Corrigendum to 'Transplant oncology - Current indications and strategies to advance the field' [JHEP Reports 6 (2024) 100965].

[This corrects the article DOI: 10.1016/j.jhepr.2023.100965.].

Transplant oncology - Current indications and strategies to advance the field.

Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.

Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.

Single Center, Propensity Score Matching Analysis of Different Reconstruction Techniques following Pancreatoduodenectomy.

BACKGROUND: Pancreatoduodenectomy is still hampered by significant morbidity. So far, there is no universally accepted technique aimed at minimizing postoperative complications. Herein, we compare three different reconstruction techniques. METHODS: This is a retrospective study of a prospectively maintained database including 283 patients operated between January 2010 and December 2020. Three reconstruction techniques were compared: (1) the Neuhaus-style telescope pancreatojejunostomy, (2) the pancreatogastrostomy, and (3) the modified Blumgart-style, duct-to-mucosa pancreatojejunostomy. The primary endpoint consisted in determining the rates of clinically relevant postoperative pancreatic fistulas (CR-POPF); the secondary endpoints included 90 days morbidity and mortality rates. A propensity score matching analysis was used. RESULTS: Rates of CR-POPF did not differ significantly between the groups (Neuhaus-style pancreatojejunostomy 16%, pancreatogastrostomy 17%, modified Blumgart-style pancreatojejunostomy 15%), neither in the unmatched nor in the matched analysis (p = 0.993 and p = 0.901, respectively). Similarly, no significant differences could be observed with regard to major morbidity (unmatched p = 0.596, matched p = 0.188) and mortality rates (unmatched p = 0.371, matched p = 0.209) within the first 90 days following surgery. Propensity-score matching analyses revealed, however, a higher occurrence of post-pancreatectomy hemorrhage after pancreatogastrostomy (p = 0.015). CONCLUSION: Similar CR-POPF rates suggest no crucial role of the applied reconstruction technique. Increased incidence of intraluminal post-pancreatectomy hemorrhages following pancreatogastrostomy demands awareness for meticulous hemostasis.

Internal Ileal Diversion as Treatment for Progressive Familial Intrahepatic Cholestasis Type 1-Associated Graft Inflammation and Steatosis after Liver Transplantation.

BACKGROUND: Progressive Familial Intrahepatic cholestasis type I (PFIC1) is a rare congenital hepatopathy causing cholestasis with progressive liver disease. Surgical interruption of the enterohepatic circulation, e.g., surgical biliary diversion (SBD) can slow down development of liver cirrhosis. Eventually, end stage liver disease necessitates liver transplantation (LT). PFIC1 patients might develop diarrhea, graft steatosis and inflammation after LT. SBD after LT was shown to be effective in the alleviation of liver steatosis and graft injury. CASE REPORT: Three PFIC1 patients received LT at the ages of two, two and a half and five years. Shortly after LT diarrhea and graft steatosis was recognized, SBD to the terminal ileum was opted to prevent risk for ascending cholangitis. After SBD, inflammation and steatosis was found to be reduced to resolved, as seen by liver biochemistry and ultrasounds. Diarrhea was reported unchanged. CONCLUSION: We present three PFIC1 cases for whom SBD to the terminal ileum successfully helped to resolve graft inflammation and steatosis.

Post-Transplant Malignancies following Pancreas Transplantation: Incidence and Implications on Long-Term Outcome from a Single-Center Perspective.

Chronic immunosuppression is associated with an increased risk of malignancy. The main objective of this study is to evaluate the incidence and effect of post-transplant malignancies (PTMs) following pancreas transplantation. The 348 first pancreas transplants performed between 1985 and 2015 were retrospectively analyzed in this study. Incidences of PTMs, as well as patient and graft survival, were evaluated. Out of 348 patients, 71 (20.4%) developed a PTM. Median time to diagnosis was 130 months. Thirty-six patients (50.7%) developed skin cancers (four patients with melanoma, 32 with NMSCs). Solid organ malignancy occurred in 25 (35.2%), hematologic malignancy in ten patients (14.1%). Affected patients were transplanted earlier [2000 (IQR 1993-2004) vs. 2003 (IQR 1999-2008); p < 0.001]. No differences in induction therapy were seen, both groups demonstrated comparable patient and graft survival. Pancreas transplant recipients with solid organ and hematologic malignancies had a three- and six-fold increased hazard of death compared to those with skin cancers [aHR 3.04 (IQR 1.17-7.91); p = 0.023; aHR 6.07 (IQR 1.87-19.71); p = 0.003]. PTMs affect every fifth patient following pancreas transplantation. Skin cancers are the most common malignancies accounting for 50% of all PTMs. These results underscore the importance of close dermatologic follow-up.

Impact of Smoking Behavior on Survival Following Allogeneic Hematopoietic Stem Cell Transplantation - Smoking Cessation Matters.

INTRODUCTION: There are only a few data on the impact of smoking and smoking cessation on the outcome of patients treated with allogeneic hematopoietic stem cell transplantation, a well-established therapy for hematologic malignancies. METHODS: In a retrospective cohort study design we examined the impact of smoking and smoking cessation on survival among 309 eligible consecutive adults who underwent allogeneic hematopoietic stem cell transplantation using reduced-intensity (n = 179) or myeloablative (n = 130) conditioning between 1999 and 2018. RESULTS: Smoking and was independently associated with increased mortality with a five-year overall survival of 25% in current smokers versus 53% in never smokers versus 48% in past smokers. Never smokers lived significantly longer (HR: 2.00, 95%CI: 1.19-3.35, p = .008) and had a better event-free survival (HR: 2.11, 95%CI: 1.27-3.49, p = .004) than current smokers. In the long run, never smokers also lived significantly longer than past smokers (HR: 1.45, 95%CI: 1.16-1.81, p = .001). Patients who quit smoking before allogeneic hematopoietic stem cell transplantation showed a tendency towards increased survival compared to those who continued smoking (HR: 1.53, 95%CI: 0.95-2.45, p = .078). In relation to life-time cigarette dose smokers with low-dose (1-10 pack-years) cigarette consumption lived significantly longer (HR: 1.60, 95%CI: 1.03-2.50, p = .037) and had a better event-free survival (HR: 1.66, 95%CI: 1.07-2.58, p = .025) than patients with high-dose (≥10 pack-years) cigarette consumption. CONCLUSIONS: In allogeneic hematopoietic stem cell transplantation for hematologic malignancies, smoking history per se, lifetime cigarette dose, and continued smoking, were significantly associated with increased all-cause mortality and reduced event-free survival. IMPLICATIONS: Continued and past smoking represent established risk factors for malignant and non-malignant diseases, however, they are also a strong risk factor for a poor outcome after allogeneic hematopoietic stem cell transplantation for hematologic diseases. Our study shows that the hazard ratio for death after such transplantation is doubled if patients continue smoking and even if they have quit smoking, their risk remains significantly elevated. This suggests that the smoking history provides important predictive factors for the outcome of allogeneic hematopoietic stem cell transplantation and that smoking cessation should be implemented in the treatment of hematologic diseases as early as possible.

A Retrospective Propensity Score Matched Analysis Reveals Superiority of Hypothermic Machine Perfusion over Static Cold Storage in Deceased Donor Kidney Transplantation.

Hypothermic machine perfusion (HMP) has been introduced as an alternative to static cold storage (SCS) in kidney transplantation, but its true benefit in the clinical routine remains incompletely understood. The aim of this study was to assess the effect of HMP vs. SCS in kidney transplantation. All kidney transplants performed between 08/2015 and 12/2019 (n = 347) were propensity score (PS) matched for cold ischemia time (CIT), extended criteria donor (ECD), gender mismatch, cytomegalovirus (CMV) mismatch, re-transplantation and Eurotransplant (ET) senior program. A total of 103 HMP and 103 SCS instances fitted the matching criteria. Prior to PS matching, the CIT was longer in the HMP group (17.5 h vs. 13.3 h; p < 0.001), while the delayed graft function (DGF) rates were 29.8% and 32.3% in HMP and SCS, respectively. In the PS matched groups, the DGF rate was 64.1% in SCS vs. 31.1% following HMP: equivalent to a 51.5% reduction of the DGF rate (OR 0.485, 95% CI 0.318-0.740). DGF was associated with decreased 1- and 3-year graft survival (100% and 96.3% vs. 90.8% and 86.7%, p = 0.001 and p = 0.008) or a 4.1-fold increased risk of graft failure (HR = 4.108; 95% CI: 1.336-12.631; p = 0.014). HMP significantly reduces DGF in kidney transplantation. DGF remains a strong predictor of graft survival.

Multi-channel lung sound classification with convolutional recurrent neural networks.

In this paper, we present an approach for multi-channel lung sound classification, exploiting spectral, temporal and spatial information. In particular, we propose a frame-wise classification framework to process full breathing cycles of multi-channel lung sound recordings with a convolutional recurrent neural network. With our recently developed 16-channel lung sound recording device, we collect lung sound recordings from lung-healthy subjects and patients with idiopathic pulmonary fibrosis (IPF), within a clinical trial. From the lung sound recordings, we extract spectrogram features and compare different deep neural network architectures for binary classification, i.e. healthy vs. pathological. Our proposed classification framework with the convolutional recurrent neural network outperforms the other networks by achieving an F-score of F1≈92%. Together with our multi-channel lung sound recording device, we present a holistic approach to multi-channel lung sound analysis.

Clinical Implementation of Prolonged Liver Preservation and Monitoring Through Normothermic Machine Perfusion in Liver Transplantation.

BACKGROUND: Normothermic machine perfusion (NMP) bears the potential for significant prolongation of liver preservation before transplantation. Although safety and feasibility have been recently published, no data are available describing the significant challenges of establishing NMP programs outside clinical studies. We herein present our experience and propose a multidisciplinary approach for liver NMP in the clinical routine. METHODS: In February 2018, liver NMP was introduced for routine use in marginal organs, logistic challenges, and complex recipients at our institution. In a multidisciplinary effort among transplant coordinators, perfusionists, transplant surgeons, anesthesia, nurses, blood bank as well as laboratory staff, a clinical routine was established and 34 NMP cases were performed without critical incidents or organ loss. RESULTS: Nine livers were discarded due to poor organ quality and function observed during NMP. Twenty-five livers were successfully transplanted after preservation of up to 38 h. The extended criteria donors rate was 100% and 92% in discarded and transplanted livers, respectively. Nighttime procedures and parallel transplantations were eventually omitted. Graft and patient survival was 88% at 20 mo. No cholangiopathy was observed despite the use of extended criteria donor organs in 92% of cases. CONCLUSIONS: NMP in a multidisciplinary approach enables a safe prolongation of liver preservation and overnight organ care. A first field test of NMP indicates safety and benefit of this approach.

Right-Sided Approach for Segmental Resection of the Left Main Bronchus-Technical Considerations.

Carcinoids of the left main bronchus are rare tumors of the bronchial system and patients often present with dyspnea, asthma-like symptoms, and pneumonia. Gold standard for therapy of carcinoids is surgical resection, but the surgical approach for segmental resection and anastomosis of the left main bronchus is a matter of discussion. With a left-sided approach the access to the bronchus is blocked by the aortic arch and the pulmonary vein. If a right-sided approach is performed, the problem of ventilation during resection and anastomosis of the bronchus occurs. We present a surgical approach from the right side using intraoperative extracorporeal membrane oxygenation to assure oxygen supply for resection of a typical carcinoid of the left main stem bronchus, and discuss the current literature.

Donor cardiac arrest and cardiopulmonary resuscitation: impact on outcomes after simultaneous pancreas-kidney transplantation - a retrospective study.

Donor cardiac arrest and cardiopulmonary resuscitation (CACPR) has been considered critically because of concerns over hypoperfusion and mechanical trauma to the donor organs. We retrospectively analyzed 371 first simultaneous pancreas-kidney transplants performed at the Medical University of Innsbruck between 1997 and 2017. We evaluated short- and long-term outcomes from recipients of organs from donors with and without a history of CACPR. A total of 63 recipients received a pancreas and kidney graft from a CACPR donor. At 1, and 5-years, patient survival was similar with 98.3%, and 96.5% in the CACPR and 97.0%, and 90.2% in the non-CACPR group (log rank P = 0.652). Death-censored pancreas graft survival was superior in the CACPR group with 98.3%, and 91.4% compared to 86.3%, and 77.4% (log rank P = 0.028) in the non-CACPR group, which remained statistically significant even after adjustment [aHR 0.49 (95% CI 0.24-0.98), P = 0.044]. Similar relative risks for postoperative complications Clavien Dindo > 3a, pancreatitis, abscess, immunologic complications, delayed pancreas graft function, and relative length of stay were observed for both groups. Donors with a history of CACPR are, in the current practice, safe for transplantation. Stringent donor selection and short CPR durations may allow for outcomes surpassing those of donors without CACPR.

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-ß and microRNA 218. OBJECTIVE: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue. METHODS: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis. RESULTS: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro. CONCLUSIONS: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.

Sex matching does not impact the outcome after simultaneous pancreas-kidney transplantation.

BACKGROUND: Several studies in solid organ transplantation have shown a correlation between donor and recipient sex mismatch and risk of graft loss. In this study, we aimed to analyze the impact of donor and recipient sex matching on patient and pancreas graft survival in a large single-center cohort. METHODS: We retrospectively analyzed all first simultaneous pancreas-kidney transplants performed between 1979 and 2017 at the Medical University of Innsbruck. RESULTS: Of 452 patients, 54.6% (247) received a sex-matched transplant. Patient survival (P = .86), death-censored pancreas graft survival (dcPGS, P = .26), and death-censored kidney graft survival (dcKGS, P = .24) were similar between the sex-matched and sex-mismatched groups. Patient survival and dcPGS at 1, 5, and 15 years were 95.9%, 90.0%, and 62.1% and 86.1%, 77.1%, and 56.7% in the sex-matched group and 93.6%, 86.2%, and 62.4% and 83.1%, 73.3%, and 54.3% in the sex-mismatched group. Sex matching led to a lower odds of severe postoperative complications (41.2% vs 49.0%; OR 0.57, 95%CI 0.33-0.97; P = .038); however, no increased odds of other adverse postoperative outcomes was detected. CONCLUSION: Our study demonstrates that sex matching reduced the odds of postoperative complications but did not impact other early and late outcome parameters in our cohort.

Whole-Body Lung Function Test-Derived Outcome Predictors in Allogenic Stem Cell Transplantation.

Despite clinical advances, late onset pulmonary complications in adult recipients of allogenic stem cell transplantation are a major cause of morbidity and mortality. Reported incidence and risk factors in the literature vary broadly and are partly contradictory. Identification of pretransplant factors associated with major complications would be helpful to define individual treatment strategies and early initiation of preventive measures. To evaluate incidence and risk factors of late onset noninfectious pulmonary complications, with special regard to small airways disease (SAD) and bronchiolitis obliterans syndrome (BOS), indicating graft-versus-host disease, following myeloablative versus nonmyeloablative allogenic stem cell transplantation. We reviewed the clinical records and assessed the course of lung function and pulmonary complications in adults who underwent allogenic stem cell transplantation for hematological malignancies between 1999 and 2015 using nonmyeloablative (n = 179) or myeloablative (n = 130) conditioning at the Division of Hematology of the Medical University of Graz. All patients underwent body plethysmography pulmonary function test (PFT), diffusion capacity for carbon monoxide, and arterial blood gas analysis before and repeatedly after transplant. SAD was defined as maximal expiratory flow at 50% and 25% of forced vital capacity <70% predicted. Ventilatory disorders and gas transfer abnormalities were common before and after allogenic stem cell transplantation, independent of conditioning regimen. SAD was common in the nonmyeloablative (34%) and myeloablative (29%) groups. The 100-day post-transplant mortality was significantly associated with reduced pretransplant total lung capacity <80%. Mortality 100 days post-transplant was significantly associated with pretransplant SAD and a pretransplant smoking history. In this subset, a smoking history was independently associated with increased mortality, with a 5-year mortality of 45% compared with 26% in never-smokers. Pretransplant SAD was not predictive for the later development of BOS. Smoking history, pretransplant restrictive PFT, and pre-existing SAD are important risk factors for death following allogenic stem cell transplantation. However, pretransplant SAD is not a predictor of long-term complications, including BOS.

Crackle and Breathing Phase Detection in Lung Sounds with Deep Bidirectional Gated Recurrent Neural Networks.

In this paper, we present a method for event detection in single-channel lung sound recordings. This includes the detection of crackles and breathing phase events (inspiration/expiration). Therefore, we propose an event detection approach with spectral features and bidirectional gated recurrent neural networks (BiGRNNs). In our experiments, we use multichannel lung sound recordings from lung-healthy subjects and patients diagnosed with idiopathic pulmonary fibrosis, collected within a clinical trial. We achieve an event-based F-score of F1 ≈ 86% for breathing phase events and F1 ≈ 72% for crackles. The proposed method shows robustness regarding the contamination of the lung sound recordings with noise, bowel and heart sounds.

Necrotizing fasciitis of the lower extremity caused by perforated sigmoid diverticulitis-a case report.

Diverticulosis of the sigmoid colon is a common condition and occurs more often in elderly patients. A well-known complication is infection or even perforation which often requires surgery. Necrotizing fasciitis as a complication of perforated diverticulitis is very rare. Here, we present a case of a covered perforated diverticulitis in an immunosuppressed patient leading to life-threatening necrotizing fasciitis requiring extracorporeal membrane oxygenation. Either hematogenous or local dissemination via the inguinal canal seemed the most probable mechanism of leg infection leading to hip articulation.