Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.

Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)-dependent covalent CXCL12-keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12-KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12-KRT19 coating, excluded T cells, and did not respond to treatment with anti-PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12-KRT19 coating, were infiltrated with activated CD8+ T cells, and growth was suppressed with anti-PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12-KRT19 coating to evade cancer immune attack.

Caregiver-reported quality of communication in pancreatic and periampullary cancer.

BACKGROUND: Communication between caregivers and clinical team members is critical for transitional care, but its quality and potential impact on outcomes are not well understood. This study reports on caregiver-reported quality of communication with clinical team members in the postpancreatectomy period and examines associations of these reports with patient and caregiver outcomes. METHODS: Caregivers of patients with pancreatic and periampullary malignancies who had undergone pancreatectomy were surveyed. Instrument measures assessed care experiences using the Caregiver Perceptions About Communication with Clinical Team Members (CAPACITY) instrument. The instrument has two main subscales: communication, assessing the extent to which providers helped caregivers comprehend details of clinical visits, and capacity, defined as the extent to which providers assessed whether caregivers were able to care for patients. RESULTS: Of 265 caregivers who were approached, 240 (90.6%) enrolled in the study. The mean communication and capacity subscale scores were 2.7 ± 0.6 and 1.5 ± 0.6, respectively (range, 0-4 [higher = better]). Communication subscale scores were lower among caregivers of patients who experienced (vs. those who did not experience) a 30-day readmission (2.6 ± 0.5 vs. 2.8 ± 0.6, respectively; p = .047). Capacity subscale scores were inversely associated with restriction in patient daily activities (a 0.04 decrement in the capacity score for every 1 point in daily activity restriction; p = .008). CONCLUSIONS: After pancreatectomy, patients with pancreatic and periampullary cancer whose caregivers reported worse communication with care providers were more likely to experience readmission. Caregivers of patients with greater daily activity restrictions were less likely to report being asked about the caregiver's skill and capacity by clinicians. PLAIN LANGUAGE SUMMARY: This prospective study used a validated survey instrument and reports on the quality of communication between health care providers and caregivers as reported by caregivers of patients with pancreatic and periampullary cancer after pancreatectomy. In an analysis of 240 caregivers enrolled in the study, lower communication scores (the extent to which providers helped caregivers understand clinical details) were associated with higher odds of 30-day patient readmission to the hospital. In addition, lower capacity scores (the extent to which providers assessed caregivers' ability to care for patients) were associated with greater impairment in caregivers. The strikingly low communication quality and capacity assessment scores suggest substantial room for improvement, with the potential to improve both caregiver and patient outcomes.

Minorities Face Delays to Pancreatic Cancer Treatment Regardless of Diagnosis Setting.

INTRODUCTION: Our analysis was designed to characterize the demographics and disparities between the diagnosis of pancreas cancer during emergency presentation (EP) and the outpatient setting (OP) and to see the impact of our institutions pancreatic multidisciplinary clinic (PMDC) on these disparities. METHODS: Institutional review board-approved retrospective review of our institutional cancer registry and PMDC databases identified patients diagnosed/treated for pancreatic ductal adenocarcinoma between 2014 and 2022. Chi-square tests were used for categorical variables, and one-way ANOVA with a Bonferroni correction was used for continuous variables. Statistical significance was set at p < 0.05. RESULTS: A total of 286 patients met inclusion criteria. Eighty-nine patients (31.1%) were underrepresented minorities (URM). Fifty-seven (64.0%) URMs presented during an EP versus 100 (50.8%) non-URMs (p = 0.037). Forty-one (46.1%) URMs were reviewed at PMDC versus 71 (36.0%) non-URMs (p = 0.10). No differences in clinical and pathologic stage between the cohorts (p = 0.28) were present. URMs took 22 days longer on average to receive treatment (66.5 days vs. 44.8 days, p = 0.003) in the EP cohort and 18 days longer in OP cohort (58.0 days vs. 40.5 days, p < 0.001) compared with non-URMs. Pancreatic Multidisciplinary Clinic enrollment in EP cohort eliminated the difference in time to treatment between cohorts (48.3 days vs. 37.0 days; p = 0.151). RESULTS: Underrepresented minorities were more likely to be diagnosed via EP and showed delayed times to treatment compared with non-URM counterparts. Our PMDC alleviated some of these observed disparities. Future studies are required to elucidate the specific factors that resulted in these findings and to identify solutions.

Organ donation after medical assistance in dying: a descriptive study from 2018 to 2022 in Quebec.

BACKGROUND: Since the implementation of medical assistance in dying (MAiD), deceased organ donation after MAiD has been possible in Quebec. We sought to describe organ donations after MAiD in the first 5 years after this practice was implemented in Quebec. METHODS: We reviewed all cases referred for donation after MAiD from January 2018 to December 2022. We presented all data descriptively with no comparison statistics. RESULTS: Transplant Québec received 245 referrals for donation after MAiD, of which 82 were retained (33.5%). Of the 163 nonretained referrals, 152 (93.2%) had a recorded reason, including 91 (55.8%) for medical unsuitability on initial screen (e.g., organ dysfunction, medical history), 34 (20.8%) for patient refusal and 21 (12.9%) instances where patients withdrew from the MAiD process entirely. Six patients died before MAiD. Eighteen of the 82 retained cases were cancelled later in the process, almost all (n = 17, 94.4%) because of medical contraindication discovered during detailed donor evaluation. Sixty-four patients became actual donors after MAiD, increasing from 8 in 2018 to 24 in 2022. The total conversion rate from referral to an actual donor was 26.1% (64/245). A total of 182 organs (116 kidneys, 20 livers and 46 lungs) were transplanted after MAiD. During the study period, MAiD donors represented 8.0% (64/803) of total deceased donors, increasing from 4.9% (8/164) in 2018 to 14.0% (24/171) in 2022. INTERPRETATION: These data describe a substantial increase in deceased donation after MAiD in the first 5 years of implementation in Quebec. Future studies should focus on how to optimize systems to ensure these requests are treated in the most ethical and medically effective way.

Pediatric Death After Withdrawal of Life-Sustaining Therapies: A Scoping Review.

OBJECTIVES: Evaluate literature on the dying process in children after withdrawal of life sustaining measures (WLSM) in the PICU. We focused on the physiology of dying, prediction of time to death, impact of time to death, and uncertainty of the dying process on families, healthcare workers, and organ donation. DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, CINAHL, and Web of Science. STUDY SELECTION: We included studies that discussed the dying process after WLSM in the PICU, with no date or study type restrictions. We excluded studies focused exclusively on adult or neonatal populations, children outside the PICU, or on organ donation or adult/pediatric studies where pediatric data could not be isolated. DATA EXTRACTION: Inductive qualitative content analysis was performed. DATA SYNTHESIS: Six thousand two hundred twenty-five studies were screened and 24 included. Results were grouped into four categories: dying process, perspectives of healthcare professionals and family, WLSM and organ donation, and recommendations for future research. Few tools exist to predict time to death after WLSM in children. Most deaths after WLSM occur within 1 hour and during this process, healthcare providers must offer support to families regarding logistics, medications, and expectations. Providers describe the unpredictability of the dying process as emotionally challenging and stressful for family members and staff; however, no reports of families discussing the impact of time to death prediction were found. The unpredictability of death after WLSM makes families less likely to pursue donation. Future research priorities include developing death prediction tools of tools, provider and parental decision-making, and interventions to improve end-of-life care. CONCLUSIONS: The dying process in children is poorly understood and understudied. This knowledge gap leaves families in a vulnerable position and the clinical team without the necessary tools to support patients, families, or themselves. Improving time to death prediction after WLSM may improve care provision and enable identification of potential organ donors.

Beliefs of physician directors on the management of devastating brain injuries at the Canadian emergency department and intensive care unit interface: a national site-level survey.

PURPOSE: Insufficient evidence-based recommendations to guide care for patients with devastating brain injuries (DBIs) leave patients vulnerable to inconsistent practice at the emergency department (ED) and intensive care unit (ICU) interface. We sought to characterize the beliefs of Canadian emergency medicine (EM) and critical care medicine (CCM) physician site directors regarding current management practices for patients with DBI. METHODS: We conducted a cross-sectional survey of EM and CCM physician directors of adult EDs and ICUs across Canada (December 2022 to March 2023). Our primary outcome was the proportion of respondents who manage (or consult on) patients with DBI in the ED. We conducted subgroup analyses to compare beliefs of EM and CCM physicians. RESULTS: Of 303 eligible respondents, we received 98 (32%) completed surveys (EM physician directors, 46; CCM physician directors, 52). Most physician directors reported participating in the decision to withdraw life-sustaining measures (WLSM) for patients with DBI in the ED (80%, n = 78), but 63% of these (n = 62) said this was infrequent. Physician directors reported that existing neuroprognostication methods are rarely sufficient to support WLSM in the ED (49%, n = 48) and believed that an ICU stay is required to improve confidence (99%, n = 97). Most (96%, n = 94) felt that providing caregiver visitation time prior to WLSM was a valid reason for ICU admission. CONCLUSION: In our survey of Canadian EM and CCM physician directors, 80% participated in WLSM in the ED for patients with DBI. Despite this, most supported ICU admission to optimize neuroprognostication and patient-centred end-of-life care, including organ donation.

RéSUMé: OBJECTIF: L'insuffisance des recommandations fondées sur des données probantes pour guider les soins aux individus atteints de lésions cérébrales dévastatrices rend ces personnes vulnérables à des pratiques incohérentes à la jonction entre le service des urgences et de l'unité de soins intensifs (USI). Nous avons cherché à caractériser les croyances des directeurs médicaux canadiens en médecine d'urgence et médecine de soins intensifs concernant les pratiques de prise en charge actuelles des personnes ayant subi une lésion cérébrale dévastatrice. MéTHODE: Nous avons réalisé un sondage transversal auprès des directeurs médicaux des urgences et des unités de soins intensifs pour adultes du Canada (décembre 2022 à mars 2023). Notre critère d'évaluation principal était la proportion de répondant·es qui prennent en charge (ou jouent un rôle de consultation auprès) des personnes atteintes de lésions cérébrales dévastatrices à l'urgence. Nous avons effectué des analyses en sous-groupes pour comparer les croyances des médecins des urgences et des soins intensifs. RéSULTATS: Sur les 303 personnes répondantes admissibles, 98 (32 %) ont répondu aux sondages (directions médicales des urgences, 46; directions médicales d'USI, 52). La plupart des directeurs médicaux ont déclaré avoir participé à la décision de retirer des traitements de maintien des fonctions vitales (TFMV) pour des patient·es atteint·es de lésions cérébrales dévastatrices à l'urgence (80 %, n = 78), mais 63 % (n = 62) ont déclaré que c'était peu fréquent. Les directions médicales ont indiqué que les méthodes de neuropronostic existantes sont rarement suffisantes pour appuyer le retrait des TMFV à l'urgence (49 %, n = 48) et croyaient qu'un séjour aux soins intensifs était nécessaire pour améliorer leur confiance en ces méthodes (99 %, n = 97). La plupart (96 %, n = 94) estimaient que le fait d'offrir du temps de visite aux personnes soignantes avant le retrait des TMFV était un motif valable d'admission aux soins intensifs. CONCLUSION: Dans le cadre de notre sondage mené auprès des directions médicales des services d'urgence et des USI au Canada, 80 % d'entre elles ont participé au retrait de TMFV à l'urgence pour des patient·es souffrant de lésions cérébrales dévastatrices. Malgré cela, la plupart d'entre elles étaient en faveur d'une admission aux soins intensifs afin d'optimiser le neuropronostic et les soins de fin de vie axés sur les patient·es, y compris le don d'organes.

Inequities in organ and tissue donation and transplantation for sexual orientation and gender identity diverse people: A scoping review.

Sexual orientation and gender identity (SOGI)-diverse populations experience discrimination in organ and tissue donation and transplantation (OTDT) systems globally. We assembled a multidisciplinary group of clinical experts as well as SOGI-diverse patient and public partners and conducted a scoping review including citations on the experiences of SOGI-diverse persons in OTDT systems globally to identify and explore the inequities that exist with regards to living and deceased OTDT. Using scoping review methods, we conducted a systematic literature search of relevant electronic databases from 1970 to 2021 including a grey literature search. We identified and screened 2402 references and included 87 unique publications. Two researchers independently coded data in included publications in duplicate. We conducted a best-fit framework synthesis paired with an inductive thematic analysis to identify synthesized benefits, harms, inequities, justification of inequities, recommendations to mitigate inequities, laws and regulations, as well as knowledge and implementation gaps regarding SOGI-diverse identities in OTDT systems. We identified numerous harms and inequities for SOGI-diverse populations in OTDT systems. There were no published benefits of SOGI-diverse identities in OTDT systems. We summarized recommendations for the promotion of equity for SOGI-diverse populations and identified gaps that can serve as targets for action moving forward.

Performance of the 7 th and 8 th Editions of the American Joint Committee on Cancer Staging System in Patients with Intraductal Papillary Mucinous Neoplasm-Associated PDAC : A Multi-institutional Analysis.

OBJECTIVE: To validate the 7 th and 8 th editions of the AJCC staging system for patients with invasive carcinomas arising in association with IPMN (IPMN-associated PDAC). BACKGROUND DATA: Although several studies have validated AJCC systems in patients with conventional PDAC, their applicability to IPMN-associated PDAC has not been assessed. METHODS: Two hundred seventy-five patients who underwent resection for IPMN-associated PDAC between 1996 and 2015 at 3 tertiary centers and had data on the size of the invasive component and lymph node status were identified. Concordance probability estimates (CPE) were calculated and recursive partitioning analysis was employed to identify optimal prognostic cutoffs for T and N. RESULTS: The CPE for the 7 th and 8 th editions of the AJCC schema were relatively good (0.64 for both) and similar for colloid and tubular subtypes (0.64 for both). The 8 th edition introduced T1a sub-staging and a new distinction between N1 and N2. The utility of the former was confirmed, although the latter did not improve prognostic discrimination. The successful validation of the 8th edition of the AJCC criteria in patients with tubular and colloid subtypes allowed us to compare these patients in early vs late T and N stages which showed that with advanced disease, the prognostic superiority of colloid tumors over their tubular counterparts diminishes. CONCLUSIONS: Our findings support the use of the AJCC 8 th edition in the IPMN-associated PDAC population, but suggest that certain cutoffs may need to be revisited. In advanced AJCC stages, patients with colloid vs tubular subtypes have comparable prognosis.

Grading Pancreatic Neuroendocrine Tumors Via Endoscopic Ultrasound-guided Fine Needle Aspiration: A Multi-institutional Study.

OBJECTIVES: To identify factors associated with concordance between World Health Organization (WHO) grade on cytological analysis (c-grade) and histopathological analysis (h-grade) of surgical specimen in patients with PanNETs and examine trends in utilization and accuracy of EUS-FNA in preoperatively predicting grade. BACKGROUND: WHO grading system is prognostic in pancreatic neuroendo-crine tumors (PanNETs). The concordance between c-grade and h-grade is reported to be between 50% and 92%. METHODS: A multicenter retrospective study was performed on patients undergoing resection for PanNETs at four high-volume centers between 2010 and 2019. Patients with functional or syndrome-associated tumors, and those receiving neoadjuvant therapy were excluded. Factors associated with concordance between c-grade and h-grade and trends of utilization of EUS-FNA were assessed. RESULTS: Of 869 patients included, 517 (59.5%) underwent EUS-FNA; 452 (87.4%) were diagnostic of PanNETs and WHO-grade was reported for 270 (59.7%) patients. The concordance between c-grade and h-grade was 80.4% with moderate concordance ( Kc = 0.52, 95% CI: 0.41-0.63). Significantly higher rates of concordance were observed in patients with smaller tumors (<2 vs. ≥2cm, 81.1% vs. 60.4%, P = 0.005). Highest concordance (98.1%) was observed in patients with small tumors undergoing assessment between 2015-2019 with a near-perfect concordance ( Kc = 0.88, 95% CI: 0.61-1.00). An increase in the utilization of EUS-FNA (56.1% to 64.1%) was observed over the last 2 decades ( P = 0.017) and WHO-grade was more frequently reported (44.2% vs. 77.6%, P < 0.001). However, concordance between c-grade and h-grade did not change significantly (P = 0.118). CONCLUSION: Recently, a trend towards increasing utilization and improved diagnostic accuracy of EUS-FNA has been observed in PanNETs. Concordance between c-grade and h-grade is associated with tumor size with near-perfect agreement when assessing PanNETs <2cm in size.

Demystifying BRAF Mutation Status in Colorectal Liver Metastases : A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions.

OBJECTIVE: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs). BACKGROUND: The clinical implications of mut BRAF status in CRLMs are largely unknown. METHODS: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. RESULTS: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis. CONCLUSIONS: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.

Death determination by neurologic criteria-what do families understand?

PURPOSE: Currently, there is little empirical data on family understanding about brain death and death determination. The purpose of this study was to describe family members' (FMs') understanding of brain death and the process of determining death in the context of organ donation in Canadian intensive care units (ICUs). METHODS: We conducted a qualitative study using semistructured, in-depth interviews with FMs who were asked to make an organ donation decision on behalf of adult or pediatric patients with death determination by neurologic criteria (DNC) in Canadian ICUs. RESULTS: From interviews with 179 FMs, six main themes emerged: 1) state of mind, 2) communication, 3) DNC may be counterintuitive, 4) preparation for the DNC clinical assessment, 5) DNC clinical assessment, and 6) time of death. Recommendations on how clinicians can help FMs to understand and accept DNC through communication at key moments were described including preparing FMs for death determination, allowing FMs to be present, and explaining the legal time of death, combined with multimodal strategies. For many FMs, understanding of DNC unfolded over time, facilitated with repeated encounters and explanation, rather than during a single meeting. CONCLUSION: Family members' understanding of brain death and death determination represented a journey that they reported in sequential meeting with health care providers, most notably physicians. Modifiable factors to improve communication and bereavement outcomes during DNC include attention to the state of mind of the family, pacing and repeating discussions according to families' expressed understanding, and preparing and inviting families to be present for the clinical determination including apnea testing. We have provided family-generated recommendations that are pragmatic and can be easily implemented.

RéSUMé: OBJECTIF: À l'heure actuelle, il y a peu de données empiriques sur la compréhension des familles de la mort cérébrale et de la détermination du décès. Le but de cette étude était de décrire la compréhension des membres de la famille de la mort cérébrale et du processus de détermination du décès dans le contexte du don d'organes dans les unités de soins intensifs (USI) canadiennes. MéTHODE: Nous avons mené une étude qualitative à l'aide d'entrevues semi-structurées et approfondies avec des membres de la famille à qui on a demandé de prendre une décision de don d'organes au nom de patients adultes ou pédiatriques dont le décès avait été déterminé selon des critères neurologiques (DCN) dans les unités de soins intensifs canadiennes. RéSULTATS: Sur la base d'entrevues avec 179 membres de la famille, six thèmes principaux ont émergé : 1) l'état d'esprit, 2) la communication, 3) le DCN peut être contre-intuitif, 4) la préparation à l'évaluation clinique pour un DCN, 5) l'évaluation clinique pour un DCN et 6) le moment du décès. Des recommandations sur la façon dont les cliniciens peuvent aider les membres de la famille à comprendre et à accepter un DCN par la communication à des moments clés ont été décrites, y compris la préparation des membres de la famille à la détermination du décès, l'autorisation de la présence des membres de la famille et l'explication de l'heure légale du décès, combinées à des stratégies multimodales. Pour de nombreux membres de la famille, la compréhension du DCN s'est développée au fil du temps et a été facilitée par des rencontres et des explications répétées plutôt qu'au cours d'une seule rencontre. CONCLUSION: La compréhension qu'ont les membres de la famille de la mort cérébrale et de la détermination du décès représente un parcours qu'ils ont décrit lors de rencontres successives avec des acteurs de soins de santé, et particulièrement avec des médecins. Les facteurs modifiables pour améliorer la communication et les issues du deuil pendant un DCN comprennent l'attention portée à l'état d'esprit de la famille, le rythme et la répétition des discussions en fonction de la compréhension exprimée par les familles, ainsi que la préparation et l'invitation des familles à être présentes pour la détermination clinique, y compris pendant le test d'apnée. Nous avons fourni des recommandations familiales qui sont pragmatiques et peuvent être facilement mises en œuvre.

Surgical debulking is associated with improved survival for patients with neuroendocrine liver metastases of unknown primary.

BACKGROUND: Resection of neuroendocrine tumors (NET) with surgical debulking of liver metastasis (NETLM) is associated with improved survival. In patients with an unknown primary (UP-NETLM), the effects of debulking remains unclear. METHODS: The National Cancer Database (2004-2016) was queried for patients with small intestine (SI) and pancreas (P) NETLMs. If the liver was listed as the primary site, the patient's disease was classified as UP-NETLM. RESULTS: Patients with UP-NETLM, SI-NETLM, and P-NETLM who were managed non-operatively demonstrated a significant difference in 5-year overall survival (OS) (21.5% vs. 39.2% vs. 17.1%; p < 0.0001). OS in patients who underwent debulking was higher (63.7% vs. 73.2% vs. 54.2%). Patients with UP-NETLMs who underwent debulking had similar OS to patient with SI-NETLM (p = 0.051), but significantly higher OS, depending on tumor differentiation, compared to patients with P-NETLMs. If well-differentiated, surgery for UP-NETLMs was associated with a higher rate of OS (p = 0.009), while no difference was observed if moderately (p = 0.209) or poorly/undifferentiated (p = 0.633). P-NETLMs were associated with worse OS (p < 0.001) on multivariate analysis. DISCUSSION: Debulking in patients with UP-NETLMs was associated with similar OS compared to patients with SI-NETLMs and better or similar OS compared to patient with P-NETLMs.

Development of a consortium to examine organ donation legislative and system reforms: A report from the LEADDR consortium.

In April 2019, the province of Nova Scotia became the first jurisdiction in North America to pass legislation that incorporated deemed consent for deceased organ donation. The reform included many other important updates, including the hierarchy for consent, enabled donor and recipient contact, and mandatory referral of potential deceased donors. Additionally, system reforms were implemented to improve the deceased donation system in Nova Scotia. A collection of national colleagues identified the magnitude of the opportunity to develop a comprehensive strategy to measure and evaluate the impact of the legislative and system reforms. This article describes the successful development of a consortium from both national and provincial jurisdictions that included experts from a variety of backgrounds and clinical and administrative disciplines. In describing the creation of this group, we hope to offer our case example as a model for the evaluation of other health system reforms from a multidisciplinary perspective.

Implications of Perineural Invasion on Disease Recurrence and Survival After Pancreatectomy for Pancreatic Head Ductal Adenocarcinoma.

OBJECTIVE: To describe PNI and to evaluate its impact on disease-free (DFS) and overall survival (OS) in patients with resected pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: Although PNI is a prognostic factor for survival in many GI cancers, there is limited knowledge regarding its impact on tumor recurrence, especially in ''early stage disease'' (PDAC ≤20 mm, R0/ N0 PDAC). METHODS: This multicenter retrospective study included patients undergoing PDAC resection between 2009 and 2014. The association of PNI with DFS and OS was analyzed using Cox proportional-hazards models. RESULTS: PNI was found in 87% of 778 patients included in the study, with lower rates in PDAC ≤20 mm (78.7%) and in R0/N0 tumors (70.6%). PNI rate did not differ between patients who underwent neoadjuvant therapy and upfront surgery (88% vs 84%, P = 0.08). Although not significant at multivariate analysis ( P = 0.07), patients with PNI had worse DFS at univariate analysis (median DFS: 20 vs 15 months, P < 0.01). PNI was the only independent predictor of DFS in R0/N0 tumors (hazard ratio [HR]: 2.2) and in PDAC ≤ 20 mm (HR: 1.8). PNI was an independent predictor of OS in the entire cohort (27 vs 50 months, P = 0.01), together with G3 tumors, pN1 status, carbohydrate antigen (CA) 19.9 >37 and pain. CONCLUSIONS: PNI represents a major determinant of tumor recurrence and patients' survival in pancreatic cancer. The role of PNI is particularly relevant in early stages, supporting the hypothesis that invasion of nerves by cancer cells has a driving role in pancreatic cancer progression.

Invasive and Noninvasive Progression After Resection of Noninvasive Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To define frequencies, pattern of progression (invasive vs noninvasive), and risk factors of progression of resected noninvasive intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: There is a risk of progression in the remnant pancreas after resection of IPMNs. METHODS: Four hundred forty-nine consecutive patients with resected IPMNs from 1995 to 2018 were included to the study. Patients with invasive carcinoma or with follow-up <6 months were excluded. Noninvasive progression was defined as a new IPMN, increased main pancreatic duct size, and increased size of an existing lesion (5 mm compared with preoperative imaging). Invasive progression was defined as development of invasive cancer in the remnant pancreas or metastatic disease. RESULTS: With a median follow-up of 48.9 months, progression was identified in 124 patients (27.6%); 108(24.1%) with noninvasive and 16(3.6%) with invasive progression. Median progression follow-up was longer for invasive progression (85.4 vs 55.9 months; P = 0.001). Five-and 10-year estimates for a cumulative incidence of invasive progression were 6.4% and 12.9% versus 26.9% and 41.5% for noninvasive progression. After risk adjustment, multifocality (HR 4.53, 95% CI 1.34-15.26; P = 0.02) and high-grade dysplasia (HGD) in the original resection (HR 3.60, 95% CI 1.13-11.48; P = 0.03) were associated with invasive progression. CONCLUSIONS: Progression to invasive carcinoma can occur years after the surgical resection of a noninvasive IPMN. HGD in the original resection is a risk factor for invasive progression but some cases of low-grade dysplasia also progressed to cancer. Patients with high-risk features such as HGD and multifocal cysts should be considered for more intensive surveillance and represent an important cohort for future trials such as anti-inflammatory or prophylactic immunotherapy.

Pancreatic Cancer Patient-derived Organoids Can Predict Response to Neoadjuvant Chemotherapy.

OBJECTIVE: To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma. BACKGROUND: PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer. METHODS: During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing. RESULTS: One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection. CONCLUSION: Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT). METHODS: Patients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes. RESULTS: Of 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81). CONCLUSIONS: Despite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

Anatomic Criteria Determine Resectability in Locally Advanced Pancreatic Cancer.

BACKGROUND: The introduction of multi-agent chemotherapy and radiation therapy has facilitated potential resection with curative intent in selected locally advanced pancreatic cancer (LAPC) patients with excellent outcomes. Nevertheless, there remains a remarkable lack of consensus on the management of LAPC. We sought to describe the outcomes of patients with LAPC and objectively define the multidisciplinary selection process for operative exploration based on anatomical factors. METHODS: Consecutive patients with LAPC were evaluated for pancreatic surgery in the multidisciplinary clinic of a high-volume institution, between 2013 and 2018. Prospective stratification (LAPC-1, LAPC-2, and LAPC-3), based on the involvement of regional anatomical structures, was performed at the time of presentation prior to the initiation of treatment. Resection rates and patient outcomes were evaluated and correlated with the initial anatomic stratification system. RESULTS: Overall, 415 patients with LAPC were included in the study, of whom 84 (20%) were successfully resected, with a median overall survival of 35.3 months. The likelihood of operative exploration was associated with the pretreatment anatomic LAPC score, with a resection rate of 49% in patients classified as LAPC-1, 32% in LAPC-2, and 11% in LAPC-3 (p < 0.001). Resected patients with improvement of the LAPC score at the time of exploration had significantly longer median overall survival compared with those with no change or progression of LAPC score (60.7 vs. 29.8 months, p = 0.006). CONCLUSIONS: Selected patients with LAPC can undergo curative-intent surgery with excellent outcomes. The proposed Johns Hopkins anatomic LAPC score provides an objective system to anticipate the probability of eventual surgical resection after induction therapy.

The experiences of family members of deceased organ donors and suggestions to improve the donation process: a qualitative study.

BACKGROUND: Decisions about organ donation are stressful for family members of potential organ donors. We sought to comprehensively explore the donation process from interviews conducted with family members of patients admitted to pediatric and adult intensive care units in Canada. METHODS: We conducted a qualitative study using semistructured, in-depth interviews with 271 family members asked to make an organ donation decision. We recruited participants from all provinces with an organ donation organization (n = 10), and analyzed themes using a modified grounded theory approach. On the basis of these interviews, suggestions were made by researchers and family members on how to improve the process of organ donation. RESULTS: We identified 3 main themes and 9 subthemes. Families need more comprehensive support around the time of donation, including having access to someone with shared experiences, support during specific moments as needed and better support during critical transitions (e.g., when the donor body goes to the operating room). The theme of better connection to recipient(s) included receiving information about the donation surgery (e.g., which organs were recovered), establishing connection with recipients (e.g., via social networks or letters) and planned encounters. Support after donation, such as updates on organ transplantation, early mental health checks and continued connection to donor organizations, could be improved. We derived 20 suggestions for improving the organ donation process, derived from interviews with family members of pediatric and adult organ donors. INTERPRETATION: We found gaps in family support during end-of-life and donation care. Feelings of abandonment, lack of support and poor-to-little follow-up provide the empirical findings needed for hospitals and organ donor organizations to provide better support to donor families.

What are the short-term annual cost savings associated with kidney transplantation?

BACKGROUND: Kidney transplantation (KT) is often reported in the literature as associated with cost savings. However, existing studies differ in their choice of comparator, follow-up period, and the study perspective. Also, there may be unobservable heterogeneity in health care costs in the patient population which may divide the population into groups with differences in cost distributions. This study estimates the cost savings associated with KT from a payer perspective and identifies and characterizes both high and low patient cost groups. METHOD: The current study was a population-based retrospective before-and-after study. The timespan involved at most three years before and after KT. The sample included end-stage kidney disease patients in Nova Scotia, a province in Canada, who had a single KT between January 1, 2011, and December 31, 2018. Each patient served as their control. The primary outcome measure was total annual health care costs. We estimated cost savings using unadjusted and adjusted models, stratifying the analyses by donor type. We quantified the uncertainty around the estimates using non-parametric and parametric bootstrapping. We also used finite mixture models to identify data-driven cost groups based on patients' pre-transplantation annual inpatient costs. RESULTS: The mean annual cost savings per patient associated with KT was $19,589 (95% CI: $14,013, $23,397). KT was associated with a 24-29% decrease in mean annual health care costs per patient compared with the annual costs before KT. We identified and characterized patients in three cost groups made of 2.9% in low-cost (LC), 51.8% in medium-cost (MC) and 45.3% in high-cost (HC). Cost group membership did not change after KT. Comparing costs in each group before and after KT, we found that KT was associated with 17% mean annual cost reductions for the LC group, 24% for the MC group and 26% for the HC group. The HC group included patients more likely to have a higher comorbidity burden (Charlson comorbidity index ≥ 3). CONCLUSIONS: KT was associated with reductions in annual health care costs in the short term, even after accounting for costs incurred during KT.