Obesity, organ failure, and transplantation: A review of the role of metabolic and bariatric surgery in transplant candidates and recipients.

Obesity is a risk factor for kidney, liver, heart, and pulmonary diseases, as well as failure. Solid organ transplantation remains the definitive treatment for the end-stage presentation of these diseases. Among many criteria for organ transplant, efficient management of obesity is required for patients to acquire transplant eligibility. End-stage organ failure and obesity are 2 complex pathologies that are often entwined. Metabolic and bariatric surgery before, during, or after organ transplant has been studied to determine the long-term effect of bariatric surgery on transplant outcomes. In this review, a multidisciplinary group of surgeons from the Society of American Gastrointestinal and Endoscopic Surgeons and the American Society for Transplant Surgery presents the current published literature on metabolic and bariatric surgery as a therapeutic option for patients with obesity awaiting solid organ transplantation. This manuscript details the most recent recommendations, pharmacologic considerations, and psychological considerations for this specific cohort of patients. Since level one evidence is not available on many of the topics covered by this review, expert opinion was implemented in several instances. Additional high-quality research in this area will allow for better recommendations and, therefore, treatment strategies for these complex patients.

Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs: A Multicenter, Real-World Risk-Matched Analysis.

OBJECTIVE: Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP). BACKGROUND: End-ischemic NMP is often used to aid logistics, yet its impact on outcomes after LT remains unclear, as does its true impact on costs associated with transplantation. METHODS: Deceased donor liver recipients at 2 centers (January 1, 2019, to June 30, 2023) were included. Retransplants, splits, and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra) was implemented in October 2022 for extended-criteria donation after brain death (DBDs), all donations after circulatory deaths (DCDs), and logistics. NMP cases were matched 1:2 with static cold storage controls (SCS) using the Balance-of-Risk [donation after brain death (DBD)-grafts] and UK-DCD Score (DCD-grafts). RESULTS: Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day comprehensive complications index (27.6 vs 41.9, P =0.028). NMP also reduced the need for early relaparotomy and renal replacement therapy, with subsequently less frequent major complications (Clavien-Dindo ≥IVa). This effect was more pronounced in DCD transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pretransplant costs in the context of shorter waiting list times. Overall costs were comparable for both cohorts. CONCLUSIONS: This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD grafts, and overall complications and post-LT renal replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day health care costs-per-transplantation were comparable.

Intensive locoregional therapy before liver transplantation for colorectal cancer liver metastasis: A novel pretransplant protocol.

We describe a novel pre-liver transplant (LT) approach in colorectal liver metastasis, allowing for improved monitoring of tumor biology and reduction of disease burden before committing a patient to transplantation. Patients undergoing LT for colorectal liver metastasis at Cleveland Clinic were included. The described protocol involves intensive locoregional therapy with systemic chemotherapy, aiming to reach minimal disease burden revealed by positron emission tomography scan and carcinoembryonic Ag. Patients with no detectable disease or irreversible treatment-induced liver injury undergo transplant. Nine patients received liver transplant out of 27 who were evaluated (33.3%). The median follow-up was 700 days. Seven patients (77.8%) received a living donor LT. Five had no detectable disease, and 4 had treatment-induced cirrhosis. Pretransplant management included chemotherapy (n = 9) +/- bevacizumab (n = 6) and/or anti-EGFR (n = 6). The median number of pre-LT cycles of chemotherapy was 16 (range 10-40). Liver-directed therapy included Yttrium-90 (n = 5), ablation (n = 4), resection (n = 4), and hepatic artery infusion pump (n = 3). Three patients recurred after LT. Actuarial 1- and 2-year recurrence-free survival were 75% (n = 6/8) and 60% (n = 3/5). Recurrence occurred in the lungs (n = 1), liver graft (n = 1), and lungs+para-aortic nodes (n = 1). Patients with pre-LT detectable disease had reduced RFS ( p = 0.04). All patients with recurrence had histologically viable tumors in the liver explant. Patients treated in our protocol (n = 16) demonstrated improved survival versus those who were not candidates (n = 11) regardless of transplant status ( p = 0.01). A protocol defined by aggressive pretransplant liver-directed treatment and transplant for patients with the undetectable disease or treatment-induced liver injury may help prevent tumor recurrence.

The impact of normothermic machine perfusion and acuity circles on waitlist time, mortality, and cost in liver transplantation: A multicenter experience.

