Changing Landscape of Open Offers in Liver Transplantation in the Machine Perfusion Era: Exposure, Equity, and Economics.

BACKGROUND: Open offers (OOs) in liver transplantation (LT) result from bypassing the traditional allocation system. Little is known about the trends of OOs or the differences in donor/recipient characteristics compared to traditionally placed organs. We aim to quantify modern practices regarding OOs and understand NMP's impact, focusing on social determinants of health (SDH), cost, and graft-associated risk. METHODS: LTs from 1/1/2018 to 12/31/2023 at a single center were included. NMP was implemented on 10/1/2022. The CDC (centers for disease control)-validated social vulnerability index (SVI) and donor risk index (DRI) were calculated. Comprehensive complications index (CCI), Clavien-Dindo grades, patient and graft survival, and costs of transplantation were included. RESULTS: 1162 LTs were performed; 193 (16.8%) from OOs. OOs were more common in the post-NMP era (26.5% vs. 13.3%, p < 0.001). Pre-NMP, patients receiving OOs had longer waitlist times (118 vs. 69 days, p < 0.001), lower MELDs (17 vs. 25 points, p < 0.001), and riskier grafts (DRI = 1.8 vs. 1.6, p = 0.004) compared to standard offers. Post-NMP, recipients receiving OOs demonstrated no difference in waitlist time (27 vs. 20 days, p = 0.21) or graft risk (DRI = 2.03 vs. 2.23, p = 0.17). OO recipient MELD remained lower (16 vs. 22, p < 0.001). OO recipients were more socially vulnerable (SVI), pre-NMP (0.41 vs. 0.36, p = 0.004), but less vulnerable after NMP (0.23 vs. 0.36, p = 0.019). Despite increased graft risk, pre-NMP OO-LTs were less expensive in the 90-day global period ($154 939 vs. $178 970, p = 0.002) and the 180-days pre-/post-LT ($208 807 vs. $228 091, p = 0.021). Cost trends remained similar with NMP. CONCLUSION: OOs are increasingly utilized and may be appealing due to demonstrated cost reductions even with NMP. Although most OO-related metrics in our center remain similar before and after machine perfusion, programs should take caution that increasing use does not worsen organ access for socially vulnerable populations.

Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy.

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

The use of artificial intelligence to detect parathyroid tissue on ex vivo specimens during thyroidectomy and parathyroidectomy procedures using near-infrared autofluorescence signals.

BACKGROUND: In thyroidectomy and parathyroidectomy procedures, diagnostic dilemmas related to whether an index tissue is of parathyroid or nonparathyroid origin frequently arise. Current options of frozen section and parathyroid aspiration are time-consuming. Parathyroid glands appear brighter than surrounding tissues on near-infrared autofluorescence imaging. The aim of this study was to develop an artificial intelligence model differentiating parathyroid tissue on surgical specimens based on near-infrared autofluorescence. METHODS: With institutional review board approval, an image library of ex vivo specimens obtained in thyroidectomy and parathyroidectomy procedures was created between November 2019 and April 2023 at a single academic center. Ex vivo autofluorescence images of surgically removed parathyroid glands, thyroid glands, lymph nodes, and thymic tissue were uploaded into an artificial intelligence platform. Two different models were trained, with the first model using autofluorescence images from all specimens, including thyroid, and the second model excluding thyroid, to prevent the effect of specimen size on the results. Deep-learning models were trained to detect autofluorescence signals specific to parathyroid glands. Randomly chosen 80% of data were used for training, 10% for validation, and 10% for testing. Recall, precision, and area under the curve of models were calculated. RESULTS: Surgical procedures included 377 parathyroidectomies, 239 total thyroidectomies, 97 thyroid lobectomies, and 32 central neck dissections. For the development of the model, 1151 images from a total of 678 procedures were used. The dataset comprised 648 parathyroid, 379 thyroid, 104 lymph node, and 20 thymic tissue images. The overall precision, recall, and area under the curve of the model to detect parathyroid tissue were 96.5%, 96.5%, and 0.985, respectively. False negatives were related to dark and large parathyroid glands. CONCLUSION: The visual deep-learning model developed to identify parathyroid tissue in ex vivo specimens during thyroidectomy and parathyroidectomy demonstrated a high sensitivity and positive predictive value. This suggests potential utility of near-infrared autofluorescence imaging to improve intraoperative efficiency by reducing the need for frozen sections and parathyroid hormone aspirations to confirm parathyroid tissue.

Utility of circulating tumor DNA in secondary liver malignancies: What we know and what is to come.

Secondary liver malignancies are a serious and challenging global health concern. Secondary metastasis to the liver is most commonly from colorectal cancer that has metastatically spread through splanchnic circulation. Metastatic diseases can portend poor prognosis due to the progressive nature typically found on detection. Improvements in detection of disease, monitoring therapy response, and monitoring for recurrence are crucial to the improvement in the management of secondary liver malignancies. Assessment of ctDNA in these patient populations poses an opportunity to impact the management of secondary liver malignancies. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within secondary liver malignancies.

Circulating tumor DNA in management of primary liver malignancy: A review of the literature and future directions.

Primary liver malignancies are a serious and challenging global health concern. The most common primary tumors are hepatocellular carcinoma and cholangiocarcinoma. These diseases portend poor prognosis when presenting with progressive, extensive disease. There is a critical need for improved diagnosis, therapeutic intervention, and monitoring surveillance in liver-related malignancies. Liquid biopsy using ctDNA provides an opportunity for growth within these domains for liver-related malignancy. However, ctDNA is relatively understudied in this field compared with other solid tumor types, possibly due to the complex nature of the pathology. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within primary liver malignancies.

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.

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.

Comparison of Perioperative Outcomes in Patients with Graves' Disease Undergoing Total Thyroidectomy With or Without Near Infrared Autofluorescence Imaging.

Background: The impact of near-infrared autofluorescence (NIRAF) imaging on postthyroidectomy hypocalcemia is controversial. As patients with Graves' disease are at increased risk, our aim was to compare postoperative parathyroid function in these patients undergoing total thyroidectomy (TT) with or without NIRAF imaging. Methods: This was a retrospective "before and after" study, comparing outcomes of patients who underwent TT without or with NIRAF imaging at a single center. Primary outcome was the incidence of temporary hypocalcemia and secondary outcomes, rates of incidental parathyroidectomy on final specimens and permanent hypocalcemia. Analyses were performed using Mann-Whitney U and chi-Square tests. Continuous data are expressed as median (interquartile range). Results: There were 85 patients in NIRAF and 100 patients in non-NIRAF group. Groups were comparable regarding age, gender, body-mass index, and thyroid weight. Number of parathyroid glands identified intraoperatively was 3 in both groups (p = 0.47). Intraoperative parathyroid implantation rate was 16.5% in NIRAF and 6% in non-NIRAF group (p = 0.02). Incidental parathyroidectomy rate on final pathology was 12.9% in NIRAF and 32% in non-NIRAF group (p = 0.002). The rates of temporary (11.7% vs. 16%) and permanent hypocalcemia (2.4% vs. 2%) were similar between the two groups, respectively (p = 0.66). Conclusion: To our knowledge, this is the first comparative study investigating the impact of NIRAF on postoperative parathyroid function after thyroidectomy for Graves' disease. The rate of incidental parathyroidectomy on final pathology was lower with use of NIRAF, without an impact on temporary or permanent hypocalcemia rates compared to conventional technique.

The utility of fluorescence imaging in detecting primary and metastatic small bowel carcinoid tumors.

BACKGROUND: Our aim was to investigate utility of indocyanine green (ICG) and autofluorescence (AF) imaging in detection of small bowel primary and metastatic carcinoids. METHODS: Using Institutional Review Board approval, ICG and AF imaging of small bowel carcinoids was performed. Imaging findings were prospectively recorded in operating room and compared with conventional imaging, surgical exploration and pathologic findings. RESULTS: There were 16 patients with 23 primary small bowel tumors, 27 mesenteric lymph nodes, 36 liver metastases and 2 peritoneal nodules. Carcinoid tumors exhibited brighter AF signals compared to background. AF imaging was superior to both DOTATATE PET and surgeon inspection/palpation in demonstrating small bowel primaries. Utility for metastatic lymph nodes and peritoneal metastases was limited. Superficial liver metastases exhibited brighter fluorescence compared to background on both ICG and AF imaging. CONCLUSIONS: This is the largest study assessing utility of near-infrared fluorescence imaging in detection of small bowel carcinoids. Our results show promise in the utilization fluorescence imaging to detect occult primary tumors and superficial liver metastases.

Sublethal effects of thiamethoxam on immune system cells in the workers of Bombus terrestris (Hymenoptera: Apidae).

Neonicotinoids harm especially bumblebees and other species in agricultural areas all over the world. The toxic effect of thiamethoxam from the neonicotinoid group has been little studied especially on bees. This research aimed to evaluate the effects of thiamethoxam on the immune system cells of Bombus terrestris workers. Different ratios of 1/1000, 1/100 and 1/10 of the recommended maximum application dose of thiamethoxam formed the experimental groups. Ten foraging workers were used for each dose and control groups. Contamination was ensured by spraying the prepared suspensions at different ratios to the bees for 20 s at a pressure of 1 atm. The effects of thiamethoxam on the structures of immune system cells of bumblebees and the amount of these cells were investigated after 48 h of exposure. In general, anomalies such as vacuolization, cell membrane irregularities and cell shape changes were detected in prohemocyte, plasmatocyte, granulocyte, spherulocyte and oenocytoid in each dose group. Hemocyte area measurements in all groups were examined comparatively between groups. In general, granulocyte and plasmatocyte sizes were decreased, while spherulocyte and oenocytoid were increased. It was also determined that there was a significant decrease in the amount of hemocytes in the 1 mm3 hemolymph as dose increased. The results of the study revealed that sublethal doses of thiamethoxam negatively affected hemocytes and their amounts of B. terrestris workers.

Effects of thiamethoxam on brain structure of Bombus terrestris (Hymenoptera: Apidae) workers.

Neonicotinoids are the most widely used pesticide compared to other major insecticide classes known worldwide and have the fastest growing market share. Many studies showed that neonicotinoid pesticides harm honeybee learning and farming activities, negatively affect colony adaptation and reduce pollination abilities. Bumblebees are heavily preferred species all over the world in order to ensure pollination in plant production. In this study, sublethal effects of the neonicotinoid insecticide thiamethoxam on the brain of Bombus terrestris workers were analyzed. Suspensions (1/1000, 1/100, 1/10) of the maximum recommended dose of thiamethoxam were applied to the workers. 48 h after spraying, morphological effects on the brains of workers were studied. According to area measurements of ICC's of Kenyon cells, there was a significant difference between 1/10 dose and all groups. On the other hand, areas of INC's of Kenyon cells showed a significant difference between the control group and all dose groups. Neuropil disorganization in the calyces increased gradually and differed significantly between the groups and was mostly detected at the highest dose (1/10). Apart from optic lobes, pycnotic nuclei were also observed in the middle region of calyces of mushroom bodies in the high dose group. Also, the width of the lamina, medulla and lobula parts of the optic lobes of each group and the areas of the antennal lobes were measured and significant differences were determined between the groups. The results of the study revealed that sublethal doses of thiamethoxam caused some negative impacts on brain morphology of B. terrestris workers.