Early discontinuation of adjuvant chemotherapy in patients with early-stage pancreatic cancer correlates with inferior survival: A multicenter population-based cohort study.

BACKGROUND: The current study aimed to determine the association between timing and completion of adjuvant chemotherapy and outcomes in real-world patients with early-stage pancreatic cancer. METHODS: In this multi-center cohort study patients with early-stage pancreatic cancer who were diagnosed from 2007-2017 and underwent complete resection in the province of Saskatchewan were examined. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. RESULTS: Of 168 patients, 71 eligible patients with median age of 69 years and M:F of 37:34 were identified. Median time to the start of adjuvant therapy from surgery was 73 days. Of all patients, 49 (69%) patients completed adjuvant chemotherapy and 22 (31%) required early treatment discontinuation. Median recurrence-free survival of patients who completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P<0.001). Median overall survival of those who completed treatment was 33 (17.5-48.5) vs. 16 months (17.5-48.5) with early treatment discontinuation (P<0.001). In the multivariate analysis, treatment discontinuation was significantly correlated with recurrent disease, hazard ratio (HR), 2.57 (1.41-4.68), P = 0.002 and inferior survival, HR, 2.55 (1.39-4.68), P = 0.003. No correlation between treatment timing and survival was noted. CONCLUSIONS: Early discontinuation but not the timing of adjuvant chemotherapy correlates with inferior outcomes.

Early Single-Center Experience With Irreversible Electroporation for Stage 2, 3, and 4 Pancreatic Adenocarcinomas.

OBJECTIVES: Irreversible electroporation (IRE) is an ablation technology that uses electrical energy delivered between electrodes. If the electrodes are placed atraumatically, there is little to no risk of collateral injury, making IRE appealing for the treatment of pancreatic tumors. METHODS: We report on 20 patients with pancreatic adenocarcinoma (PAC) who underwent 21 IRE in our center. There were 6 IRE for stage 2 PAC, 11 for stage 3 PAC, 1 for stage 4 PAC, and 2 patients treated with IRE for recurrence after pancreaticoduodenectomy. One patient had local progression 18 months after IRE and received a second IRE treatment. Using propensity score matching (age, sex, stage, tumor size, and chemotherapy), cases were matched 2 to 1 with patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 7 cases experienced 8 complications; 4 complications were mild, and 4 were severe. Significant survival benefit was seen for patients with stage 3 PAC (27.5 vs 14.6 months for the matched group, P = 0.003); for stage 2, median survival was 15 months, and the single stage 4 patient survived 9 months after IRE treatment. CONCLUSIONS: Pancreatic cancers were safely and effectively treated with image-guided IRE in our medium-sized center.

PATCH-DP: a single-arm phase II trial of intra-operative application of HEMOPATCH™ to the pancreatic stump to prevent post-operative pancreatic fistula following distal pancreatectomy.

BACKGROUND: Post-operative pancreatic fistula (POPF) is the most significant cause of morbidity following distal pancreatectomy. Hemopatch™ is a thin, bovine collagen-based hemostatic sealant. We hypothesized that application of Hemopatch™ to the pancreatic stump following distal pancreatectomy would decrease the incidence of clinically-significant POPF. METHODS: We conducted a prospective, single-arm, multicentre phase II study of application of Hemopatch™ to the pancreatic stump following distal pancreatectomy. The primary outcome was clinically-significant POPF within 90 days of surgery. A sample size of 52 patients was required to demonstrate a 50% relative reduction in Grade B/C POPF from a baseline incidence of 20%, with a type I error of 0.2 and power of 0.75. Secondary outcomes included incidence of POPF (all grades), 90-day mortality, 90-day morbidity, re-interventions, and length of stay. RESULTS: Adequate fixation Hemopatch™ to the pancreatic stump was successful in all cases. The rate of grade B/C POPF was 25% (95%CI: 14.0-39.0%). There was no significant difference in the incidence of grade B/C POPF compared to the historical baseline (p = 0.46). The 90-day incidence of Clavien-Dindo grade ≥3 complications was 26.9% (95%CI: 15.6-41.0%). CONCLUSION: The use of Hemopatch™ was not associated with a decreased incidence of clinically-significant POPF compared to historical rates. (NCT03410914).

Proteomic Analysis of Perfusate from Machine Cold Perfusion of Transplant Kidneys: Insights Into Protection from Injury.

BACKGROUND Machine cold perfusion is beneficial to the preservation of kidneys for transplantation. At the end of preservation, the perfusion solution contains many proteins. Using a proteomics approach, we searched for useful biomarkers and potential therapeutic targets in the perfusate. Our program is unique in that all transplant kidneys (even living donor kidneys, LKD) are placed on machine cold perfusion prior to transplantation. MATERIAL AND METHODS Perfusates from donation after neurological and circulatory determination of death (DNDD and DCDD respectively) and LKD were collected (n=41) and analyzed for LDH, neutrophil gelatinase-associated lipocalin (NGAL), and matrix metalloproteinase-2 (MMP-2) as markers of injury. Perfusate from each kidney was subjected to 2-dimensional gel electrophoresis, then analyzed using software to identify those spots which are significantly different between the 3 groups. Mass spectrometry was used to identify the proteins and their identity was confirmed with Western blot. RESULTS The highest levels of MMP-2, LDH, and NGAL were seen for the DCDD kidneys, followed by the DNDD kidneys and then LDK. Peroxiredoxin-2, NGAL, and alpha-1-antitrypsin were identified as significantly different between the different types of donor kidneys, and their role and possible therapeutic strategies are discussed. Collagen fragments, albumin, and immunoglobulin were also identified as possible byproducts of the injury and may be useful is assessing the degree of injury. CONCLUSIONS Comparison of the perfusates from the different types of kidneys has allowed us to identify proteins that will be useful in future research into reducing injury in transplant kidneys.

Early experience with hypothermic machine perfusion of living donor kidneys - a retrospective study.

Although hypothermic machine perfusion (HMP) has been shown to be beneficial to deceased donor kidneys, the effect of HMP on living donor kidneys (LDK) is unknown. LDK are subjected to minutes of normothermic ischemia at the time of recovery. Comparison of 16 LDK preserved by HMP with 16 LDK preserved by static cold storage (SCS). Outcomes of interest are resistive indices (RI), both while on HMP and postoperatively, and creatinine clearance (CrCl). Injury markers NGAL and LDH were seen in the perfusate of LDK in amounts similar to what is found for donation after neurological determination of death kidneys. Compared to SCS kidneys, CrCl was significantly higher in the HMP group from days 2 through 7 post-transplant [ie: day 7 (78.8 ± 5.4 vs. 54.0 ± 4.6 ml/min, P = 0.005)]. CrCl at 1 year was higher in the HMP group (81.2 ± 5.8 vs. 70.0 ± 5.3 ml/min, P = 0.03). Early post-transplant RI was significantly lower in the HMP group (0.61 ± 0.02 vs. 0.71 ± 0.02, P < 0.0001). Our data support the assertion that injury does occur during LDK procurement and suggest that some of this injury may be reversed with HMP, resulting in more favorable early RI and graft function compared to SCS kidneys.

Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases.

BACKGROUND: Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion. METHODS: Human kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD). RESULTS: Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers. CONCLUSIONS: Based on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.

What information about donation after circulatory death is available on the Internet for potential donor families?

INTRODUCTION: The purpose of this study is to determine what information about donation after circulatory death (DCD) is available on the Internet and to document the common statements for and against DCD. METHODS: The search terms non-heart-beating donor, donation after cardiac death, DCD, deceased donor, organ donation, and organ harvesting were entered into the four most-accessed English-language Internet search engines. The top 10 webpages from each search (240 webpages) yielded 116 unique sites. Three reviewers reviewed each webpage and recorded statements for and against DCD as well as site type, tone, and mention of DCD. RESULTS: While 59 (50.9%) of the overall 116 sites included DCD information, only 10% of sites found with the term "organ donation" mentioned DCD at all. The sites that did include DCD were mostly (78%) of the type "medical journal" or "hospital or university webpage" and 89% of these had a positive or neutral tone. Nine positive and nine negative tropes were defined using the Grounded Theory Method. CONCLUSION: This study reveals the lack of information regarding DCD in organ donation webpages. Thoughtful responses to these statements should be considered in family discussions and in the design of future webpages.

Inferior survival in liver transplant recipients with hepatocellular carcinoma receiving donation after cardiac death liver allografts.

The impact of ischemia/reperfusion injury in the setting of transplantation for hepatocellular carcinoma (HCC) has not been thoroughly investigated. The present study examined data from the Scientific Registry of Transplant Recipients for all recipients of deceased donor liver transplants performed between January 1, 1995 and October 31, 2011. In a multivariate Cox analysis, significant predictors of patient survival included the following: HCC diagnosis (P < 0.01), donation after cardiac death (DCD) allograft (P < 0.001), hepatitis C virus-positive status (P < 0.01), recipient age (P < 0.01), donor age (P < 0.001), Model for End-Stage Liver Disease score (P < 0.001), recipient race, and an alpha-fetoprotein level > 400 ng/mL at the time of transplantation. In order to test whether the decreased survival seen for HCC recipients of DCD grafts was more than would be expected because of the inferior nature of DCD grafts and the diagnosis of HCC, a DCD allograft/HCC diagnosis interaction term was created to look for potentiation of effect. In a multivariate analysis adjusted for all other covariates, this interaction term was statistically significant (P = 0.049) and confirmed that there was potentiation of inferior survival with the use of DCD allografts in recipients with HCC. In conclusion, patient survival and graft survival were inferior for HCC recipients of DCD allografts versus recipients of donation after brain death allografts. This potentiation of effect of inferior survival remained even after adjustments for the inherent inferiority observed in DCD allografts as well as other known risk factors. It is hypothesized that this difference could reflect an increased rate of recurrence of HCC.