.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreas adenocarcinoma: influence of vascular margin status and type of chemotherapy.

BACKGROUND: The influence of chemotherapy type and vascular margin status after sequential chemotherapy and stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic cancer (BRPC) is unknown. METHODS: A retrospective review was performed on BRPC patients treated with chemotherapy and 5-fraction SBRT from 2009 to 2021. Surgical outcomes and SBRT-related toxicity were reported. Clinical outcomes were estimated by Kaplan-Meier with log rank comparisons. RESULTS: A total of 303 patients received neoadjuvant chemotherapy and SBRT to a median dose of 40 Gy prescribed to the tumor-vessel interface and median dose of 32.4 Gyto 95% of the gross tumor volume. One hundred and sixty-nine patients (56%) were resected and benefited from improved median OS (41.1 vs 15.5 months, P < 0.001). Close/positive vascular margins were not associated with worse OS or FFLRF. Type of neoadjuvant chemotherapy did not influence OS for resected patients, but FOLFIRINOX was associated with improved median OS in unresected patients (18.2 vs 13.1 months, P = 0.001). CONCLUSION: For BRPC, the effect of a positive or close vascular margin may be mitigated by neoadjuvant therapy. Shorter duration neoadjuvant chemotherapy as well as the optimal biological effective dose of radiotherapy should be prospectively explored.

Xerna™ TME Panel is a machine learning-based transcriptomic biomarker designed to predict therapeutic response in multiple cancers.

Introduction: Most predictive biomarkers approved for clinical use measure single analytes such as genetic alteration or protein overexpression. We developed and validated a novel biomarker with the aim of achieving broad clinical utility. The Xerna™ TME Panel is a pan-tumor, RNA expression-based classifier, designed to predict response to multiple tumor microenvironment (TME)-targeted therapies, including immunotherapies and anti-angiogenic agents. Methods: The Panel algorithm is an artificial neural network (ANN) trained with an input signature of 124 genes that was optimized across various solid tumors. From the 298-patient training data, the model learned to discriminate four TME subtypes: Angiogenic (A), Immune Active (IA), Immune Desert (ID), and Immune Suppressed (IS). The final classifier was evaluated in four independent clinical cohorts to test whether TME subtype could predict response to anti-angiogenic agents and immunotherapies across gastric, ovarian, and melanoma datasets. Results: The TME subtypes represent stromal phenotypes defined by angiogenesis and immune biological axes. The model yields clear boundaries between biomarker-positive and -negative and showed 1.6-to-7-fold enrichment of clinical benefit for multiple therapeutic hypotheses. The Panel performed better across all criteria compared to a null model for gastric and ovarian anti-angiogenic datasets. It also outperformed PD-L1 combined positive score (>1) in accuracy, specificity, and positive predictive value (PPV), and microsatellite-instability high (MSI-H) in sensitivity and negative predictive value (NPV) for the gastric immunotherapy cohort. Discussion: The TME Panel's strong performance on diverse datasets suggests it may be amenable for use as a clinical diagnostic for varied cancer types and therapeutic modalities.

The impact of age and comorbidity on localized pancreatic cancer outcomes: A US retrospective cohort analysis with implications for surgical centralization.

Introduction: Age and comorbidity are independently associated with worse outcomes for pancreatic adenocarcinoma (PDAC). However, the effect of combined age and comorbidity on PDAC outcomes has rarely been studied. This study assessed the impact of age and comorbidity (CACI) and surgical center volume on PDAC 90-day and overall survival (OS). Methods: This retrospective cohort study used the National Cancer Database from 2004 to 2016 to evaluate resected stage I/II PDAC patients. The predictor variable, CACI, combined the Charlson/Deyo comorbidity score with additional points for each decade lived ≥50 years. The outcomes were 90-day mortality and OS. Results: The cohort included 29,571 patients. Ninety-day mortality ranged from 2 % for CACI 0 to 13 % for CACI 6+ patients. There was a negligible difference (1 %) in 90-day mortality between high- and low-volume hospitals for CACI 0-2 patients; however, there was greater difference for CACI 3-5 (5 % vs. 9 %) and CACI 6+ (8 % vs. 15 %). The overall survival for CACI 0-2, 3-5, and 6+ cohorts was 24.1, 19.8, and 16.2 months, respectively. Adjusted overall survival showed a 2.7 and 3.1 month survival benefit for care at high-volume vs. low-volume hospitals for CACI 0-2 and 3-5, respectively. However, there was no OS volume benefit for CACI 6+ patients. Conclusions: Combined age and comorbidity are associated with short- and long-term survival for resected PDAC patients. A protective effect of higher-volume care was more impactful for 90-day mortality for patients with a CACI above 3. A centralization policy based on volume may have greater benefit for older, sicker patients. Key message: Combined comorbidity and age are strongly associated with 90-day mortality and overall survival for resected pancreatic cancer patients. When assessing the impact of age and comorbidity on resected pancreatic adenocarcinoma outcomes, 90-day mortality was 7 % higher (8 % vs. 15 %) for older, sicker patients treated at high-volume vs. low-volume centers but only 1 % (3 % vs. 4 %) for younger, healthier patients.

Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART).

PURPOSE: Treatment options for pancreatic ductal adenocarcinoma (PDAC) are commonly limited for patients with advanced age due to medical comorbidities and/or poor performance status. These patients may not be candidates for more aggressive chemotherapy regimens and/or surgical resection leaving few, if any, other effective treatments. Ablative stereotactic MRI-guided adaptive radiation therapy (A-SMART) is both efficacious and safe for PDAC and can achieve excellent long-term local control, however, the appropriateness of A-SMART for elderly patients with inoperable PDAC is not well understood. METHODS: A retrospective analysis was performed of inoperable non-metastatic PDAC patients aged 75 years or older treated on the MRIdian Linac at 2 institutions. Clinical outcomes of interest included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional (LRC). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE, v5). RESULTS: A total of 49 patients were evaluated with a median age of 81 years (range, 75-91) and a median follow-up of 14 months from diagnosis. PDAC was classified as locally advanced (46.9%), borderline resectable (36.7%), or medically inoperable (16.3%). Neoadjuvant chemotherapy was delivered to 84% of patients and all received A-SMART to a median 50 Gy (range, 40-50 Gy) in 5 fractions. 1 Year LRC, PFS, and OS were 88.9%, 53.8%, and 78.9%, respectively. Nine patients (18%) had resection after A-SMART and benefited from PFS improvement (26 vs 6 months, P = .01). ECOG PS <2 was the only predictor of improved OS on multivariate analysis. Acute and late grade 3 + toxicity rates were 8.2% and 4.1%, respectively. CONCLUSIONS: A-SMART is associated with encouraging LRC and OS in elderly patients with initially inoperable PDAC. This novel non-invasive treatment strategy appears to be well-tolerated in patients with advanced age and should be considered in this population that has limited treatment options.

A pilot study to evaluate tissue- and plasma-based DNA driver mutations in a cohort of patients with pancreatic intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic ductal adenocarcinoma that are challenging to manage due to limited imaging, cytologic, and molecular markers that accurately classify lesions, grade of dysplasia, or focus of invasion preoperatively. The objective of this pilot study was to determine the frequency and type of DNA mutations in a cohort of surgically resected, pathologically confirmed IPMN, and to determine if concordant mutations are detectable in paired pretreatment plasma samples. Formalin-fixed paraffin-embedded (FFPE) tissue from 46 surgically resected IPMNs (31 low-grade, 15 high-grade) and paired plasma from a subset of 15 IPMN cases (10 low-grade, 5 high-grade) were subjected to targeted mutation analysis using a QIAseq Targeted DNA Custom Panel. Common driver mutations were detected in FFPE from 44 of 46 (95.6%) IPMN cases spanning all grades; the most common DNA mutations included: KRAS (80%), RNF43 (24%), and GNAS (43%). Of note, we observed a significant increase in the frequency of RNF43 mutations from low-grade to high-grade IPMNs associated or concomitant with invasive carcinoma (trend test, P = 0.01). Among the subset of cases with paired plasma, driver mutations identified in the IPMNs were not detected in circulation. Overall, our results indicate that mutational burden for IPMNs is a common occurrence, even in low-grade IPMNs. Furthermore, although blood-based biopsies are an attractive, noninvasive method for detecting somatic DNA mutations, the QIAseq panel was not sensitive enough to detect driver mutations that existed in IPMN tissue using paired plasma in the volume we were able to retrieve for this retrospective study.

