Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study.

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial.

PURPOSE: This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS: We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS: Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 (nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 (nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent (nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION: The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Use of Transcarotid Artery Revascularization, Transfemoral Carotid Artery Stenting, and Carotid Endarterectomy in the US From 2015 to 2019.

Importance: A transcarotid artery revascularization (TCAR) device was approved by the US Food and Drug Administration in 2015 for carotid revascularization in patients at high risk for stroke, cranial nerve injury, or major cardiac event. It is unclear how the introduction of TCAR has changed the use of carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS). Objective: To quantify the temporal changes in the operative approach to carotid revascularization (CEA vs TFCAS vs TCAR), and to identify patient and disease characteristics commonly associated with each approach. Design, Setting, and Participants: This retrospective cohort study obtained data from the Vascular Quality Initiative database from January 1, 2015, to December 31, 2019. Patients with carotid artery stenosis who underwent CEA, TFCAS, or TCAR were included. Data were analyzed from January to April 2022. Exposures: Month and year of surgery as well as patient risk status. Main Outcomes and Measures: Number and proportion of carotid revascularization procedures by operative approach. Results: A total of 108 676 patients (mean [SD] age 56.6 [12.5] years; 66 684 men [61.4%]) were included in the analysis. The most common operative approach overall was CEA (n = 81 508 [75.0%]), followed by TFCAS (n = 15 578 [14.3%]) and TCAR (n = 11 590 [10.7%]). The number of procedures increased over the study period (16 754 in 2015 vs 27 269 in 2019; P < .001). In 2015, CEA was used in 84.9% of all cases, followed by TFCAS (14.4%) and TCAR (0.8%). In 2019, CEA was used in 64.8% of cases, followed by TCAR (21.9%) and TFCAS (13.3%). The proportional use of CEA decreased by 5.0% (95% CI, -7.4% to -2.6%) per year, and TCAR use increased by 5.3% (95% CI, 2.3%-8.3%) per year. Among patients at high risk, the change was greater: CEA use decreased by 7.8% (95% CI, -11.9% to -3.8%) per year, TFCAS decreased by 4.8% (95% CI, -9.5% to -0.14%) per year, and TCAR increased by 12.6% (95% CI, 7.1%-18.1%) per year. Multinomial logistic regression showed that patient risk status was the most important characteristic associated with TCAR compared with CEA (relative risk ratio, 36.10; 95% CI, 29.24-44.66; P < .001) and TFCAS (relative risk ratio, 14.10; 95% CI, 11.86-16.66; P < .001). Linear regression revealed no association between year of surgery and in-hospital myocardial infarction, stroke, or mortality. Conclusions and Relevance: Results of this study indicate that TCAR has become the dominant carotid revascularization approach, surpassing TFCAS and CEA in patients at high risk for stroke, cranial nerve injury, or cardiovascular events. Patient high-risk status was the main characteristic associated with a stenting approach, highlighting the perceived importance of carotid stenting therapies in this patient population.

Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells.

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence. Here, we evaluate the therapeutic effect of CO on metastatic cancer progression. We show that 250 ppm CO inhibits the migration of multiple types of cancer cell lines, including breast, pancreatic, colon, prostate, liver, and lung cancer and reduces the ability to adhere to fibronectin. We demonstrate that in mouse models, 250 ppm inhaled CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer. Moreover, low-dose CO suppresses recurrence and increases survival after surgical removal of primary pancreatic cancer in mice. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Taken together, low-dose CO therapy inhibits cell migration, reduces adhesion to fibronectin, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis.

Neutralizing antibodies to SARS-CoV-2 variants of concern including Delta and Omicron in subjects receiving mRNA-1273, BNT162b2, and Ad26.COV2.S vaccines.

SARS-CoV-2 vaccines have contributed to the control of COVID-19 in some parts of the world. However, the constant emergence of variants of concern (VOCs) challenges the effectiveness of SARS-CoV-2 vaccines over time. In particular, Omicron contains a high number of mutations in the spike (S) protein gene, on which most vaccines were developed. In this study, we quantitated neutralizing antibodies in vaccine recipients at various times postvaccination using S protein-based pseudoviruses derived from wild type (WT) SARS-CoV-2 and five VOCs including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). We found that two-dose mRNA-1273 and BNT162b2 vaccines elicited robust neutralizing antibodies against WT, Alpha, Beta, Gamma, and Delta, but wanned after 6 months with a faster decline observed for BNT162b2. Both mRNA-1273 and BNT162b2 elicited weak neutralizing antibodies against Omicron. One dose of Ad26.COV2.S vaccine induced weaker neutralizing antibodies against WT and most VOCs than mRNA-1273 and BNT162b2 did but moderate neutralizing antibodies against Delta and Omicron, which lasted for 6 months. These results support current recommendations of the Centers for Disease Control and Prevention for a booster 5 months after full immunization with an mRNA-based vaccine and the use of an mRNA-based vaccine 2 months after Ad26.COV2.S vaccination.

HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations.

The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.

Transcarotid artery revascularization is associated with similar outcomes to carotid endarterectomy regardless of patient risk status.

BACKGROUND: Carotid artery stenting (CAS), including both transfemoral carotid artery stenting (TFCAS) and transcarotid artery revascularization (TCAR), reimbursement has been limited to high-risk patients by the Centers for Medicare & Medicaid Services (CMS) since 2005. We aimed to assess the association of CMS high-risk status with perioperative outcomes for carotid endarterectomy (CEA), TFCAS, and TCAR. METHODS: We performed a retrospective review of all Vascular Quality Initiative patients who underwent carotid revascularization between 2015 and 2020. Patients were stratified by whether they met CMS CAS criteria, and univariable and multivariable logistic regression analyses were performed to assess the association of procedure type (CEA, TFCAS, TCAR) with perioperative outcomes. RESULTS: Of 124,531 individuals who underwent carotid revascularization procedures, 91,687 (73.6%) underwent CEA, 17,247 (13.9%) underwent TFCAS, and 15,597 (12.5%) underwent TCAR. Among patients who met the CMS CAS criteria (ie, high-risk patients), the incidence of perioperative stroke was 2.7% for CEA, 3.4% for TFCAS, and 2.4% for TCAR (P < .001). Among standard-risk patients, the incidence of perioperative stroke was 1.7% for CEA, 2.7% for TFCAS, and 1.8% for TCAR (P < .001). After adjusting for baseline demographic and clinical characteristics, the odds of perioperative stroke were lower for TCAR versus CEA in high-risk patients (adjusted odds ratio [aOR], 0.82; 95% confidence interval [CI], 0.68-0.99) and similar in standard-risk patients (aOR, 1.05; 95% CI, 0.84, 1.31). In contrast, the adjusted odds of perioperative stroke were higher for TFCAS versus CEA in high-risk patients (aOR, 1.23; 95% CI, 1.03-1.46) and standard-risk patients (aOR, 1.60; 95% CI, 1.37-1.86). In both populations, TFCAS and TCAR patients had significantly lower odds of myocardial infarction than CEA patients (both P < .001). CONCLUSIONS: The perioperative risks associated with CEA, TFCAS, and TCAR in high-risk patients support the current CMS criteria, although the risks associated with each revascularization approach in standard-risk patients suggest that distinguishing TCAR from TFCAS may be warranted.

Preoperative Opioid Dose and Surgical Outcomes in Colorectal Surgery.

BACKGROUND: The worsening opioid epidemic has led to an increased number of surgical patients with chronic preoperative opioid use. However, the impact of opioids on perioperative outcomes has yet to be fully elucidated. The purpose of this study was to assess the association between preoperative opioid dose and surgical outcomes among colectomy patients. METHODS: Adult colectomy patients in the IBM MarketScan database (2010-2017) were stratified based on preoperative opioid dose, calculated as the average opioid dose in morphine milligram equivalents (MME) in the 90 days prior to surgery: 0 MME, 1 to 49 MME, and 50 or more MME. The association between preoperative opioid dose and anastomotic leak, the primary outcome of interest, as well as other postoperative complications, was assessed using multivariable regression. RESULTS: Among 45,515 adult colectomy patients, 71.4% did not use opioids (0 MME), 27.4% had an opioid dose between 1 and 49 MME, and 1.2% had an opioid dose at or above 50 MME. Patients with preoperative opioid use exhibited a higher incidence of anastomotic leak (0 MME: 4.8%, 1-49 MME: 5.5%, ≥50 MME: 8.3%; p trend = 0.001). Multivariable analysis demonstrated a dose-response relationship between preoperative opioids and surgical outcomes, as the odds of anastomotic leak worsened with increasing opioid dose (1-49 MME: OR 1.19, 95% CI 1.08-1.31, p < 0.001; ≥50 MME: OR 1.64, 95% CI 1.20-2.24, p = 0.002). Similar dose-response relationships were seen after risk-adjustment for lung complications, pneumonia, delirium, and 30-day readmission (p < 0.05 for all). CONCLUSIONS: Providers should exercise caution when prescribing opioids preoperatively, as increasing doses of preoperative opioids were associated with worse surgical outcomes and higher 30-day readmission among adult colectomy patients.

Association of preoperative vein mapping with hemodialysis access characteristics and outcomes in the Vascular Quality Initiative.

BACKGROUND: Preoperative vein mapping before arteriovenous fistula (AVF) or arteriovenous graft (AVG) placement has been debated as a possible method of improving hemodialysis access outcomes for patients. However, high-quality national studies that have addressed this relationship are lacking. Thus, we assessed the association of preoperative vein mapping with hemodialysis access configuration and outcomes. METHODS: In the present cohort study, we analyzed all patients who had undergone AVF or AVG placement with data captured in the Vascular Quality Initiative hemodialysis access dataset from August 2011 to September 2019. The patients were stratified by whether they had undergone preoperative vein mapping. The primary (configuration) outcomes were access type (AVF vs AVG) and location (upper arm vs forearm). The secondary (longitudinal) outcomes were the successful initiation of hemodialysis, maintenance of secondary patency, and the need for reintervention 1 year after the index operation. RESULTS: Overall, 85.6% of the 46,010 included patients had undergone preoperative vein mapping. Of the 46,010 patients, 76.1% and 23.9% had undergone AVF and AVG creation, respectively. AVF creation (77.6% vs 67.3%) and forearm location (54.6% vs 47.3%) were more frequent for the patients who had undergone preoperative vein mapping than for those who had not (P < .001). After adjusting for baseline differences between the groups, preoperative vein mapping was associated with increased odds of receiving an AVF vs AVG (adjusted odds ratio, 1.64; 95% confidence interval [CI], 1.55-1.75) and forearm vs upper arm access (adjusted odds ratio, 1.22; 95% CI, 1.16-1.30). The incidence of the loss of secondary patency was lower for patients with preoperative vein mapping (P < .001), and persisted after risk adjustment (adjusted hazard ratio, 0.81; 95% CI, 0.75-0.88). CONCLUSIONS: Preoperative vein mapping was associated with favorable hemodialysis access configurations and outcomes in real-world practice. These data suggest that the use of preoperative vein mapping could improve the likelihood of favorable outcomes for patients requiring hemodialysis access.

Converting laparoscopic colectomies to open is associated with similar outcomes as a planned open approach among Crohn's disease patients.

PURPOSE: There has been a noted reluctance to offer laparoscopic surgery to Crohn's Disease patients due to the potential risks, and high rate, of converting the procedure to open. The purpose of this study was to compare clinical outcomes between Crohn's Disease patients undergoing a planned open colectomy, to those undergoing a laparoscopic colectomy that was converted to open. METHODS: Crohn's Disease patients undergoing an elective colectomy were identified using the ACS-NSQIP database (2012-2019). Patients were stratified based on operative approach: open, laparoscopic, and laparoscopic converted to open. Multivariable logistic regression was used to assess the impact of conversion to open on overall and serious postoperative morbidity. RESULTS: Among 8039 elective colectomies, 40.5% were performed open, 46.9% were completed laparoscopically, and 12.6% were converted to open. The conversion rate among all laparoscopic cases was 21.3%. On unadjusted analysis, conversion to open demonstrated similar rates of overall morbidity (P = 0.355) and serious morbidity (P = 0.724) compared to a planned open approach. On multivariable analysis, conversion to open was not associated with increased odds of overall morbidity (OR 1.12, 95% CI 0.94-1.30, P = 0.238) or serious morbidity (OR 1.20, 95% CI 0.98-1.46, P = 0.074), when compared to an open approach. CONCLUSION: Among Crohn's Disease patients, cases converted from laparoscopic to open exhibited similar outcomes as a planned open approach. Despite the limitations associated with this retrospective study, our findings suggest that laparoscopic surgery may be safely pursued among Crohn's Disease patients, as the risks of conversion are potentially balanced by the benefits of laparoscopic surgery.

Image-guided spinal injection for pain management.

Radiculopathy and spinal pain are debilitating conditions affecting millions of people worldwide each year. While most cases can be managed conservatively with physiotherapy and nonsteroidal anti-inflammatory medications, minimally invasive corticosteroid injections are the mainstay intervention for those not responsive to conservative treatment. Historically, spinal injections were performed in the absence of imaging guidance; however, imaging modalities, in particular fluoroscopy and computer tomography (CT), have become the standard of care in performing most of these procedures. Under imaging guidance, operators can accurately confirm needle placement and safely target localised pathologies.

Operative Approach Does Not Impact Radial Margin Positivity in Distal Rectal Cancer.

BACKGROUND: Robotic surgery is attractive for resection of low rectal cancer due to greater dexterity and visualization, but its benefit is poorly understood. We aimed to determine if operative approach impacts radial margin positivity (RMP) and postoperative outcomes among patients undergoing abdominoperineal resection (APR). METHODS: This was a retrospective cohort study of patients from the National Surgical Quality Improvement Program who underwent APR for low rectal cancer from 2016 to 2019. Patients were stratified by operative approach: robotic, laparoscopic, and open APR (R-APR, L-APR, and O-APR). Emergent cases were excluded. The primary outcome was RMP. 30-day postoperative outcomes were also evaluated, using logistic regression analysis. RESULTS: Among 1,807 patients, 452 (25.0%) underwent R-APR, 474 (26.2%) L-APR, and 881 (48.8%) O-APR. No differences regarding RMP (13.5% R-APR vs. 10.8% L-APR vs. 12.3% O-APR, p = 0.44), distal margin positivity, positive nodes, readmission, or operative time were observed between operative approaches. Adjusted analysis confirmed that operative approach did not predict RMP (p > 0.05 for all). Risk factors for RMP included American Society of Anesthesiologists (ASA) classification III (ASA I-II ref; OR 1.46, p = 0.039), pT3-4 stage (T0-2 ref, OR 4.02, p < 0.001), pN2 stage (OR 1.98, p = 0.004), disseminated cancer (OR 1.90, p = 0.002), and lack of preoperative radiation (OR 1.98, p < 0.01). CONCLUSIONS: No difference in RMP was observed among R-APR, L-APR, and O-APR. Postoperatively, R-APR yielded greater benefit when compared to O-APR, but was comparable to that of L-APR. Minimally invasive surgery may be an appropriate option and worthy consideration for patients with distal rectal cancer requiring APR.

History of depression is associated with worsened postoperative outcomes following colectomy.

AIM: Depression is a prevalent disorder that is associated with adverse health outcomes, but an understanding of its effect in colorectal surgery remains limited. The purpose of this study was to examine the impact of history of depression among patients undergoing colectomy. METHOD: United States patients from Marketscan (2010-2017) who underwent colectomy were included and stratified by whether they had a history of depression within the past year, defined as (1) a diagnosis of depression during the index admission, (2) a diagnosis of depression during any inpatient or (3) outpatient admission within the year, and/or (4) a pharmacy claim for an antidepressant within the year. The primary outcomes were length of stay (LOS) and inpatient hospital charge. Secondary outcomes included in-hospital mortality and postoperative complications. Logistic, negative binomial, and quantile regressions were performed. RESULTS: Among 88 981 patients, 21 878 (24.6%) had a history of depression. Compared to those without, patients with a history of depression had significantly longer LOS (IRR = 1.06, 95% CI [1.05, 1.07]), increased inpatient charge (ß = 467, 95% CI [167, 767]), and increased odds of in-hospital mortality (OR = 1.37, 95% CI [1.08, 1.73]) after adjustment. History of depression was also independently associated with increased odds of respiratory complication, pneumonia, and delirium (all P < 0.05). CONCLUSION: History of depression was prevalent among individuals undergoing colectomy, and associated with greater mortality and inpatient charge, longer LOS, and higher odds of postoperative complication. These findings highlight the impact of depression in colorectal surgery patients and suggest that proper identification and treatment may reduce postoperative morbidity.

The reduced risk of septic shock/sepsis with laparoscopic surgery among ulcerative colitis patients with preoperative chronic steroid use.

BACKGROUND: Preoperative steroid use has been associated with worse surgical outcomes. The purpose of this study was to determine whether laparoscopic surgery reduces the risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use. METHODS: Patients with ulcerative colitis undergoing a total abdominal colectomy were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (2005-2019). Patients were stratified based on preoperative chronic steroid use and operative approach (open versus laparoscopic). The primary outcome was septic shock/sepsis. Multivariable regression models were used to assess the association between laparoscopic surgery and rates of septic shock/sepsis among steroid users and non-steroid users in both the elective and emergent settings. RESULTS: Among 8,644 patients undergoing a total abdominal colectomy, 67.1% were steroid users and 32.9% were non-steroid users. Compared with an open approach, elective laparoscopic surgery was associated with lower rates of septic shock/sepsis, albeit with higher readmission rates for both steroid users (15.1% [laparoscopic] vs 12.0% [open], P = .005) and non-steroid users (12.6% [laparoscopic] vs 9.4% [open], P = .019). On adjusted analysis, ulcerative colitis patients with chronic steroid use undergoing an elective laparoscopic total abdominal colectomy demonstrated a reduced risk of septic shock/sepsis compared to open surgery (odds ratio 0.61, 95% confidence interval 0.49-0.76, P < .001). Similar findings were seen among chronic steroid users undergoing emergent laparoscopic procedures (odds ratio 0.54, 95% confidence interval 0.31-0.95, P = .031). CONCLUSION: Laparoscopic surgery was associated with a reduced risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use, suggesting that minimally invasive surgery may be a promising option among this unique patient population.

High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer.

Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMRΔexon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMRΔexon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMRΔexon8-16 was not apparent in these short lifespan mice. In addition, HMMRΔexon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMRΔexon8-16 , which lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC), accelerated pancreatic cancer progression.