Ex situ normothermic machine perfusion (NMP) helps increase the use of extended criteria donor livers. However, the impact of an NMP program on waitlist times and mortality has not been evaluated. Adult patients listed for liver transplant (LT) at 2 academic centers from January 1, 2015, to September 1, 2023, were included (n=2773) to allow all patients ≥6 months follow-up from listing. Routine NMP was implemented on October 14, 2022. Waitlist outcomes were compared from pre-NMP pre-acuity circles (n=1460), pre-NMP with acuity circles (n=842), and with NMP (n=381). Median waitlist time was 79 days (IQR: 20-232 d) at baseline, 49 days (7-182) with acuity circles, and 14 days (5-56) with NMP ( p <0.001). The rate of transplant-per-100-person-years improved from 61-per-100-person-years to 99-per-100-person-years with acuity circles and 194-per-100-person-years with NMP ( p <0.001). Crude mortality without transplant decreased from 18.3% (n=268/1460) to 13.3% (n=112/843), to 6.3% (n=24/381) ( p <0.001) with NMP. The incidence of mortality without LT was 15-per-100-person-years before acuity circles, 19-per-100 with acuity circles, and 9-per-100-person-years after NMP ( p <0.001). Median Model for End-Stage Liver Disease at LT was lowest with NMP, but Model for End-Stage Liver Disease at listing was highest in this era ( p <0.0001). The median donor risk index of transplanted livers at baseline was 1.54 (1.27-1.82), 1.66 (1.42-2.16) with acuity circles, and 2.06 (1.63-2.46) with NMP ( p <0.001). Six-month post-LT survival was not different between eras ( p =0.322). The total cost of health care while waitlisted was lowest in the NMP era ($53,683 vs. $32,687 vs. $23,688, p <0.001); cost-per-day did not differ between eras ( p =0.152). The implementation of a routine NMP program was associated with reduced waitlist time and mortality without compromising short-term survival after liver transplant despite increased use of riskier grafts. Routine NMP use enables better waitlist management with reduced health care costs.

Update to 'A Contemporary Systematic Review on Liver Transplantation for Unresectable Liver Metastasis of Colorectal Cancer'.

Colorectal cancer is the second most common cause of cancer-related death worldwide, and half of patients present with colorectal liver metastasis (CRLM). Liver transplant (LT) has emerged as a treatment modality for otherwise unresectable CRLM. Since the publication of the Lebeck-Lee systematic review in 2022, additional evidence has come to light supporting LT for CRLM in highly selected patients. This includes reports of >10-year follow-up with over 80% survival rates in low-risk patients. As these updated reports have significantly changed our collective knowledge, this article is intended to serve as an update to the 2022 systematic review to include the most up-to-date evidence on the subject.

Obesity, organ failure, and transplantation: a review of the role of metabolic and bariatric surgery in transplant candidates and recipients.

Obesity is a risk factor for kidney, liver, heart, and pulmonary diseases, as well as failure. Solid organ transplantation remains the definitive treatment for the end-stage presentation of these diseases. Among many criteria for organ transplant, efficient management of obesity is required for patients to acquire transplant eligibility. End-stage organ failure and obesity are 2 complex pathologies that are often entwined. Metabolic and bariatric surgery before, during, or after organ transplant has been studied to determine the long-term effect of bariatric surgery on transplant outcomes. In this review, a multidisciplinary group of surgeons from the Society of American Gastrointestinal and Endoscopic Surgeons and the American Society for Transplant Surgery presents the current published literature on metabolic and bariatric surgery as a therapeutic option for patients with obesity awaiting solid organ transplantation. This manuscript details the most recent recommendations, pharmacologic considerations, and psychological considerations for this specific cohort of patients. Since level one evidence is not available on many of the topics covered by this review, expert opinion was implemented in several instances. Additional high-quality research in this area will allow for better recommendations and, therefore, treatment strategies for these complex patients.

Ileal Pouch-anal Anastomosis in Primary Sclerosing Cholangitis-inflammatory Bowel Disease (PSC-IBD): Long-term Pouch and Liver Transplant Outcomes.

OBJECTIVE: To compare the effect of liver transplantation (LT) on ileal pouch-anal anastomosis (IPAA) outcomes in patients with primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD). BACKGROUND: Patients with PSC-IBD may require both IPAA for colitis and LT for PSC. METHODS: Patients with PSC-IBD from out institutional pouch registry (1985-2022) were divided according to LT status and timing of LT (before and after IPAA) and their outcomes analyzed. RESULTS: A total of 160 patients were included: 112 (70%) nontransplanted at last follow-up; 48 (30%) transplanted, of which 23 (14%) before IPAA and 25 (16%) after. Nontransplanted patients at IPAA had more laparoscopic procedures [37 (46%) vs 8 (18%), P =0.002] and less blood loss (median 250 vs 400 mL, P =0.006). Morbidity and mortality at 90 days were similar. Chronic pouchitis was higher in transplanted compared with nontransplanted patients [32 (67%) vs 51 (45.5%), P =0.03], but nontransplanted patients had a higher rate of chronic antibiotic refractory pouchitis. Overall survival was similar, but nontransplanted patients had more PSC-related deaths (12.5% vs 2%, P =0.002). Pouch survival at 10 years was 90% for nontransplanted patients and 100% for transplanted patients (log-rank P =0.052). Timing of LT had no impact on chronic pouchitis, pouch failure, or overall survival. PSC recurrence was 6% at 10 years. For transplanted patients, graft survival was similar regardless of IPAA timing. CONCLUSIONS: In patients with PSC-IBD and IPAA, LT is linked to an increased pouchitis rate but does not affect overall and pouch survival. Timing of LT does not influence short-term and long-term pouch outcomes.

Left Lobe First With Purely Laparoscopic Approach: A Novel Strategy to Maximize Donor Safety in Adult Living Donor Liver Transplantation.

OBJECTIVE: Evaluate outcome of left-lobe graft (LLG) first combined with purely laparoscopic donor hemihepatectomy (PLDH) as a strategy to minimize donor risk. BACKGROUND: An LLG first approach and a PLDH are 2 methods used to reduce surgical stress for donors in adult living donor liver transplantation (LDLT). But the risk associated with application LLG first combined with PLDH is not known. METHODS: From 2012 to 2023, 186 adult LDLTs were performed with hemiliver grafts, procured by open surgery in 95 and PLDH in 91 cases. LLGs were considered first when graft-to-recipient weight ratio ≥0.6%. Following a 4-month adoption process, all donor hepatectomies, since December 2019, were performed laparoscopically. RESULTS: There was one intraoperative conversion to open (1%). Mean operative times were similar in laparoscopic and open cases (366 vs 371 minutes). PLDH provided shorter hospital stays, lower blood loss, and lower peak aspartate aminotransferase. Peak bilirubin was lower in LLG donors compared with right-lobe graft donors (1.4 vs 2.4 mg/dL, P < 0.01), and PLDH further improved the bilirubin levels in LLG donors (1.2 vs 1.6 mg/dL, P < 0.01). PLDH also afforded a low rate of early complications (Clavien-Dindo grade ≥ II, 8% vs 22%, P = 0.007) and late complications, including incisional hernia (0% vs 13.7%, P < 0.001), compared with open cases. LLG was more likely to have a single duct than a right-lobe graft (89% vs 60%, P < 0.01). Importantly, with the aggressive use of LLG in 47% of adult LDLT, favorable graft survival was achieved without any differences between the type of graft and surgical approach. CONCLUSIONS: The LLG first with PLDH approach minimizes surgical stress for donors in adult LDLT without compromising recipient outcomes. This strategy can lighten the burden for living donors, which could help expand the donor pool.

Combined Liver Transplant and Cardiac Surgery: Long-Term Outcomes and Predictors of Success.

OBJECTIVE: We aim to report our institutional outcomes of single-staged combined liver transplantation (LT) and cardiac surgery (CS). SUMMARY BACKGROUND DATA: Concurrent LT and CS is a potential treatment for combined cardiac dysfunction and end-stage liver disease, yet only 54 cases have been previously reported in the literature. Thus, the outcomes of this approach are relatively unknown, and this approach has been previously regarded as extremely risky. METHODS: Thirty-one patients at our institution underwent combined cardiac surgery and liver transplant. Patients with at least one-year follow-up were included. The Leave-One-Out Cross-Validation (LOOCV) machine-learning approach was used to generate a model for mortality. RESULTS: Median follow-up was 8.2 years (IQR 4.6-13.6 y). One- and five-year survival was 74.2% (N=23) and 55% (N=17), respectively. Negative predictive factors of survival included recipient age>60 years (P=0.036), NASH-cirrhosis (P=0.031), Coronary Artery Bypass-Graft (CABG)-based CS (P=0.046) and pre-operative renal dysfunction (P=0.024). The final model demonstrated that renal dysfunction had a relative weighted impact of 3.2 versus CABG (1.7), age ≥60y (1.7) or NASH (1.3). Elevated LT+CS risk score was associated with an increased five-year mortality after surgery (AUC=0.731, P=<0.001). Conversely, the widely accepted STS-PROM calculator was unable to successfully stratify patients according to 1- (P>0.99) or 5-year (P=0.695) survival rates. CONCLUSIONS: This is the largest series describing combined LT+CS, with joint surgical management appearing feasible in highly selected patients. CABG and pre-operative renal dysfunction are important negative predictors of mortality. The four-variable LT+CS score may help predict patients at high risk for post-operative mortality.

How to Handle Arterial Conduits in Liver Transplantation? Evidence From the First Multicenter Risk Analysis.

OBJECTIVE: The aims of the present study were to identify independent risk factors for conduit occlusion, compare outcomes of different AC placement sites, and investigate whether postoperative platelet antiaggregation is protective. BACKGROUND: Arterial conduits (AC) in liver transplantation (LT) offer an effective rescue option when regular arterial graft revascularization is not feasible. However, the role of the conduit placement site and postoperative antiaggregation is insufficiently answered in the literature. STUDY DESIGN: This is an international, multicenter cohort study of adult deceased donor LT requiring AC. The study included 14 LT centers and covered the period from January 2007 to December 2016. Primary endpoint was arterial occlusion/patency. Secondary endpoints included intra- and perioperative outcomes and graft and patient survival. RESULTS: The cohort was composed of 565 LT. Infrarenal aortic placement was performed in 77% of ACs whereas supraceliac placement in 20%. Early occlusion (≤30 days) occurred in 8% of cases. Primary patency was equivalent for supraceliac, infrarenal, and iliac conduits. Multivariate analysis identified donor age >40 years, coronary artery bypass, and no aspirin after LT as independent risk factors for early occlusion. Postoperative antiaggregation regimen differed among centers and was given in 49% of cases. Graft survival was significantly superior for patients receiving aggregation inhibitors after LT. CONCLUSION: When AC is required for rescue graft revascularization, the conduit placement site seems to be negligible and should follow the surgeon's preference. In this high-risk group, the study supports the concept of postoperative antiaggregation in LT requiring AC.

Expanding Selection Criteria in Deceased Donor Liver Transplantation for Hepatocellular Carcinoma: Long-term Follow-up of a National Registry and 2 Transplant Centers.

BACKGROUND: This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes. METHODS: The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT's for HCC (2003-2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated. RESULTS: Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9-10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551-0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n = 0.513, UCSF = 0.506, 5-5-500 = 0.522, U7 = 0.511, HALT-HCC = 0.559, and Metroticket 2.0 = 0.520), as was Harrall's c-statistic (0.507 < c-statistic < 0.532). All scores predicted survival to P < 0.001 on competing risk analysis. Median follow-up in our enterprise was 9.8 y (interquartile range 7.1-13.3). U7 (13.0%, n = 58), UCSF (11.1%, n = 50), HALT-HCC (6.4%, n = 29), and Metroticket 2.0 (6.3%, n = 28) allowed candidate expansion. HALT-HCC (AUC = 0.768, 0.713-0.823) and Metroticket 2.0 (AUC = 0.739, 0.677-0.801) were the most predictive of recurrence. All scores predicted recurrence and survival to P < 0.001 using competing risk analysis. CONCLUSIONS: Less restrictive criteria such as Metroticket 2.0, UCSF, or U7 allow broader application of transplants for HCC without sacrificing outcomes. Thus, the criteria for Model for End-stage Liver Disease-exception points for HCC should be expanded to allow more patients to receive life-saving transplantation.

Risk assessment in liver transplantation for hepatocellular carcinoma: long-term follow-up of a two-centre experience.

BACKGROUND: Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC), but there are ongoing debates regarding outcomes and selection. This study examines the experience of LT for HCC at a high-volume centre. METHODS: A prospectively maintained database was used to identify HCC patients undergoing LT from 2000 to 2020 with more than or equal to 3-years follow-up. Data were obtained from the centre database and electronic medical records. The Metroticket 2.0 HCC-specific 5-year survival scale was calculated for each patient. Kaplan-Meier and Cox-regression analyses were employed assessing survival between groups based on Metroticket score and individual donor and recipient risk factors. RESULTS: Five hundred sixty-nine patients met criteria. Median follow-up was 96.2 months (8.12 years; interquartile range 59.9-147.8). Three-year recurrence-free (RFS) and overall survival (OS) were 88.6% ( n =504) and 86.6% ( n =493). Five-year RFS and OS were 78.9% ( n =449) and 79.1% ( n =450). Median Metroticket 2.0 score was 0.9 (interquartile range 0.9-0.95). Tumour size greater than 3 cm ( P =0.012), increasing tumour number on imaging ( P =0.001) and explant pathology ( P <0.001) was associated with recurrence. Transplant within Milan ( P <0.001) or UCSF criteria ( P <0.001) had lower recurrence rates. Increasing alpha-fetoprotein (AFP)-values were associated with more HCC recurrence ( P <0.001) and reduced OS ( P =0.008). Chemoembolization was predictive of recurrence in the overall population ( P =0.043) and in those outside-Milan criteria ( P =0.038). A receiver-operator curve using Metroticket 2.0 identified an optimal cut-off of projected survival greater than or equal to 87.5% for predicting recurrence. This cut-off was able to predict RFS ( P <0.001) in the total cohort and predict both, RFS ( P =0.007) and OS ( P =0.016) outside Milan. Receipt of donation after brain death (DBD) grafts (55/478, 13%) or living-donor grafts (3/22, 13.6%) experienced better survival rates compared to donation after cardiac death (DCD) grafts ( n =15/58, 25.6%, P =0.009). Donor age was associated with a higher HCC recurrence ( P =0.006). Both total ischaemia time (TIT) greater than 6hours ( P =0.016) and increasing TIT correlated with higher HCC recurrence ( P =0.027). The use of DCD grafts for outside-Milan candidates was associated with increased recurrence ( P =0.039) and reduced survival ( P =0.033). CONCLUSION: This large two-centre analysis confirms favourable outcomes after LT for HCC. Tumour size and number, pre-transplant AFP, and Milan criteria remain important recipient HCC-risk factors. A higher donor risk (i.e. donor age, DCD grafts, ischaemia time) was associated with poorer outcomes.

Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.

Circulating Tumor DNA Profiling in Liver Transplant for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Liver Metastases: A Programmatic Proof of Concept.

INTRODUCTION: Circulating tumor DNA (ctDNA) is emerging as a promising, non-invasive diagnostic and surveillance biomarker in solid organ malignancy. However, its utility before and after liver transplant (LT) for patients with primary and secondary liver cancers is still underexplored. METHODS: Patients undergoing LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM) with ctDNA testing were included. CtDNA testing was conducted pre-transplant, post-transplant, or both (sequential) from 11/2019 to 09/2023 using Guardant360, Guardant Reveal, and Guardant360 CDx. RESULTS: 21 patients with HCC (n = 9, 43%), CRLM (n = 8, 38%), CCA (n = 3, 14%), and mixed HCC/CCA (n = 1, 5%) were included in the study. The median follow-up time was 15 months (range: 1-124). The median time from pre-operative testing to surgery was 3 months (IQR: 1-4; range: 0-5), and from surgery to post-operative testing, it was 9 months (IQR: 2-22; range: 0.4-112). A total of 13 (62%) patients had pre-transplant testing, with 8 (62%) having ctDNA detected (ctDNA+) and 5 (32%) not having ctDNA detected (ctDNA-). A total of 18 (86%) patients had post-transplant testing, 11 (61%) of whom were ctDNA+ and 7 (33%) of whom were ctDNA-. The absolute recurrence rates were 50% (n = 5) in those who were ctDNA+ vs. 25% (n = 1) in those who were ctDNA- in the post-transplant setting, though this difference was not statistically significant (p = 0.367). Six (29%) patients (HCC = 3, CCA = 1, CRLM = 2) experienced recurrence with a median recurrence-free survival of 14 (IQR: 6-40) months. Four of these patients had positive post-transplant ctDNA collected following diagnosis of recurrence, while one patient had positive post-transplant ctDNA collected preceding recurrence. A total of 10 (48%) patients had sequential ctDNA testing, of whom n = 5 (50%) achieved ctDNA clearance (+/-). The remainder were ctDNA+/+ (n = 3, 30%), ctDNA-/- (n = 1, 10%), and ctDNA-/+ (n = 1, 11%). Three (30%) patients showed the acquisition of new genomic alterations following transplant, all without recurrence. Overall, the median tumor mutation burden (TMB) decreased from 1.23 mut/Mb pre-transplant to 0.00 mut/Mb post-transplant. CONCLUSIONS: Patients with ctDNA positivity experienced recurrence at a higher rate than the ctDNA- patients, indicating the potential role of ctDNA in predicting recurrence after curative-intent transplant. Based on sequential testing, LT has the potential to clear ctDNA, demonstrating the capability of LT in the treatment of systemic disease. Transplant providers should be aware of the potential of donor-derived cell-free DNA and improved approaches are necessary to address such concerns.

Omicron SARS-CoV-2 infection management and outcomes in patients with hematologic disease and recipients of cell therapy.

Introduction: Scarce real-life data exists for COVID-19 management in hematologic disease (HD) patients in the Omicron era. Purpose: To assess the current clinical management and outcome of SARS-CoV-2 infection diagnosed, identify the risk factors for severe outcomes according to the HD characteristics and cell therapy procedures in a real-world setting. Methods: A retrospective observational registry led by the Spanish Transplant Group (GETH-TC) with 692 consecutive patients with HD from December 2021 to May 2023 was analyzed. Results: Nearly one-third of patients (31%) remained untreated and presented low COVID-19-related mortality (0.9%). Nirmatrelvir/ritonavir was used mainly in mild COVID-19 cases in the outpatient setting (32%) with a low mortality (1%), while treatment with remdesivir was preferentially administered in moderate-to-severe SARS-CoV-2 infection cases during hospitalization (35%) with a mortality rate of 8.6%. The hospital admission rate was 23%, while 18% developed pneumonia. COVID-19-related mortality in admitted patients was 14%. Older age, autologous hematopoietic stem cell transplantation (SCT), chimeric antigen receptor T-cell therapy, corticosteroids and incomplete vaccination were factors independently associated with COVID-19 severity and significantly related with higher rates of hospital admission and pneumonia. Incomplete vaccination status, treatment with prior anti-CD20 monoclonal antibodies, and comorbid cardiomyopathy were identified as independent risk factors for COVID-19 mortality. Conclusions: The results support that, albeit to a lower extent, COVID-19 in the Omicron era remains a significant problem in HD patients. Complete vaccination (3 doses) should be prioritized in these immunocompromised patients. The identified risk factors may help to improve COVID-19 management to decrease the rate of severe disease, ICU admissions and mortality.

Sequential hypothermic and normothermic perfusion preservation and transplantation of expanded criteria donor livers.

BACKGROUND: The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation. METHODS: With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device. RESULTS: Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference. CONCLUSION: Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.

One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients.

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.

SARS-CoV-2-reactive antibody waning, booster effect and breakthrough SARS-CoV-2 infection in hematopoietic stem cell transplant and cell therapy recipients at one year after vaccination.

The kinetics of SARS-CoV-2 reactive IgG antibodies after full vaccination and booster in allogeneic and autologous stem cell transplantation (allo-HSCT, ASCT) and chimeric antigen receptor T-cell therapy (CAR-T) are of utmost importance for estimating risk of infection. A prospective multicenter registry-based cohort study, conducted from December 2020 to July 2022 was used to analyze antibody waning over time, booster effect and the relationship of antibody response and breakthrough infection in 572 recipients (429 allo-HSCT, 121 ASCT and 22 CAR-T cell therapy). A significant decline in antibody titers was observed at 3 and 6 months after full vaccination in recipients without pre-vaccine SARS-CoV-2 infection, whereas recipients infected prior to vaccination showed higher and stable antibody titers over time. In poor responders, a booster dose was able to increase antibody titers in 83% of allo-HSCT and 58% of ASCT recipients but not in CART-T cell recipients [0%] (p < 0.01). One-year cumulative incidence of breakthrough infection was 15%, similar among cell therapy procedures. Immunosuppressive drugs at the time of vaccination [hazard ratio (HR) 1.81, p = 0.0028] and reduced intensity conditioning (HR 0.49, p = 0.011) were identified as the only conditions associated with different risk of breakthrough infection in allo-HSCT recipients. Antibody titers were associated with breakthrough infection and disease severity. No death was observed among the 72 breakthrough infections. Antibody level decay after the first two vaccine doses was common except in recipients with pre-vaccination SARS-CoV-2 infection. Poorly responding allo-HSCT recipients showed a response advantage with the booster as compared to ASCT and, especially, the null response found in CAR-T cell recipients. Antibody titers were positively correlated with the risk of breakthrough SARS-CoV-2 infection which was mainly driven by the immunosuppression status.

Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients.

BACKGROUND: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. METHODS: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. RESULTS: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. CONCLUSIONS: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.