Surgical and Pathologic Outcomes of Pancreatic Adenocarcinoma (PA) After Preoperative Ablative Stereotactic Magnetic Resonance Image Guided Adaptive Radiation Therapy (A-SMART).

Purpose: Preoperative radiation therapy (RT) for pancreatic adenocarcinoma reduces positive surgical margin rates, and when delivered to an ablative dose range it may improve local control and overall survival for patients with unresectable disease. Use of stereotactic body RT to achieve a higher biologically effective dose has been limited by toxicity to adjacent radiosensitive structures, but this can be mitigated by stereotactic magnetic resonance image guided adaptive radiation therapy (SMART). Methods and Materials: We describe our single-institution experience of high biologically effective dose SMART before resection of localized pancreatic adenocarcinoma. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (V 5.0). Tumor response was evaluated according to the College of American Pathologists tumor regression grading criteria. Results: We analyzed 26 patients with borderline resectable (80.8%), locally advanced (11.5%), and resectable (7.7%) tumors who received ablative dose SMART (A-SMART) followed by surgical resection. Median age at diagnosis was 68 years (range, 34-86). Most patients received chemotherapy (80.8%) before RT. All patients received A-SMART to a median dose of 50 (range, 40-50) Gy in 5 fractions. Toxicity data were collected prospectively and there were no acute grade 2+ toxicities associated with RT. The median time to resection was 50 days (range, 37-115), and the procedure types included Whipple (69%), distal (23%), or total pancreatectomy (8%). The R0 resection rate was 96% and no perioperative deaths occurred within 90 days. Pathologic response was observed in 88% of cases. The time from RT to surgery was associated with tumor regression grade (P = .0003). The median follow-up after RT was 16.5 months (range, 3.9-26.2). The derived median progression-free survival from RT was 13.2 months. Conclusions: The initial surgical and pathologic outcomes after A-SMART are encouraging. Preoperative A-SMART was associated with low toxicity rates and no surgical or RT-associated mortality. The surgical morbidity was comparable to historic rates after upfront resection. These data also suggest that the time from stereotactic body RT to surgical resection is associated with pathologic response.

Hospital Surgical Volume Is Poorly Correlated With Delivery of Multimodal Treatment for Localized Pancreatic Cancer: A National Retrospective Cohort Study.

Using Donabedian's quality of care model, this study assessed process (hospital multimodal treatment) and structure (hospital surgical case volume) measures to evaluate localized pancreatic cancer outcomes. Background: Treatment at high surgical volume hospitals has been shown to improve short-term outcomes. However, multimodal treatment-surgery and chemotherapy-is the standard of care yet only received by 35% of US patients and has not been examined at the hospital level. Methods: The National Cancer Database was used to identify a cohort of clinical stage I pancreatic cancer patients eligible for multimodal treatment from 2004 to 2016. Hospital multimodal treatment was defined as the number of patients receiving surgery and chemotherapy by the number of eligible patients per hospital. Descriptive statistics and survival analyses were conducted. Results: A total of 16,771 patients met inclusion criteria, of whom 68.0% received curative-intent surgery and 35.8% received multimodal treatment. There was poor correlation between hospital surgical volume and delivery of multimodal treatment (Spearman correlation 0.214; P < 0.001). Of patients cared for at the highest surgical volume hospitals, 18.8% and 52.1% were treated at hospitals with low (0%-25%) and moderate (>25%-50%) multimodal treatment delivery, respectively. Higher hospital multimodal treatment delivery was associated with improved overall survival. Discussion: Although the volume-outcome relationship for pancreatic cancer has demonstrated improved outcomes, this work identified poor correlation between hospital surgical volume and delivery of multimodal treatment. The role of care coordination in the delivery of multimodal treatment warrants further investigation as it is associated with improved survival for patients with localized pancreatic cancer.

Patient-caregiver dyads in pancreatic cancer: identification of patient and caregiver factors associated with caregiver well-being.

We aimed to examine the psychosocial well-being in the pancreas cancer patient-caregiver dyad, and determine patient and caregiver characteristics that predict caregiver distress. This was a cross-sectional, observational study. Demographics and caregiving characteristics were gathered from patients and caregivers. Caregivers completed validated instruments investigating anxiety, depression, perceived stress and caregiver burden. Over a period of eleven months, 128 patient-caregiver dyads were enrolled. Patient and caregiver distress scores were not associated with patient clinical disease burden. Patient distress was a significant predictor of concurrent caregiver distress, anxiety, depression, and perceived burden. Younger caregivers were also associated with higher caregiver anxiety and perceived burden. Additionally, number of caregiving activities and caregiver overall health status were predictors of concurrent caregiver depression and perceived stress. Certain pancreatic cancer patient and caregiver variables may negatively impact the well-being of caregivers. Future efforts should focus on development and implementation of comprehensive caregiver support programs for those at risk for psychosocial distress.

Prophylactic Perioperative Antibiotics in Open Pancreaticoduodenectomy: When Less Is More and When It Is Not. A National Surgical Quality Improvement Program Propensity-Matched Analysis.

INTRODUCTION: We hypothesized that first-generation cephalosporins (G1CEP) provide adequate antimicrobial coverage for pancreaticoduodenectomy (PD) when no biliary stent is present but might be inferior to second-generation cephalosporins or broad-spectrum antibiotics (G2CEP/BS) in decreasing surgical-site infection (SSI) rates when a biliary stent is present. METHODS: The National Surgical Quality Improvement Program 2014-2019 was used to select patients who underwent elective open PD. We divided the population into no-stent versus stent groups based on the status of biliary drainage and then divided each group into G1CEP versus G2CEP/BS subgroups based on the choice of perioperative antibiotics. We matched the subgroups per a propensity score match and analyzed postoperative outcomes. RESULTS: Six thousand two hundred forty five cases of 39,779 were selected; 2821 in the no-stent (45.2%) versus 3424 (54.8%) in the stent group. G1CEP were the antibiotics of choice in 2653 (42.5%) versus G2CEP/BS in 3592 (57.5%) cases. In the no-stent group, we matched 1129 patients between G1CEP and G2CEP/BS. There was no difference in SSI-specific complications (20.3% versus 21.0%; P = 0.677), general infectious complications (25.7% versus 26.9%; P = 0.503), PD-specific complications, overall morbidity, length of stay, or mortality. In the stent group, we matched 1244 pairs. G2CEP/BS had fewer SSI-specific complications (19.9% versus 26.6%; P < 0.001), collections requiring drainage (9.6% versus 12.9%; P = 0.011), and general infectious complications (28.5% versus 34.1%; P = 0.002) but no difference in overall morbidity, mortality, length of stay, and readmission rates. CONCLUSIONS: G2CEP/BS are associated with reduced rates of SSI-specific and infectious complications in stented patients undergoing open elective PD. In patients without prior biliary drainage, G1CEP seems to provide adequate antimicrobial coverage.

A pilot study to troubleshoot quality control metrics when assessing circulating miRNA expression data reproducibility across study sites.

BACKGROUND: Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical. OBJECTIVE: The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions. METHODS: Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs. RESULTS: Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples. CONCLUSIONS: Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.

Pancreatic Ductal Carcinoma Risk Associated With Hereditary Cancer-Risk Genes.

BACKGROUND: Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined and are potentially biased because of the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings. METHODS: This is a retrospective analysis of 676 667 individuals, 2445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013 and 2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC because of pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal and/or family cancer history, and ancestry. RESULTS: Overall, 11.1% of patients with PDAC had a PV. Statistically significantly elevated PDAC risk (2-sided P < .05) was observed for CDK2NA (p16INK4a) (OR = 8.69, 95% CI = 4.69 to 16.12), ATM (OR = 3.44, 95% CI = 2.58 to 4.60), MSH2 (OR = 3.17, 95% CI = 1.70 to 5.91), PALB2 (OR = 3.09, 95% CI = 2.02 to 4.74), BRCA2 (OR = 2.55, 95% CI = 1.99 to 3.27), and BRCA1 (OR = 1.62, 95% CI = 1.07 to 2.43). CONCLUSIONS: This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly because of adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer.