KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Risk Factor Analysis for Developing Major Complications Following Esophageal Surgery-A Two-Center Study.

BACKGROUND: Esophagectomy carries a high risk of morbidity and mortality compared to other major surgeries. With the aim of creating an easy-to-use clinical preoperative risk assessment tool and to validate previously described risk factors for major complications following surgery, esophagectomies at two tertiary medical centers were analyzed. METHODS: A total of 450 patients who underwent esophagectomy for esophageal carcinoma at the University Medical Centre, Hamburg, or at the Medical Center University Duisburg-Essen, Germany (January 2008 to January 2020) were retrospectively analyzed. Epidemiological and perioperative data were analyzed to identify the risk factors that impact major complication rates. The primary endpoint of this study was to determine the incidence of major complications. RESULTS: The mean age of the patients was 63 years with a bimodal distribution. There was a male predominance across the cohort (81% vs. 19%, respectively). Alcohol abuse (p = 0.0341), chronic obstructive pulmonary disease (p = 0.0264), and cardiac comorbidity (p = 0.0367) were associated with a significantly higher risk of major complications in the multivariate analysis. Neoadjuvant chemotherapy significantly reduced the risk of major postoperative complications (p < 0.0001). CONCLUSIONS: Various patient-related risk factors increased the rate of major complications following esophagectomy. Patient-tailored prehabilitation programs before esophagectomy that focus on minimizing these risk factors may lead to better surgical outcomes and should be analyzed in further studies.

AI-based digital histopathology for perihilar cholangiocarcinoma: A step, not a jump.

Introduction: Perihilar cholangiocarcinoma (PHCC) is a rare malignancy with limited survival prediction accuracy. Artificial intelligence (AI) and digital pathology advancements have shown promise in predicting outcomes in cancer. We aimed to improve prognosis prediction for PHCC by combining AI-based histopathological slide analysis with clinical factors. Methods: We retrospectively analyzed 317 surgically treated PHCC patients (January 2009-December 2018) at the University Hospital of Essen. Clinical data, surgical details, pathology, and outcomes were collected. Convolutional neural networks (CNN) analyzed whole-slide images. Survival models incorporated clinical and histological features. Results: Among 142 eligible patients, independent survival predictors were tumor grade (G), tumor size (T), and intraoperative transfusion requirement. The CNN-based model combining clinical and histopathological features demonstrates proof of concept in prognosis prediction, limited by histopathological complexity and feature extraction challenges. However, the CNN-based model generated heatmaps assisting pathologists in identifying areas of interest. Conclusion: AI-based digital pathology showed potential in PHCC prognosis prediction, though refinement is necessary for clinical relevance. Future research should focus on enhancing AI models and exploring novel approaches to improve PHCC patient prognosis prediction.

Preoperative Computed Tomography Volumetry and Graft Weight Estimation of Left Lateral Segment in Pediatric Living Donor Liver Transplant.

OBJECTIVES: Liver volumetry based on a computed tomography scan is widely used to estimate liver volume before any liver resection, especially before living donorliver donation. The 1-to-1 conversion rule for liver volume to liver weight has been widely adopted; however, debate continues regarding this approach. Therefore, we analyzed the relationship between the left-lateral lobe liver graft volume and actual graft weight. MATERIALS AND METHODS: This study retrospectively included consecutive donors who underwent left lateral hepatectomy for pediatric living donor liver transplant from December 2008 to September 2020. All donors were healthy adults who met the evaluation criteria for pediatric living donor liver transplant and underwent a preoperative contrast-enhanced computed tomography scan. Manual segmentation of the leftlateral liverlobe for graft volume estimation and intraoperative measurement of an actual graft weight were performed. The relationship between estimated graft volume and actual graft weight was analyzed. RESULTS: Ninety-four living liver donors were included in the study. The mean actual graft weight was ~283.4 ± 68.5 g, and the mean graft volume was 244.9 ± 63.86 mL. A strong correlation was shown between graft volume and actual graft weight (r = 0.804; P < .001). Bland-Altman analysis revealed an interobserver agreement of 38.0 ± 97.25, and intraclass correlation coefficient showed almost perfect agreement(r = 0.840; P < .001). The conversion formula for calculating graft weight based on computed tomography volumetry was determined based on regression analysis: 0.88 × graft volume + 41.63. CONCLUSIONS: The estimation of left liver graft weight using only the 1-to-1 rule is subject to measurable variability in calculated graft weights and tends to underestimate the true graft weight. Instead, a different, improved conversion formula should be used to calculate graft weight to more accurately determine donor graft weight-to-recipient body weightratio and reduce the risk of underestimation of liver graft weightin the donor selection process before pediatric living donor liver transplant.

Transplantation for Primary Sclerosing Cholangitis: Outcomes and Recurrence.

Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18-70) with a median (range) lab-MELD of 16 (7-40). Median (range) ICU and hospital stays were 4.6 days (0-147) and 21 days (1-176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates.

Donor, Recipient and Surgeon Sex and Sex-Concordance and their Impact on Liver Transplant Outcome.

(1) Background: Patient sex is associated with differential outcome of many procedures although the exact mechanisms remain unknown. Especially in transplant surgery, surgeon-patient sex-concordance is rarely present for female patients and outcome may be negatively affected. (2) Methods: In this single-center retrospective cohort study, recipient, donor, and surgeon sex were evaluated and short- and long-term outcome was analyzed with regards to sex and sex-concordance of patients, donors, and surgeons. (3) Results: We included 425 recipients in our study; 50.1% of organ donors, 32.7% of recipients, and 13.9% of surgeons were female. Recipient-donor sex concordance was present in 82.7% of female recipients and in 65.7% of male recipients (p = 0.0002). Recipient-surgeon sex concordance was present in 11.5% of female recipients and in 85.0% of male recipients (p < 0.0001). Five-year patient survival was comparable between female and male recipients (70.0% vs. 73.3%, p = 0.3978). Five-year patient survival of female recipients treated by female surgeons was improved without reaching significance (81.3% vs. 68.4%, p = 0.3621). (4) Conclusions: Female recipients and female surgeons are underrepresented in liver transplant surgery. Societal factors influencing outcome of female patients suffering from end-stage organ failure need to be further examined and acted upon to possibly improve the outcome of female liver transplant recipients.

Kidney transplantation following iliac revascularization in severe atherosclerosis: a comparative study.

BACKGROUND: Kidney transplantation (KT) has become the standard of care for patients with end-stage renal disease. However, as atherosclerosis progresses with time on dialysis, it causes increasing difficulties in implanting the graft. This is a comparative study analyzing complications and graft survival of recipients with iliac revascularization before transplantation. METHODS: Between January 2006 and December 2015, 1691 kidney transplants were performed at our institution. We retrospectively analyzed eighteen patients with peripheral arterial disease (PAD) with the necessity of vascular revascularization before kidney transplantation to protect the inflow to the renal graft and to optimizing blood supply to the extremities. The primary endpoint included patient survival and graft survival. The secondary endpoints evaluate perioperative and early postoperative complication rates after kidney transplantation. RESULTS: All patients enrolled in this study underwent two consecutive surgical procedures. No patient reported limb loss, and there was no additional perioperative morbidity or mortality related to the vascular procedure. Primary endpoints such as graft survival without dialysis and overall patient survival show 1-month survival of 100%, 1-year survival of 94.1%, and 5-year survival of 84.70%, respectively. One graft failure occurred 8 months after transplantation due to acute rejection, and there were two deaths over follow-up period due to myocardial infarction. CONCLUSIONS: Vascular repair before kidney transplantation is safe, and results are suggestive that it prolongs graft survival. These promising results should encourage other centers to address vascular repair before the transplantation to optimize blood supply to the extremity and the future graft. Although, the interpretation of our results must be cautiously because of the small and heterogeneous sample size, and the limitations of retrospective study design. Prospective trials with larger study populations are needed to confirm the results of this study and to identify significant differences.

A Phase II Study of Nab-Paclitaxel and Gemcitabine as First-Line Therapy in Patients with Cholangiocarcinoma Ineligible for Cisplatin-Based Chemotherapy (NACHO).

INTRODUCTION: Gemcitabine and cisplatin is the standard first-line systemic treatment in patients with advanced cholangiocarcinoma (CCA). However, a substantial number of patients do not qualify for cisplatin due to comorbidities or poor performance status. The phase II pilot study NACHO evaluated the efficacy of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) given on days 1, 8, and 15 every 4 weeks as first-line therapy in patients with advanced CCA ineligible for cisplatin-based chemotherapy. METHODS: Patients with any comorbidity precluding cisplatin therapy, such as renal impairment, impaired hearing, increased risk or history for thromboembolic events, intolerance of extensive hydration, or significant cardiovascular disease were eligible. Primary endpoint was overall response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and patient reported outcome. RESULTS: From December 2016 to July 2017, 10 patients were prospectively enrolled and treated. The ORR with nab-paclitaxel/gemcitabine was 50%, the disease control rate (DCR) was 90%. Median PFS was 5.7 months (95% CI: 5.3-6.1), and median OS was 7.8 months (95% CI: 5.4-10.2). In total, 13 SAEs were documented without any new safety signals. There were 14 grade 3-4 treatment-related adverse events (TRAEs) in 10 patients of the ITT population. Exploratory subgroup analyses including known prognostic markers were performed. CONCLUSIONS: The NACHO trial supports safety and efficacy of nab-paclitaxel and gemcitabine in patients with advanced CCA ineligible for cisplatin-based therapy and should be further evaluated in a larger prospective trial.

Clinical Outcome and Treatment Sequences of Patients with Advanced Pancreatic Cancer Treated with Contemporary Chemotherapy Protocols.

INTRODUCTION: Systemic therapy is firmly established in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Clinical efficacy is still modest and options are limited. Combination therapy protocols such as FOLFIRINOX and gemcitabine/nab-paclitaxel (Gem/NP) define standard-of-care. Patients may receive a sequence of both regimens as first- and second-line palliative treatment. However, there is no guidance regarding a preferred order. METHODS: This is a retrospective analysis of clinical characteristics, treatment trajectories, and outcomes of patients with advanced PDAC treated at the West German Cancer Center Essen from 2014 to 2020 to inform treatment decisions with respect to predictive factors, impact of chemotherapy regimen sequence, and maintenance treatment. RESULTS: We identified 170 patients with available follow-up. Of those, 160 (94.1%) patients received palliative CTX for primary metastatic, locally advanced, or recurrent PDAC. Median progression-free survival (PFS) upon first palliative chemotherapy was 4.1 (3.1-5.9) months. First-line FOLFIRINOX was associated with superior PFS (median 6.3 months) and OS (9.7 months, HR 0.7, p = 0.03) as compared to Gem/NP or other regimens (PFS 3.0, OS 6.9 months). However, OS benefit of first-line FOLFIRINOX was lost in patients who received at least two treatment lines (median OS 12.1 vs. 13.1 months, p = 0.43). A landmark analysis of patients with clinical benefit (defined as CR/PR/SD for at least 20 weeks) upon first-line therapy revealed improved OS (HR 0.53, p = 0.02) for patients receiving continued deescalated maintenance therapy. Second-line regimens resulted in similar PFS (overall log-rank p = 0.92, median PFS upon second-line therapy 2.3 [1.8-2.9], per-regimen median between 1.8 and 3.9 months). A previously established systemic inflammation score proved to be strongly prognostic and allowed identification of a patient subgroup with dismal prognosis (OS 2.9 vs. 11.4 months, HR 5.23, p < 0.001), independent of other prognostic factors and with no relevant interaction with the choice of first-line regimen. CONCLUSION: In this real-world population of PDAC patients treated with contemporary combination chemotherapies, a positive impact of first-line FOLFIRINOX was only observed when no second or further line treatment was administered. Intensity-reduced maintenance therapy may lead to superior survival.

Deep learning-based assessment of body composition and liver tumour burden for survival modelling in advanced colorectal cancer.

BACKGROUND: Personalized therapy planning remains a significant challenge in advanced colorectal cancer care, despite extensive research on prognostic and predictive markers. A strong correlation of sarcopenia or overall body composition and survival has been described. Here, we explore whether automated assessment of body composition and liver metastases from standard of care CT images can add to clinical parameters in personalized survival risk prognostication. METHODS: We retrospectively analysed clinical imaging data from 85 patients (50.6% female, mean age 58.9 SD 12.2 years) with colorectal cancer and synchronous liver metastases. Pretrained deep learning models were used to assess body composition and liver metastasis geometry from abdominal CT images before the initiation of systemic treatment. Abdominal muscle-to-bone ratio (MBR) was calculated by dividing abdominal muscle volume by abdominal bone volume. MBR was compared with body mass index (BMI), abdominal muscle volume, and abdominal muscle volume divided by height squared. Differences in overall survival based on body composition and liver metastasis parameters were compared using Kaplan-Meier survival curves. Results were correlated with clinical and biomarker data to develop a machine learning model for survival risk prognostication. RESULTS: The MBR, unlike abdominal muscle volume or BMI, was significantly associated with overall survival (HR 0.39, 95% CI: 0.19-0.80, P = 0.009). The MBR (P = 0.022), liver metastasis surface area (P = 0.01) and primary tumour sidedness (P = 0.007) were independently associated with overall survival in multivariate analysis. Body composition parameters did not correlate with KRAS mutational status or primary tumour sidedness. A prediction model based on MBR, liver metastasis surface area and primary tumour sidedness achieved a concordance index of 0.69. CONCLUSIONS: Automated segmentation enables to extract prognostic parameters from routine imaging data for personalized survival modelling in advanced colorectal cancer patients.

Identification of a new prognostic score for patients with high-grade metastatic GEP-NEN treated with palliative chemotherapy.

PURPOSE: High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN G3) are rare and heterogeneous malignancies with poor prognosis. Aim of this study was to develop prognosticators identifying those patients that derive the most benefit from currently available systemic therapies. METHODS: This retrospective analysis included 78 patients with metastatic GEP-NEN G3. For patients with imaging data available (n = 52), the overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Cox proportional hazard model was used to analyze the prognostic value of selected clinical and blood-based biomarkers. The impact of palliative chemotherapy regimens on time-to-treatment-failure (TTF) and overall survival (OS) was assessed. RESULTS: Median OS of the study cohort was 9.0 months (95% CI 7.0-11.1). The majority of patients received first-line treatment with platinum plus etoposide (83.3%). The ORR and DCR of the RECIST-evaluable subgroup were 34.6% and 76.9%. Median TTF upon first-line treatment was 4.9 months (95% CI 3.4-6.4). Multivariate analysis identified the Eastern Cooperative Oncology Group performance status (ECOG PS), lactate dehydrogenase (LDH) and absolute lymphocyte count as independent prognostic factors. A prognostic score based on these parameters discriminated patients with favorable and unfavorable outcomes. CONCLUSION: Outcomes of patients with GEP-NEN G3 are still limited. A new prognostic score identifying those patients benefitting from current platinum/etoposide-based chemotherapy protocols may help as stratification factor in future trial design.

Plasma Sequencing for Patients with GIST-Limitations and Opportunities in an Academic Setting.

Circulating tumor DNA (ctDNA) from circulating free DNA (cfDNA) in GIST is of interest for the detection of heterogeneous resistance mutations and treatment monitoring. However, methodologies for use in a local setting are not standardized and are error-prone and difficult to interpret. We established a workflow to evaluate routine tumor tissue NGS (Illumina-based next generation sequencing) panels and pipelines for ctDNA sequencing in an academic setting. Regular blood collection (Sarstedt) EDTA tubes were sufficient for direct processing whereas specialized tubes (STRECK) were better for transportation. Mutation detection rate was higher in automatically extracted (AE) than manually extracted (ME) samples. Sensitivity and specificity for specific mutation detection was higher using digital droplet (dd)PCR compared to NGS. In a retrospective analysis of NGS and clinical data (133 samples from 38 patients), cfDNA concentration correlated with tumor load and mutation detection. A clinical routine pipeline and a novel research pipeline yielded different results, but known and resistance-mediating mutations were detected by both and correlated with the resistance spectrum of TKIs used. In conclusion, NGS routine panel analysis was not sensitive and specific enough to replace solid biopsies in GIST. However, more precise methods (hybridization capture NGS, ddPCR) may comprise important research tools to investigate resistance. Future clinical trials need to compare methodology and protocols.

[68Ga]FAPI-PET/CT for radiation therapy planning in biliary tract, pancreatic ductal adeno-, and adenoidcystic carcinomas.

Biliary-tract-carcinomas (BTC), pancreatic-ductal-adenocarcinomas (PDAC) and adenoidcystic-carcinomas (AC) have in common that they are traditionally treated with large clinical-target-volumes (CTV). The aim of this study is to examine the impact of pretreatment-[68Ga]FAPI-PET/CT on target-volume-definition and posttreatment-[68Ga]FAPI-PET/CT-response-assessment for BTC-, PDAC- and AC-patients referred to radiation-therapy. All consecutive BTC-, PDAC-, and AC-patients who received pretreatment-[68Ga]FAPI-PET/CT±[18F]FDG-PET/CT were included from 01.01.2020 to 01.03.2022. MTV and SUVmax were separately generated based on [68Ga]FAPI- and [18F]FDG-PET/CT-images. A [68Ga]FAPI- and [18F]FDG-based-CTV was defined. Treatment-plans were compared. Treatment-response was reassessed by a second [68Ga]FAPI-PET/CT and [18F]FDG-PET/CT after treatment-completion. Intermodality comparison of lesion-to-background-ratios [SUVmax_lesion/SUVmean_background] for individual timepoints t1 and t2 revealed significant higher values for [68Ga]FAPI compared to [18F]FDG (t1, p = 0.008; t2, p = 0.005). Intermodality comparison of radiation-therapy-plans showed that [68Ga]FAPI-based planning resulted in D100% = 97.2% and V95% = 98.8% for the [18F]FDG-MTV. [18F]FDG-based-planning resulted in D100% = 35.9% and V95% = 78.1% for [68Ga]FAPI-MTV. [18F]FDG-based-planning resulted only in 2 patients in V95% > 95% for [68Ga]FAPI-MTV, and in 1 patient in D100% > 97% for [68Ga]FAPI-MTV. GTV-coverage in terms of V95% was 76.4% by [18F]FDG-based-planning and 99.5% by [68Ga]FAPI-based-planning. Pretreatment [68Ga]FAPI-PET/CT enhances radiation-treatment-planning in this particular group of patients. While perilesional and tumoral follow-up [18F]FDG-uptake behaved uniformly, perilesional and tumoral reaction may differ in follow-up [68Ga]FAPI-imaging. Complementary [68Ga]FAPI- and [18F]FDG-imaging enhance treatment-response-assessment.

Is preoperative CT-guided biopsy a valuable tool in the diagnostic workup of patients with visceral and retroperitoneal sarcoma?

PURPOSE: We aimed to analyze the diagnostic accuracy of preoperative CT-guided biopsy to identify patients that might profit from neoadjuvant chemotherapy in a specialized high-volume sarcoma center. MATERIAL AND METHODS: We retrospectively reviewed all patients with suspected soft tissue tumors of the abdomen cavity including the retroperitoneum, who received CT-guided biopsy followed by surgical tumor resection. Sensitivity, specificity, PPV and NPV were calculated in all patients with abdominal sarcomas at our hospital. A subgroup analysis was performed for patients with liposarcoma. RESULTS: A total of 82 patients (35 female, 47 male, age: 62.0 ± 14.7) received preoperative CT-guided biopsy followed by surgical resection. Overall accordance of CT-guided biopsy to identify final histology was 77 %. CT-guided biopsy revealed the diagnosis of liposarcoma in 23 patients whereas final analysis of the surgical specimen identified liposarcoma in 29 patients. Here, sensitivity, specificity, PPV and NPV was 79.3 %, 100.0 %, 100.0 % and 89.8 % respectively. Subgroup analysis revealed a better accuracy for correctly identifying patients with well-differentiated liposarcoma than patients with dedifferentiated liposarcoma (75.0 % vs 62.5 %). In patients with other sarcoma, sensitivity, specificity, PPV, NPV and diagnostic accuracy was 87.5 %, 95.5 %, 82.4 % and 96.9 %, respectively. CONCLUSION: CT-guided biopsy in a specialized high-volume sarcoma center is an accurate and effective method to assess patients with abdominal sarcoma and especially abdominal liposarcoma. Therefore, it is an indispensable tool in the pretherapeutic workup process. Nevertheless, our study underlines the previously reported difficulties in dedifferentiated liposarcoma diagnostics, whereby these patient cohort would profit the most from a neoadjuvant therapy regime.

Bridging treatment prior to liver transplantation for hepatocellular carcinoma: radioembolization or transarterial chemoembolization?

BACKGROUND: In hepatocellular carcinoma (HCC) patients, intraarterial therapies are regularly employed as a bridge to liver transplantation to prevent tumor progression during waiting time. Objective of this study was to compare HCC recurrence after liver transplantation following TACE or radioembolization bridging treatment. METHODS: We retrospectively analyzed prospectively collected data on 131 consecutive HCC patients who underwent liver transplantation between January 2007 and December 2017 at our liver transplant center (radioembolization n = 44, TACE n = 87). Multivariable logistic regression and cox proportional hazard regression models were used to evaluate factors associated with tumor recurrence and post-transplant survival. RESULTS: Between groups, patients were comparable with regards to age and gender. In the radioembolization group, Milan criteria for HCC were met significantly less frequently (20.5% vs. 65.5%, p < 0.0001). Patients in the radioembolization group required significantly fewer intraarterial treatments (1 [1-2] vs. 1 [1-7], p = 0.0007). On explant specimen, tumor differentiation, microvascular invasion and tumor necrosis were comparable between the groups. HCC recurrence and overall survival were similar between the groups. Multivariable analysis detected increasing recipient age, male gender, complete tumor necrosis and absence of microvascular invasion being independently associated with decreased odds for HCC recurrence. Increasing model of end-stage liver disease (MELD) score and tumor recurrence were independently associated with increased odds of post-transplant death. CONCLUSIONS: Intraarterial bridging treatment leading to tumor necrosis may not only prevent waitlist drop-out but also facilitate long-term successful liver transplantation in HCC patients. Both radioembolization and TACE represent potent treatment strategies.

Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'.

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann-Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories 'regulome', 'inflammaging', 'regeneration', and 'pharmacogenes'. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed 'aging cascade', wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.

Localized Angiosarcoma, Not One Disease: A Retrospective Single-Center Study on Prognosis Depending on the Primary Site and Etiology.

BACKGROUND: Angiosarcomas are rare and heterogeneous tumors with poor prognosis. The clinical subtypes are classified depending on the primary site and etiology. METHODS: We conducted a retrospective, monocentric study of 136 patients with localized AS between May 1985 and November 2018. Overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were estimated using the Kaplan-Meier method. To identify prognostic factors, univariate and multivariate analyses were performed based on Cox regressions. RESULTS: The median age was 67 years (19-72.8 years). Primary sites were cutaneous (27.2%), breast (38.2%), and deep soft tissue (34.6%). The majority was primary angiosarcomas (55.9%) followed by postradiation (40.4%) and chronic lymphedema angiosarcomas (2.9%). Prognosis significantly differed depending on the primary site and etiology. Shortest median OS and MFS were observed in deep soft tissue angiosarcomas, whereas cutaneous angiosarcomas, angiosarcomas of the breast, and radiation-associated angiosarcomas displayed worse median LRFS. Univariate analyses showed better OS for tumor size <10 cm (p = 0.009), negative surgical margins (p = 0.021), and negative lymph node status (p = 0.007). LRFS and MFS were longer for tumor size <10 cm (p = 0.012 and p = 0.013). In multivariate analyses, age <70 years was the only independent positive prognostic factor for OS in all subgroups. For LRFS, secondary AS of the breast was a negative prognostic factor (HR: 2.35; p = 0.035). CONCLUSIONS: Different behaviors and prognoses depending on the primary site and etiology should be considered for the treatment of this heterogeneous disease. In cutaneous angiosarcomas of the head/neck and postradiation angiosarcomas of the breast, local recurrence seems to have a crucial impact on OS. Therefore, improved local therapies and local tumor staging may have to be implemented. However, in deep soft tissue angiosarcomas, distant recurrence seems to have a major influence on prognosis, which indicates a benefit of additional perioperative chemotherapy.

First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.

Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re-introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell-free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold-induced reperfusion injury or to evaluate graft performance.

Long-term outcome of third, fourth and fifth kidney transplantation: technical aspects and immunological challenges.

BACKGROUND: The number of patients on waiting lists for repeated kidney transplantation has increased. However, retransplanted patients have a greater surgical and immunological risk than first-time kidney recipients. METHODS: We retrospectively analysed all kidney recipients that underwent third, fourth or fifth kidney transplantation (Group 3+) at the University Hospital Essen, Essen, Germany from October 1973 to January 2017. A historical cohort of recipients retransplanted with a second kidney (Group 2) served as the control. Donor and recipient demographic data, cold ischaemia time (CIT), warm ischaemia time, overall operation time and methods, transplantectomy of previous kidney grafts, incidence of surgical and immunological complications as well as patient- and death-censored survival were analysed. RESULTS: We identified 108 recipients transplanted with the third, fourth or fifth renal allograft. Patients with more than one transplantation had significantly higher surgical risk due to atherosclerosis (P = 0.002) and higher immunological risk due to higher panel reactive antibody levels preoperatively (current panel reactive antibody P = 0.004; highest panel reactive antibody value P = 0.0001). Group 3+ patients had more often undergone previous transplant nephrectomy (P = 0.0001). There was a significant difference in CIT (P = 0.009), overall operative time (P = 0.0001) and post-transplantation thrombotic events (P = 0.02). We could not demonstrate any differences in graft and patient survival. CONCLUSION: Third, fourth and fifth transplant recipients are a high-risk patient cohort. Our results suggest that patient survival after more than three renal transplantations is similar to that of second graft recipients. This supports the concept of repeated kidney retransplantations.

Analysis of Data from the Oxygen Persufflation in Liver Transplantation (OPAL) Study to Determine the Role of Factors Affecting the Hepatic Microcirculation and Early Allograft Dysfunction.

BACKGROUND Adequate microcirculatory perfusion is essential for the provision of oxygen to the liver following transplantation. Data from the Oxygen Persufflation in Liver Transplantation (OPAL) study (ISRCTN00167887) were analyzed from liver transplants performed at a single center to determine the role of factors affecting the hepatic microcirculation and early allograft dysfunction (EAD). MATERIAL AND METHODS Retrospective data from 116 patients from the Oxygen Persufflation as Adjunction in Liver Transplantation (OPAL) study who underwent liver transplantation at a single center were analyzed. Oxygen saturation of hemoglobin (SO2), relative capillary hemoglobin concentration (rHb), relative tissue blood flow (rBF) using laser Doppler flow measurements, and the Oxygen-to-See (O2C) spectrometry were measured and with post-transplant allograft function were analyzed using univariate and multivariate logistic regression statistics. RESULTS Livers donors had a median donor risk index of 1.8. Most liver transplant recipients were men (60.3%), with a median age of 54 years (IQR, 23-68 years). Mean post-transplant 3-month survival was 90.5%. The EAD rate was 22.4%, the median SO2 was 78% (IQR, 29.5-95.8%), the median rHb was 55.6 AU (IQR, 16.8-74.8 AU), and the median rBF was 110.1 AU (IQR, 35.8-406.8 AU). Multivariate logistic regression analysis showed that tissue SO2 (p=0.01), body mass index (BMI) of the transplant recipient (p=0.002), serum alanine transaminase (ALT) of the donor (p=0.02), and portal blood flow (p=0.01) were predictive factors for EAD. CONCLUSIONS Non-invasive investigations of the liver microcirculation and hemoglobin oxygenation were shown to be predictive factors for EAD following liver transplantation.