Update on the Screening, Diagnosis, and Management of Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a neoplasm of the biliary tract that has become increasingly prevalent throughout the world. Common risk factors for developing CCA include cirrhosis, primary sclerosing cholangitis, and trematode fluke infestation, although there are no set screening guidelines in high-risk groups. Lesions are typically identified via cross-sectional imaging and/or elevated serum carbohydrate antigen 19-9 levels, often followed by cytology or brushings with fluorescence in situ hybridization for confirmation. Treatments can vary among CCA subtypes but frequently involve systemic therapies such as gemcitabine and cisplatin with durvalumab or pembrolizumab. Targeted therapies may also be effective (eg, ivosidenib, pemigatinib, infigratinib, futibatinib) depending on the molecular alterations present. Resection is the most common surgical treatment for CCA, although liver transplantation is also an option in highly selected patients with liver-limited unresectable disease. Radiotherapy may also be a treatment option, as well as transarterial radioembolization (eg, yttrium-90), which is often utilized in combination with systemic therapy. Although patients with CCA have traditionally had a poor prognosis, recent advances in treatment, including new systemic therapies and increased utilization of liver transplantation, have improved expected survival. This article reviews screening modalities, pros and cons of diagnostic techniques, and therapies that are currently available to treat patients with CCA.

Single-center Outcomes After Liver Transplantation With SARS-CoV-2-Positive Donors: An Argument for Increased Utilization.

Background: The COVID-19 pandemic has led to an increase in SARS-CoV-2-test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19-positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19-positive donors at a single center are presented here. Methods: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19-positive (n = 29 total; 25 index, 4 redo) and COVID-19-negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results: COVID-19-positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19-negative donors. Recipients of COVID-19-positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19-positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions: The utilization of liver grafts from COVID-19-positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19-positive donors may be used safely to expand the deceased donor pool.

Bloodstream infections after solid organ transplantation: clinical epidemiology and antimicrobial resistance (2016-21).

Background: Solid organ transplant (SOT) recipients are at risk of bloodstream infections (BSIs) with MDR organisms (MDROs). Objectives: To describe the epidemiology of BSI in the year after several types of SOT, as well as the prevalence of MDRO infections in this population. Methods: We conducted a single-centre, retrospective study of kidney, liver, heart, and multi-organ transplantation patients. We examined BSIs ≤1 year from SOT and classified MDRO phenotypes for Staphylococcus aureus, enterococci, Enterobacterales, Pseudomonas aeruginosa and Candida spp. We compared BSI characteristics between SOT types and determined risk factors for 90 day mortality. Results: We included 2293 patients [1251 (54.6%) kidney, 663 (28.9%) liver, 219 (9.6%) heart and 160 (7.0%) multi-organ transplant]. Overall, 8.5% of patients developed a BSI. BSIs were most common after multi-organ (23.1%) and liver (11.3%) transplantation (P < 0.001). Among 196 patients with BSI, 323 unique isolates were recovered, 147 (45.5%) of which were MDROs. MDROs were most common after liver transplant (53.4%). The most frequent MDROs were VRE (69.8% of enterococci) and ESBL-producing and carbapenem-resistant Enterobacterales (29.2% and 27.2% of Enterobacterales, respectively). Mortality after BSI was 9.7%; VRE was independently associated with mortality (adjusted OR 6.0, 95% CI 1.7-21.3). Conclusions: BSI incidence after SOT was 8.5%, with a high proportion of MDROs (45.5%), especially after liver transplantation. These data, in conjunction with local antimicrobial resistance patterns and prescribing practices, may help guide empirical antimicrobial selection and stewardship practices after SOT.

Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions.

Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with high mortality rate. Complete resection of the iCCA lesion is the first choice of treatment, with good prognosis after margin-negative resection. Unfortunately, only 12%-40% of patients are eligible for resection at presentation due to cirrhosis, portal hypertension, or large tumor size. Liver transplantation (LT) offers margin-negative iCCA extirpation for patients with unresectable tumors. Initially, iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes. Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA. Another selection criterion is the tumor response to neoadjuvant therapy. Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy. Another index that helps predict the treatment outcome is the biomarker. Improved survival outcomes have also opened the door for living donor LT for iCCA. Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection. The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Molecular profiling in the management of hepatocellular carcinoma.

PURPOSE OF REVIEW: The purpose of this review is to both summarize the current knowledge of hepatocellular carcinoma molecular biology and to suggest a framework in which to prospectively translate this knowledge into patient care. This is timely as recent guidelines recommend increased use of these technologies to advance personalized liver cancer care. RECENT FINDINGS: The main themes covered here address germline and somatic genetic alterations recently discovered in hepatocellular carcinoma, largely owing to next generation sequencing technologies, and nascent efforts to translate these into contemporary practice. SUMMARY: Early efforts of translating molecular profiling to hepatocellular carcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking are a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care.

Progress in Combined Liver-lung Transplantation at a Single Center.

Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology.

The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.

Modern Outcomes After Liver Retransplantation: A Single-center Experience.

BACKGROUND: The need for liver retransplantation (reLT) has increased proportionally with greater numbers of liver transplants (LTs) performed, use of marginal donors, degree of recipient preoperative liver dysfunction, and longer survival after LT. However, outcomes following reLT have been historically regarded as poor. METHODS: To evaluate reLT in modern recipients, we retrospectively examined our single-center experience. Analysis included 1268 patients undergoing single LT and 68 patients undergoing reLT from January 2008 to December 2021. RESULTS: Pre-LT mechanical ventilation, body mass index at LT, donor-recipient ABO incompatibility, early acute rejection, and length of hospitalization were associated with increased risk of needing reLT following index transplant. Overall and graft survival outcomes in the reLT cohort were equivalent to those after single LT. Mortality after reLT was associated with Kidney Donor Profile Index, national organ sharing at reLT, and LT donor death by anoxia and blood urea nitrogen levels. Survival after reLT was independent of the interval between initial LT and reLT, intraoperative packed red blood cell use, cold ischemia time, and preoperative mechanical ventilation, all previously linked to worse outcomes. CONCLUSIONS: These data suggest that reLT is currently a safer option for patients with liver graft failure, with comparable outcomes to primary LT.

Intrahepatic cholangiocarcinoma: The role of liver transplantation, adjunctive treatments, and prognostic biomarkers.

Intrahepatic cholangiocarcinoma (iCCA) is a primary epithelial cell malignancy of the liver with rising incidence rate globally. Its insidious presentation, heterogeneous and aggressive biology, and recalcitrance to current therapies results in unacceptably high morbidity and mortality. This has spurred research efforts in the last decade to better characterize it molecularly with translation to improved diagnostic tools and treatments. Much of this has been driven by patient advocacy. This has renewed interest in orthotopic liver transplantation (LT) with adjunctive therapies for iCCA, which was historically disparaged due to poor recipient outcomes and donor organ scarcity. However, the optimal use of LT as a treatment for iCCA care remains unclear. Here, we review the epidemiology of iCCA, the history of LT as a treatment modality, alternative approaches to iCCA local control, the evidence for peri-operative systemic therapies, and the potential roles of biomarkers and targeted agents. In doing so, we hope to prioritize areas for continued research and identify areas where multidisciplinary care can improve outcomes.

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes. METHODS: Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury. RESULTS: The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints. CONCLUSIONS: This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.

Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data.

Pancreatic ductal adenocarcinoma (PDAC), already among the deadliest epithelial malignancies, is rising in both incidence and contribution to overall cancer deaths. Decades of research have improved our understanding of PDAC carcinogenesis, including characterizing germline predisposition, the cell of origin, precursor lesions, the sequence of genetic alterations, including simple and structural alterations, transcriptional changes and subtypes, tumour heterogeneity, metastatic progression and the tumour microenvironment. These fundamental advances inform contemporary translational efforts in primary prevention, screening and early detection, multidisciplinary management and survivorship, as prospective clinical trials begin to adopt molecular-based selection criteria to guide targeted therapies. Genomic and transcriptomic data on PDAC were also included in the international pan-cancer analysis of approximately 2,600 cancers, a milestone in cancer research that allows further insight through comparison with other tumour types. Thus, this is an ideal time to review our current knowledge of PDAC evolution and heterogeneity, gained from the study of preclinical models and patient biospecimens, and to propose a model of PDAC evolution that takes into consideration findings from varied sources, with a particular focus on the genomics of human PDAC.

Impact of Research Training on Performance in General Surgery Residency.

INTRODUCTION: It is common for North American surgical trainees to interrupt clinical training to complete 2 or more years of research training. The impact of this practice on surgical aptitudes is unknown. The University of Toronto has large general surgery and surgeon scientist training programs. We compared the examination scores of general surgery residents in continuous clinical training with those of residents whose training was interrupted by research. METHODS: We collected anonymized scores obtained at written and oral annual in-training examinations by general surgery residents at the University of Toronto from 2011 to 2016, inclusive. The written exam assessed knowledge, while the oral exam assessed judgment. Residents were dichotomized into continuous versus non-continuous clinical training streams. We compared performance prior to, during, and following divergence for research training both within and between the 2 groups. RESULTS: At the junior resident level, future enrollment in research training was associated with higher examination performance (Pwritten = .003). Annual scores plateaued during research training, while scores of residents who continued in continuous clinical training improved year over year (Pwritten = .009). Non-continuous stream resident exam scores remained stagnant after 1 year then improved in the second year after return to clinical training (Pwritten = .00007). Scores obtained in the final year of residency training did not significantly differ between residents who underwent continuous versus non-continuous clinical training. Results from written and oral exams trended concordantly. CONCLUSIONS: We demonstrate that interruption of clinical training for 2 or more years of research is associated with a stagnation of performance on annual in-training examinations assessing both knowledge and judgment. This phenomenon is followed by an eventual catching-up after at least 2 years return to full-time clinical training. This may inform residency program curriculum design.

Spontaneous Ureterocolic Fistula between Nonfunctioning Kidney Transplant Ureter and Colon in Setting of Diverticulitis.

Ureterocolic fistula is a rare condition that most commonly occurs in the setting of diverticular disease. The development of a ureterocolic fistula following kidney transplantation is even rarer, with no prior cases in the literature to our knowledge. We describe the case of a patient with three prior failed kidney transplants who developed a fistula between the sigmoid colon and nonfunctioning renal transplant ureter in the setting of diverticulitis.

Decreased graft loss following implementation of the kidney allocation score (KAS).

BACKGROUND: The Kidney Allocation System (KAS) was developed to improve equity and utility in organ allocation. We examine the effect of this change on kidney graft distribution and survival. METHODS: UNOS data was used to identify first-time adult recipients of a deceased donor kidney-alone transplant pre-KAS (Jan 2012-Dec 2014, n = 26,612) and post-KAS (Jan 2015-Dec 2017, n = 30,701), as well as grafts recovered Jan 2012-Jun 2019. RESULTS: Post-KAS, kidneys were more likely to experience cold ischemia time >24 h (20.0% vs. 18.8%, p < 0.001) and experienced more delayed graft function, though competing risks modeling demonstrated a lower hazard of graft loss post-KAS, HR 0.90 (95% CI 0.84-0.97, p = 0.007). Post-policy, KDPI >85% kidneys were more likely to be shared regionally (37% vs. 14%), and more likely to be discarded (60.6% vs. 54.9%) after the policy change. KDPI >85% graft and patient survival did not change. CONCLUSIONS: Implementation of the KAS has increased sharing of high-KDPI kidneys and has decreased the hazard of graft loss without an impact on patient survival.

Outcomes in Kidney Transplantation Between Veterans Affairs and Civilian Hospitals: Considerations in the Context of the MISSION Act.

OBJECTIVE: We sought to compare kidney transplantation outcomes between Veterans Affairs (VA) and non-VA transplant centers. SUMMARY BACKGROUND DATA: Transplant care at the VA has previously been scrutinized due to geographic and systematic barriers. The recently instituted MISSION Act entered effect June 6th, 2019, which enables veteran access to surgical care at civilian hospitals if certain eligibility criteria are met. METHODS: We evaluated observed-to-expected outcome ratios (O:E) for graft loss and mortality using the Scientific Registry of Transplant Recipients database for all kidney transplants during a 15-year period (July 1, 2001-June 30, 2016). Of 229,188 kidney transplants performed during the study period, 1508 were performed at VA centers (N = 7), 7750 at the respective academic institutions affiliated with these VA centers, and 227,680 at non-VA centers nationwide (N = 286). RESULTS: Aggregate O:E ratios for mortality were lower in VA centers compared with non-VA centers at 1 month and 1 year (O:E = 0.27 vs 1.00, P = 0.03 and O:E = 0.62 vs 1.00, P = 0.03, respectively). Graft loss at 1 month and 1 year was similar between groups (O:E = 0.65 vs 1.00, P = 0.11 and O:E = 0.79 vs 1.00, P = 0.15, respectively). Ratios for mortality and graft loss were similar between VA centers and their respective academic affiliates. Additionally, a subgroup analysis for graft loss and mortality at 3 years (study period January 1, 2009-December 31, 2013) demonstrated no significant differences between VA centers, VA-affiliates, and all non-VA centers. CONCLUSIONS: Despite low clinical volume, VA centers offer excellent outcomes in kidney transplantation. Veteran referral to civilian hospitals should weigh the benefit of geographic convenience and patient preference with center outcomes.

Author Correction: Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.

Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.

Metastatic Urothelial Carcinoma from Transplanted Kidney with Complete Response to an Immune Checkpoint Inhibitor.

BACKGROUND: Donor-derived malignancy is a rare complication in patients who undergo organ transplant. Approaches to treatment have largely been individualized based on clinical circumstances given the lack of evidence-based guidelines, with therapeutic options ranging from discontinuation of immunosuppression and transplantectomy to the addition of chemotherapy or radiotherapy. Case Presentation. Herein, we describe a 60-year-old woman with metastatic donor-derived upper tract urothelial carcinoma (UTUC) discovered nine years postrenal transplant. Molecular diagnostic studies using polymerase chain reaction amplification of short tandem repeat alleles and HLA tissue typing proved that the urothelial carcinoma originated from donor tissue. She achieved sustained complete remission with transplant nephroureterectomy, retroperitoneal lymphadenectomy, immunosuppression withdrawal, and immunotherapy with pembrolizumab. Routine radiologic surveillance has demonstrated 15-month progression-free survival to date off pembrolizumab, and she is now under consideration for retransplantation. CONCLUSIONS: Immunotherapy using checkpoint inhibitors can serve as a novel treatment option for patients in the clinical predicament of having a solid organ transplant and simultaneous metastatic malignancy. In this report, we also discuss the oncogenic potential of BK virus, the use of checkpoint inhibitors in urothelial carcinoma, and the feasibility of retransplant for this patient population.

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases.

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

Mutations in Mitochondrial DNA From Pancreatic Ductal Adenocarcinomas Associate With Survival Times of Patients and Accumulate as Tumors Progress.

Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress.