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BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Protein-Lysine 6-Oxidase , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Animals , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Protein-Lysine 6-Oxidase/antagonists & inhibitors , Mice , Humans , Tumor Microenvironment/drug effects , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Male , Amino Acid Oxidoreductases/antagonists & inhibitors , Disease Models, Animal , Cell Line, TumorABSTRACT
This cohort study compares survival outcomes between patients with unresectable colorectal liver metastasis who received chemotherapy-based multimodal therapy and patients who underwent liver transplant.
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BACKGROUND: At early stages of the pandemic, most organ procurements organizations considered COVID-19 infected donors to be ineligible for organ donation. The aim of this survey is to describe the current practices of the utilization of COVID-19 positive organs donors among American Society of Transplant Surgeons (ASTS) members. METHODS: An anonymous 40-question redcap survey was emailed to ASTS members from June to August 2022. RESULTS: One hundred forty-nine surveys from 10 countries were included for analysis. The majority of the responders were men (66.7%) from North America (95%) and identified as transplant surgeons (68.5%). Most work at academic institutions (76.5%). Almost all responders (94%) were willing to accept an organ from a donor with a history of COVID-19 who tested negative at the time of donation, however, there was no consensus on the length of time after the disease was resolved. Approximately 70% indicated they accept organs from asymptomatic donors with active disease. Only 32 responders indicated they would accept an organ from an individual with a history of "severe" COVID-19 infection and less than one third of the responders would accept an organ from a donor who died from COVID-19 infection. Interestingly, 80% indicated they have protocols at their institution to guide the acceptance of such organs. DISCUSSION: Despite new evidence that the transmission of COVID-19 in non-lung organs is extremely rare, the results of this survey suggest significant heterogeneity in practice and perceptions of the use of COVID-19 positive organs across international centers. We suggest that the implementation of a standardized protocol is of paramount importance to continue safe transplant activity.
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OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.
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Multiple hepatocellular carcinoma (HCC) staging systems have been proposed and used clinically over time. These may consider clinical, pathological, radiological, or treatment response factors, depending on the model. Given the heterogeneity of HCC treatment in its different stages and the validation of the systems in different populations, they are not universal. Likewise, the improvement in diagnostic tools, as well as novel therapeutic alternatives, have made these models more complex. Despite this, some have been modified over time in line with advances in the field, and although there is no universally accepted one, each has its usefulness, strengths, and weaknesses.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/pathology , Neoplasm StagingABSTRACT
Healthcare systems in Latin America are broadly heterogeneous, but all of them are burdened by a dramatic rise in liver disease. Some challenges that these countries face include an increase in patients requiring a transplant, insufficient rates of organ donation, delayed referral, and inequitable or suboptimal access to liver transplant programs and post-transplant care. This could be improved by expanding the donor pool through the implementation of education programs for citizens and referring physicians, as well as the inclusion of extended criteria donors, living donors and split liver transplantation. Addressing these shortcomings will require national shifts aimed at improving infrastructure, increasing awareness of organ donation, training medical personnel, and providing equitable access to care for all patients.
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PURPOSE OF REVIEW: To summarize the current state of liver transplantation (LT) for unresectable colorectal liver metastases (uCRLM), and to address future directions. RECENT FINDINGS: The Norwegian secondary cancer (SECA) I and SECA II studies demonstrated that after LT the 5-year survival of a highly selected group of patients with uCRLM could be as high as 60% and 83%, respectively. After long-term follow-up, the 5- and 10-year survival was shown to be 43% and 26%, respectively. Furthermore, data has accumulated in other countries and a North American study reported a 1.5-year survival of 100%. In addition, steady growth has been demonstrated in the US, with 46 patients transplanted to date and 19 centers enrolling patients for this indication. Lastly, although recurrence is almost universal in patients with a high tumor burden, it has not been an accurate surrogate for survival, reflecting the relatively indolent nature of recurrence after LT. SUMMARY: Growing evidence has shown that excellent survival and even cure can be achieved in highly selected patients with uCRLM, with survival rates far superior than in patients treated with chemotherapy. The next step is to create national registries to standardize selection criteria and establish the optimal approach and best practices for incorporating LT for uCRLM into the treatment armamentarium.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Liver Transplantation , Humans , Liver Transplantation/adverse effects , Treatment Outcome , Liver Neoplasms/pathology , Colorectal Neoplasms/pathologyABSTRACT
OBJECTIVE: To describe the rate of occult carcinoma deposits in total hepatectomy specimens from patients treated with liver transplant (LT) for colorectal liver metastases (CRLM). BACKGROUND: Previous studies have shown that patients with CRLM treated with systemic therapy demonstrate a high rate of complete radiographic response or may have disappearing liver metastases. However, this does not necessarily translate into a complete pathologic response, and residual invasive cancer may be found in up to 80% of the disappearing tumors after resection. METHODS: Retrospective review of 14 patients who underwent LT for CRLM, at 2 centers. Radiographic and pathologic correlation of the number of tumors and their viability before and after LT was performed. RESULTS: The median (interquartile range) number of tumors at diagnosis was 11 (4-23). The median number of chemotherapy cycles was 24 (16-37). Hepatic artery infusion was used in 5 patients (35.7%); 6 (42.9%) underwent surgical resection, and 5 (35.7%) received locoregional therapy. The indication for LT was unresectability in 8 patients (57.1%) and liver failure secondary to oncologic treatment in the remaining 6 (42.9%). Before LT, 7 patients (50%) demonstrated fluorodeoxyglucose-avid tumors and 7 (50%) had a complete radiographic response. Histopathologically, 11 patients (78.6%) had a viable tumor. Nine (64.2%) of the 14 patients were found to have undiagnosed metastases on explant pathology, with at least 22 unaccounted viable tumors before LT. Furthermore, 4 (57.1%) of the 7 patients who demonstrated complete radiographic response harbored viable carcinoma on explant pathology. CONCLUSIONS: A complete radiographic response does not reliably predict a complete pathologic response. In patients with unresectable CRLM, total hepatectomy and LT represent a promising treatment options to prevent indolent disease progression from disappearing CRLM.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Liver Transplantation , Humans , Colorectal Neoplasms/pathology , Hepatectomy , Incidence , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liver Neoplasms/secondaryABSTRACT
BACKGROUND: The safety and efficacy data of the different types of available vaccines is still needed. The goal of the present analysis was to evaluate the humoral response to the COVID-19 vaccines in orthotopic liver transplant (OLT) recipients. METHODS: Participants were included from February to September 2021. No prioritized vaccination roll call applied for OLT patients. Controls were otherwise healthy people. Blood samples were drawn after 15 days of the complete vaccine doses. The samples were analyzed according to the manufacturer's instructions using the Liaison XL platform from DiaSorin (DiaSorin S.p.A., Italy), and SARS-COV-2 IgG II Quant (Abbott Diagnostics, IL, USA). RESULTS: A total of 187 participants (133 OLT, 54 controls, median age: 60 years, 58.8% women) were included for the analysis; 74.3% had at least one comorbidity. The serologic response in OLT patients was lower than in controls (median 549 AU/mL vs. 3450 AU/mL, respectively; p = 0.001). A positive humoral response was found in 133 OLT individuals: 89.2% with BNT162b2 (Pfizer-BioNTech), 60% ChAdOx1 nCOV-19 (Oxford-AstraZeneca), 76.9% with CoronaVac (Sinovac, Life Sciences, China), 55.6% Ad5-nCov (Cansino, Biologics), 68.2% Gam-COVID-Vac (Sputnik V) and 100% with mRNA-1273. In controls the serological response was 100%, except for Cansino (75%). In a multivariable model, personal history of COVID-19 and BNT162b2 inoculation were associated with the serologic response, while the use of prednisone (vs. other immunosuppressants) reduced this response. CONCLUSION: The serologic response to COVID-19 vaccines in OLT patients is lower than in healthy controls. The BNT162b2 vaccine was associated with a higher serologic response.
Subject(s)
COVID-19 , Liver Transplantation , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , ChAdOx1 nCoV-19 , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Transplant RecipientsABSTRACT
This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p < 0.001). Low-dose aspirin was associated with a lower risk of ACR and HAT after LT, especially in the first vulnerable year after transplantation. Therefore, low-dose aspirin use after primary LT should be evaluated to protect the liver graft from ACR and to maintain arterial patency.
Subject(s)
Liver Transplantation , Thrombosis , Adult , Humans , Liver Transplantation/adverse effects , Cohort Studies , Graft Rejection/prevention & control , Thrombosis/etiology , Thrombosis/prevention & control , Allografts , Graft Survival , Retrospective Studies , Risk FactorsABSTRACT
OBJECTIVE: To analyze the perioperative and long-term outcomes of patients undergoing LT due to BDI in a tertiary care center. BACKGROUND: BDI is associated with significant morbidity and long-term impact on quality of life. LT represents the only possibility of a cure in patients with BDI who develop SBC. METHODS: Retrospective cohort study from a prospective LT database. Between 2008 and 2019, patients with SBC due to BDI after cholecystectomy and requiring LT were identified. Perioperative and long-term outcomes were analyzed. RESULTS: Among 354 LT, 12 patients underwent LT to treat post-cholecystectomy BDI and accounted for 3.4% of all LT. The median time from BDI to SBC diagnosis was 9.3âyears (2.4-14). The mean time from SBC to inclusion on the waitlist was 2.4years (± 2.2). Postoperative complications occurred in 11 patients (91.6%); mainly infectious (9/12 patients, 75%), followed by renal complications (4/12 patients, 33.3%). Only 2 patients developed major complications, which were the patients who died, resulting in a 90-day mortality of 16.7%. After a mean follow-up of 40.3âmonths (± 42.2) survival at 1, 3, and 5âyears was 83%. CONCLUSIONS: Although BDI is an unusual indication for LT worldwide, it accounted for 3.4% of all LT in our center. Although postoperative mortality remains high, LT is the only possibility of a cure, with acceptable long-term outcomes. Early referral to a tertiary care center is essential to avoid long-term complications of BDI, such as SBC.
Subject(s)
Bile Duct Diseases , Cholecystectomy, Laparoscopic , Liver Transplantation , Bile Duct Diseases/etiology , Bile Ducts/surgery , Cholecystectomy/adverse effects , Cholecystectomy, Laparoscopic/adverse effects , Humans , Liver Transplantation/adverse effects , Prospective Studies , Quality of Life , Retrospective StudiesABSTRACT
BACKGROUND: Bile duct injury (BDI) is accompanied by significant morbidity and long-term impact in quality of life. Subtotal cholecystectomy (STC) is an alternative to prevent this outcome but is associated with other complications. The aim of this work is to demonstrate that BDI associated morbidity exceeds STC associated morbidity, underscoring STC as a reasonable bail out strategy. METHODS: We compared 115 patients who underwent STC with 293 patients who were referred to our center with BDI type E1-E3 and underwent surgical repair. The groups were comparable because in both instances the surgeon had the opportunity to decide not to perform a total cholecystectomy once critical view of safety (CVS) was not achieved. RESULTS: Bile leakage was found in 21% of the STC group with only one BDI (0.9%). More Accordion ≥ 4 were found in the STC group (10.4% vs 4.8%, p = 0.035); however, reoperations were more frequent in the BDI group (8.2% vs 0.9%, p = 0.006). No patient in the STC group required reintervention for completion cholecystectomy. After 3.8 years follow-up, 2.4% of patients had secondary biliary cirrhosis in the BDI group; none in the STC group. CONCLUSIONS: Despite complications of STC, morbidity associated with BDI is much higher due to high long-term reoperation rate, in addition to secondary biliary cirrhosis. STC is a safe alternative that can prevent BDI if properly and timely performed in the context of difficult cholecystectomy.
Subject(s)
Cholecystectomy, Laparoscopic , Quality of Life , Bile Ducts/surgery , Cholecystectomy , Cholecystectomy, Laparoscopic/adverse effects , Humans , Retrospective StudiesABSTRACT
BACKGROUND: A short right renal vein (RRV) remains a challenge for renal transplant surgery, especially in the living donor. Different techniques exist to obtain an RRV with a suitable length in cadaveric donor; however, in living donors the options are limited. MATERIAL AND METHODS: We present 2 living kidney transplants in which we obtained a very short RRV, making the implantation very difficult. We describe our technique to overcome this problem by using cadaveric iliac vessels retrieved from previous cadaveric donations and preserved at 4°C in histidine-tryptophan-ketoglutarate (HTK) solution, without intraoperative or postoperative complications. We complied with the Helsinki Congress and the Istanbul Declaration regarding the donor source. RESULTS: In both cases, kidney grafts had optimal primary function, with good creatinine clearance after transplant and good patency of vascular anastomosis by Doppler ultrasounds. CONCLUSIONS: We believe the use of cadaveric vessel grafts in living donor kidney transplant is a valuable resource as a rescue tool in emergency situations like the ones being presented in this article in order to avoid discarding a kidney graft with damage or short vessels. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Subject(s)
Iliac Artery/transplantation , Kidney Transplantation/methods , Living Donors , Renal Veins , Allografts , Cadaver , Humans , Male , Middle Aged , Transplantation, HomologousABSTRACT
Doege-Potter syndrome with acromegaloid facial changes is extremely rare. Uncooked cornstarch along with glucocorticoids have been used as supportive care in patients with non-islet cell tumor hypoglycemia (NICTH). Preoperative embolization of hepatic solitary fibrous tumors (SFT) with NICTH has yielded unsatisfactory results. Herein we present the case of a 61-year-old man with a 3-month history of severe frequent hypoglycemic episodes and acromegaloid facial changes. During a spontaneous hypoglycemia (26 mg/dL), laboratory values showed a hypoinsulinemic pattern with low levels of GH, IGFPB3, and an IGF2/IGF1 ratio of 8.5:1. Cross-sectional imaging revealed a large (16 × 13 × 11 cm) hepatic tumor, and cytology was consistent with SFT. A preoperative right portal embolization was performed in an effort to induce normal remnant liver hypertrophy to allow for safe tumor resection. After the procedure, uncooked starch treatment followed by prednisone was started, achieving complete remission of hypoglycemic episodes in the preoperative setting. He subsequently underwent partial hepatectomy. The histologic diagnosis was compatible with a potentially malignant SFT. The patient had an excellent outcome with complete remission of hypoglycemia, improvement of facial acromegaloid changes, and no further evidence of disease. To our knowledge, this is the first case of a patient with Doege-Potter syndrome with acromegaloid facial changes induced by a potentially malignant liver SFT, treated successfully with a multimodal approach consisting of uncooked cornstarch, low-dose prednisone, preoperative embolization, and complete surgical resection. The use of cornstarch and low-dose glucocorticoids may be an adequate treatment in advance of undergoing surgery.