The circadian clock is disrupted in pancreatic cancer.

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.

Racial Disparity in Pathologic Response following Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: A Multi-Institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection. METHODS: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS). RESULTS: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts. CONCLUSIONS: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation.

Gender Differences in Entrustable Professional Activity Evaluations of General Surgery Residents.

OBJECTIVE: To determine differences in entrustable professional activity (EPA) assessments between male and female general surgery residents. SUMMARY BACKGROUND DATA: Evaluations play a critical role in career advancement for physicians. However, female physicians in training receive lower evaluations and underrate their own performance. Competency-based assessment frameworks, such as EPAs, may help address gender bias in surgery by linking evaluations to specific, observable behaviors. METHODS: In this cohort study, EPA assessments were collected from July 2018 to May 2020. The effect of resident sex on EPA entrustment levels was analyzed using multiple linear and ordered logistic regressions. Narrative comments were analyzed using latent dirichlet allocation to identify topics correlated with resident sex. RESULTS: Of the 2480 EPAs, 1230 EPAs were submitted by faculty and 1250 were submitted by residents. After controlling for confounding factors, faculty evaluations of residents were not impacted by resident sex (estimate = 0.09, P = 0.08). However, female residents rated themselves lower by 0.29 (on a 0-4 scale) compared to their male counterparts (P < 0.001). Within narrative assessments, topics associated with resident sex demonstrated that female residents focus on the "guidance" and "supervision" they received while performing an EPA, while male residents were more likely to report "independent" action. CONCLUSIONS: Faculty assessments showed no difference in EPA levels between male and female residents. Female residents rate themselves lower by nearly an entire post graduate year (PGY) level compared to male residents. Latent dirichlet allocation -identified topics suggest this difference in self-assessment is related to differences in perception of autonomy.

ASO Author Reflections: An Opportunity to Provide Cost-Conscious Care for Patients Undergoing CRS-HIPEC.

The substantial cost of care for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy can be augmented by changes in practice patterns. This report discusses the recent publication of the authors' group and their thoughts on cost-conscious cancer care.

Rethinking Routine Intensive Care After Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy: The Fiscal Argument.

BACKGROUND: Patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) are frequently admitted to the intensive care unit (ICU) for mitigation of potential complications, although ICU length of stay (LOS) is a significant driver of cost. This study asked whether a fiscal argument could be made for the selective avoidance of ICU admission after CRS/HIPEC. METHODS: Prospective data for select low-risk patients (e.g., lower peritoneal cancer index [PCI]) admitted to the intermediate care unit (IMC) instead of the ICU after CRS/HIPEC were matched with a historic cohort routinely admitted to the ICU. Cohort comparisons and the impact of the intervention on cost were assessed. RESULTS: The study matched 81 CRS/HIPEC procedures to form a cohort of 49 pre- and 15 post-intervention procedures for patients with similar disease burdens (mean PCI, 8 ± 6.7 vs. 7 ± 5.1). The pre-intervention patients stayed a median of 1 day longer in the ICU (1 day [IQR, 1-1 day] vs. 0 days [IQR, 0-0 days]) and had a longer LOS (8 days [IQR, 7-11 days] vs. 6 days [IQR, 5.5-9 days]). Complications and complication severity did not differ statistically. The median total hospital cost was lower after intervention ($30,845 [IQR, $30,181-$37,725] vs. $41,477 [IQR, $33,303-$51,838]), driven by decreased indirect fixed cost ($8984 [IQR, $8643-$11,286] vs. $14,314 [IQR, $12,206-$18,266]). In a weighted multiple variable linear regression analysis, the intervention was associated with a savings of $2208.68 per patient. CONCLUSIONS: Selective admission to the IMC after CRS/HIPEC was associated with $2208.68 in savings per patient without added risk. In this era of cost-conscious practice of medicine, these data highlight an opportunity to decrease cost by more than 5% for patients undergoing CRS/HIPEC.

Chronic jetlag-induced alterations in pancreatic diurnal gene expression.

Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shift work, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking. Herein, we report an evaluation of the diurnal variations encountered in the pancreatic transcriptome following exposure to an established chronic jetlag protocol. We found approximately 5.4% of the pancreatic transcriptome was rhythmic. Following chronic jetlag, we found the number of rhythmic transcripts decreased to approximately 3.6% of the transcriptome. Analysis of the core clock genes, which orchestrate circadian physiology, revealed that nearly all exhibited a shift in the timing of peak gene expression-known as a phase shift. Similarly, over 95% of the rhythmically expressed genes in the pancreatic transcriptome exhibited a phase shift, many of which were found to be important for metabolism. Evaluation of the genes involved in pancreatic exocrine secretion and insulin signaling revealed many pancreas-specific genes were also rhythmically expressed and several displayed a concomitant phase shift with chronic jetlag. Phase differences were found 9 days after normalization, indicating a persistent failure to reentrain to the new light-dark cycle. This study is the first to evaluate the endogenous pancreatic clock and rhythmic gene expression in whole pancreas over 48 h, and how the external perturbation of chronic jetlag affects the rhythmic expression of genes in the pancreatic transcriptome.

Renal Function After Retroperitoneal Sarcoma Resection with Nephrectomy: A Matched Analysis of the United States Sarcoma Collaborative Database.

BACKGROUND: Nephrectomy often is required during en bloc resection of a retroperitoneal sarcoma (RPS) to achieve an R0 or R1 resection. The impact of nephrectomy on postoperative renal function in this patient population, who also may benefit from subsequent nephrotoxic systemic therapy, is not well described. METHODS: The United States Sarcoma Collaborative (USSC) database was queried for patients undergoing RPS resection between 2000 and 2016. Patients with missing pre- or postoperative measures of renal function were excluded. A matched cohort was created using coarsened exact matching. Weighted logistic regression was used to control further for differences between the nephrectomy and non-nephrectomy cohorts. The primary outcomes were postoperative acute kidney injury (AKI), acute renal failure (ARF), and dialysis. RESULTS: The initial cohort consisted of 858 patients, 3 (0.3%) of whom required postoperative dialysis. The matched cohort consisted of 411 patients, 108 (26%) of whom underwent nephrectomy. The patients who underwent nephrectomy had higher rates of postoperative AKI (14.8% vs 4.3%; p < 0.01) and ARF (4.6% vs 1.3%; p = 0.04), but no patients required dialysis postoperatively. Logistic regression modeling showed that the risk of AKI (odds ratio [OR], 5.16; p < 0.01) and ARF (OR 5.04; p < 0.01) after nephrectomy persisted despite controlling for age and preoperative renal function. CONCLUSIONS: Nephrectomy is associated with an increased risk of postoperative AKI and ARF after RPS resection. This study was unable to statistically assess the impact of nephrectomy on postoperative dialysis, but the risk of postoperative dialysis is 0.5% or less regardless of nephrectomy status.

Sentinel lymph node biopsy is associated with increased cost in higher risk thin melanoma.

INTRODUCTION: National Comprehensive Cancer Network guidelines recommend that sentinel lymph node biopsy (SLNB) be discussed with patients with thin melanoma at higher risk for lymph node metastasis (T1b or T1a with positive deep margins, lymphovascular invasion, or high mitotic index). We examined the association between SLNB and resource utilization in this cohort. METHODS: We conducted a retrospective cohort study of patients that underwent wide local excision for higher risk thin melanomas from 2009 to 2018 at a tertiary care center. Patients who underwent SLNB were compared to those who did not undergo SLNB with regard to resource utilization, including total hospital cost. RESULTS: A total of 70 patients were included in the analysis and 50 patients (71.4%) underwent SLNB. SLNB was associated with increased hospital costs ($6700 vs. $3767; p < .01) and increased operative time (68.5 vs. 36.0 min; p < .01). This cost difference persisted in multivariable regression (p < .01). Of patients who underwent successful SLN mapping, 3 out of 49 patients had a positive SLN (6.1%). The cost to identify a single positive sentinel lymph node (SLN) was $47,906. CONCLUSION: In patients with a higher risk of thin melanoma, SLNB is associated with increased cost despite a low likelihood of SLN positivity. These data better inform patient-provider discussions as the role of SLNB in thin melanoma evolves.

What Drives High Costs of Cytoreductive Surgery and HIPEC: Patient, Provider or Tumor?

INTRODUCTION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is utilized for peritoneal malignancies and is associated with significant resource use. To address potentially modifiable factors contributing to excessive cost, we sought to determine predictors of high cost of care for patients undergoing CRS/HIPEC. METHODS: An institutional CRS/HIPEC database was queried for adult patients from 2014 to 2018. Cost was defined as cost for the index hospitalization, and high-cost cases were defined as > 75th percentile for cost. Bivariate analyses for cost were performed, and all significant tumor, patient, and surgeon-specific variables were entered in a linear regression for cost. A separate linear regression was performed for length of stay (LOS). RESULTS: In total, 59 patients underwent 61 CRS/HIPEC procedures. The median direct variable cost was $20,509 (16,395-25,240). Median length of stay (LOS) was 8 (7-11.5) days and ICU stay was 1 (1-1.5) day. LOS, length of ICU stay and operative time were predictive of cost. Factors associated with increased LOS were Clavien-Dindo grade II complications and ostomy creation. Patient-related factors, including age and BMI, tumor-related factors, such as PCI and CCR, and surgeon were not predictive of cost nor LOS. DISCUSSION: Our results, the first to identify predictors of high cost of CRS/HIPEC-related care in the US, reveal cost was largely related to length and intensity of care. In turn, these drivers were influenced by complications and operative factors. Future work will focus on identifying an appropriate ERAS protocol following CRS/HIPEC and selection of those patients that may avoid routine ICU admission.

Operative Delay in Adults with Appendicitis: Time is Money.

BACKGROUND: Evidence suggests that operative delay of up to 24 h is not associated with adverse outcomes among patients undergoing emergent appendectomy. However, the fiscal implication of operative delay is not well described in adults. We sought to examine the effect of delayed appendectomy on clinical outcomes and hospital cost. METHODS: We conducted a retrospective cohort study of patients undergoing nonelective laparoscopic appendectomy from 2014 to 2018 at both a tertiary care center and an affiliated short-stay hospital. Using a unique data set constructed from merged electronic health record and patient-level hospital financial data, patients with delayed surgery, defined as >12 h from emergency department (ED) arrival to operation, were compared with patients who underwent surgery within 12 h. Patient-specific variables were analyzed for their association with resource utilization, and subsequent multivariable linear regression was performed for total hospital cost. RESULTS: 1372 patients underwent laparoscopic appendectomy during the study period. 938 patients (68.3%) underwent surgery within 12 h of ED arrival, and 434 patients (31.6%) underwent delayed surgery. Delayed cases had longer length of stay (44.6 ± 42.5 versus 34.5 ± 36.5 h, P < 0.01) and increased total hospital cost ($9326 ± 4691 versus $8440 ± 3404, P < 0.01). The cost difference persisted on multivariable analysis (P < 0.01). There were no significant differences between delayed cases and nondelayed cases for operative time, intraoperative findings, including rate of perforation, or postoperative complications. CONCLUSIONS: Although safe, delayed appendectomy is associated with an increased length of stay and increased total hospital costs compared with appendectomy within 12 h of reaching the ED.

PLR and NLR Are Poor Predictors of Survival Outcomes in Sarcomas: A New Perspective From the USSC.

BACKGROUND: Elevations in inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR), are reportedly associated with decreased overall survival (OS) or recurrence-free survival (RFS) in patients with numerous cancers. A large multicenter sarcoma data set was used to determine if elevated NLR or PLR was associated with worse survival and can guide treatment selection. MATERIALS AND METHODS: A total of 409 patients with a primary retroperitoneal sarcoma (n = 268) or truncal (n = 141) sarcoma from 2000 to 2015 were analyzed using the US Sarcoma Collaboration database. Binary NLR and PLR values were developed using receiver operating characteristic curves. Kaplan-Meier model and Cox proportional hazards model identified predictors of decreased OS and RFS. Point biserial analyses were used to correlate binary and continuous data. RESULTS: Neither elevated NLR nor PLR was predictive of decreased OS or RFS. These findings persisted despite exclusion of comorbid inflammatory conditions. Further, NLR and PLR were not correlated with tumor grade. In multivariate models, decreased RFS was associated with tumor factors (e.g., positive margins, tumor grade, tumor size, necrosis, positive nodes); decreased OS was associated with histologic subtype, male gender, and nodal involvement. CONCLUSIONS: Although several small studies have suggested that elevated NLR and PLR are associated with decreased survival in patients with abdominal or truncal sarcoma, this large multicenter study demonstrates no association with decreased OS, decreased RFS, or tumor grade. Rather, survival outcomes are best predicted using previously established tumoral factors.

Retroperitoneal sarcoma perioperative risk stratification: A United States Sarcoma Collaborative evaluation of the ACS-NSQIP risk calculator.

BACKGROUND: The ACS-NSQIP risk calculator predicts perioperative risk. This study tested the calculator's ability to predict risk for outcomes following retroperitoneal sarcoma (RPS) resection. METHODS: The United States Sarcoma Collaborative database was queried for adults who underwent RPS resection. Estimated risk for outcomes was calculated twice in the risk calculator, once using sarcoma-specific CPT codes and once using codes indicative of most comorbid organ resection (eg nephrectomy). ROC curves were generated, with area under the curve (AUC) and Brier scores reported to assess discrimination and calibration. An AUC < 0.6 was considered ineffective discrimination. A negative ▲ Brier indicated improved performance relative to baseline outcome rates. RESULTS: In total, 482 patients were identified with a 42.3% 90-day complication rate. Discrimination was poor for all outcomes except "all complications" and "renal failure." Baseline outcome rates were better predictors than calculator estimates except for "discharge to nursing or rehab facility" and "renal failure." Replacing sarcoma-specific CPT codes with resection-specific codes did not improve performance. CONCLUSION: The ACS-NSQIP risk calculator poorly predicted outcomes following RPS resection. Changing sarcoma-specific CPT to resection-specific codes did not improve performance. Comorbidities in the calculator may not effectively capture perioperative risk. Future work should evaluate a sarcoma-specific calculator.

Sphincter of Oddi Dysfunction After Gastric Bypass: Surgical or Endoscopic Therapy?

BACKGROUND: Management of Sphincter of Oddi Dysfunction (SOD) requires advanced techniques (endoscopic retrograde cholangiopancreatography via gastrostomy [GERCP]) after Roux-en-Y gastric bypass (RYGB) for obesity. Transduodenal sphincteroplasty (TS) is also performed yet carries the risks of surgery. We hypothesized that TS would have increased morbidity and mortality but provide a more durable remission of symptoms. METHODS: All patients between 2005 and 2016 with RYGB for obesity undergoing endoscopic or surgical management for type I or II SOD were included in the study. Patients with type III SOD, or who underwent RYGB for nonobesity indications, were excluded. RESULTS: Thirty-eight patients were identified. GERCP was initially performed in 17 patients, whereas TS was performed in 21. Thirty-day mortality was 0% in our cohort, and 30-d morbidity was similar between GERCP and TS (29% versus 10%; P = 0.207). Resolution of symptoms after initial therapy was seen in 41% of GERCP (7/17) and 67% of TS (14/21) (P = 0.190), respectively, and overall after 35% (8/23) and 64% (16/24) of procedures performed (P = 0.042). Symptom resolution, as defined by the median ratio of days of total remission by total days of observed follow-up, was shorter after initial and all interventions with GERCP compared with TS (0.67 versus 1.00, P = 0.036 and 0.52 versus 1.00, P = 0.028, respectively). CONCLUSIONS: Endoscopic and surgical treatment of SOD had similar morbidity and mortality. However, treatment success and duration of remission was higher in those treated with surgery.

Role of radiation therapy for retroperitoneal sarcomas: An eight-institution study from the US Sarcoma Collaborative.

BACKGROUND: The use of radiation therapy in the treatment of retroperitoneal sarcomas has increased in recent years. Its impact on survival and recurrence is unclear. METHODS: A retrospective propensity score matched (PSM) analysis of patients with primary retroperitoneal soft tissue sarcomas, who underwent resection from 2000 to 2016 at eight institutions of the US Sarcoma Collaborative, was performed. Patients with metastatic disease, desmoid tumors, and palliative resections were excluded. RESULTS: Total 425 patients were included, 56 in the neoadjuvant radiation group (neo-RT), 75 in the adjuvant radiation group (adj-RT), and 294 in the no radiotherapy group (no-RT). Median age was 59.5 years, 186 (43.8%) were male with a median follow up of 31.4 months. R0 and R1 resection was achieved in 253 (61.1%) and 143 (34.5%), respectively. Overall 1:1 match of 46 adj-RT and 59 neo-RT patients was performed using histology, sex, age, race, functional status, tumor size, grade, resection status, and chemotherapy. Unadjusted recurrence-free survival (RFS) was 35.9 months (no-RT) vs 33.5 months (neo-RT) and 27.2 months (adj-RT), P = .43 and P = .84, respectively. In the PSM, RFS was 17.6 months (no-RT) vs 33.9 months (neo-RT), P = .28 and 19 months (no-RT) vs 27.2 months (adj-RT), P = .1. CONCLUSIONS: Use of radiotherapy, both in adjuvent or neoadjuvent setting, was not associated with improved survival or reduced recurrence rate.

Indication for en bloc pancreatectomy with colectomy: when is it safe?

INTRODUCTION: Aggressive en bloc resection of adjacent organs is often necessary to resect pancreatic or colonic lesions. However, it is debated whether simultaneous pancreatectomy with colectomy (P+C) is warranted as it potentially increases morbidity and mortality (MM). We hypothesized that MM would be increased in P+C, especially in cases of pancreatitis. METHODS: All patients who underwent pancreatectomy (P) and simultaneous pancreatectomy with colectomy (P+C) at a high-volume center from November 2006 to 2015 were prospectively collected using ACS-NSQIP at our institution. Patients with additional multivisceral or enucleation procedures were excluded. Data were augmented to 90-day outcomes using our institutional database. RESULTS: Forty-three patients with a mean age of 62 years (27:16 male: female) underwent P+C, accounting for 2.39% (43/1797) of pancreatectomies performed. Pancreatoduodenectomy (PD) was performed in 61% (n = 26), distal pancreatectomy (DP) in 37% (n = 16), and total pancreatectomy (TP) in 2% (n = 1) of patients. The 30- and 90-day MM were higher in P+C than P (30-day: 54 vs. 37%, p = 0.037 and 9 vs. 2%, p = 0.022; 90-day: 61 vs. 42%, p = 0.019 and 14 vs. 3%, p = 0.002). Logistical regression modeling revealed an association between 90-day mortality and colectomy (p = 0.013, OR = 3.556). When P+C MM were analyzed according to intraoperative factors, there was no significant difference according to type of pancreatectomy (PD vs. DP vs. TP), origin of primary lesion (pancreas vs. colon), surgical indication (malignant vs. non-malignant), or case status (planned colectomy vs. intraoperative decision). CONCLUSIONS: Addition of colectomy to pancreatectomy substantially increased MM. Subanalysis revealed that type of resection performed, etiology, and planning status did not account for increased risk when performing P+C. However, colectomy was found to be an independent risk factor for mortality. Therefore, patients should be informed of the risk of increased postoperative complications until a further study can identify potential patients or perioperative factors that can be used for risk stratification.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutant Kras-driven pancreatic cancer model.

OBJECTIVES: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers, and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC pre-cancerous lesions in vivo. METHODS: We created a global AHR-null, mutant Kras-driven PDAC mouse model (A-/-KC) and evaluated the changes in PDAC precursor lesion formation (Pan-IN 1, 2, and 3) and associated fibro-inflammation between KC and A-/-KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS: We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A-/-KC vs KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSION: These findings show the loss of AHR results in heightened Kras-induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.