Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report.

INTRODUCTION: The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. CASE REPORT: We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

Baseline Histological Findings Do Not Predict the Risk of Subsequent Extension in Patients with Limited Ulcerative Colitis.

BACKGROUND: Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. AIMS: We sought to determine whether histologic features correlate with disease extension. METHODS: The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. RESULTS: Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r = - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). CONCLUSIONS: Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.

Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze-thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.

Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE.NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

Donor-Transmitted Cancers in Transplanted Livers: Analysis of Clinical Outcomes.

The risk of transmission of malignancy from donor to recipient is low. However, this occurrence has dramatic consequences. Many reports of donor-derived cancers in liver transplant recipients have been published, but they have not been systematically summarized into a lucid and unified analysis. The present study is an attempt to provide clarity to this unusual but clinically important problem. We systematically reviewed all patient reports, patient series, and registries published on cancer transmission events through the end of December 2019. We identified a total of 67 publications with 92 transmission events. The most frequently transmitted cancers were lymphomas (30; 32.6%), melanomas (8; 8.7%), and neuroendocrine tumors (8; 8.7%). Most of the melanomas were metastasizing, whereas most of the lymphomas were localized to the graft. The median time to cancer diagnosis after transplantation was 7 months, with 78.1% of diagnoses established in the first year. Melanoma carried the worst prognosis, with no recipients alive at 1 year after cancer diagnosis. Lymphoma recipients had a better outcome, with more than 75% surviving at 2 years. A metastatic cancer carries a worse prognosis for recipients, and recipients with localized cancer can benefit from the chance to undergo transplantation again. The findings confirm the need to pay attention to donors with a history of melanoma but also suggest the need for a more careful evaluation of groups of donors, such as those dying from cerebral hemorrhage. Finally, recipients of organs from donors with cancer should be carefully followed to detect potential transmission.

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

[18F]-Fluciclovine PET/CT for preoperative nodal staging in high-risk primary prostate cancer: final results of a prospective trial.

PURPOSE: The conventional imaging flowchart for prostate cancer (PCa) staging may fail in correctly detecting lymph node metastases (LNM). Pelvic lymph node dissection (PLND) represents the only reliable method, although invasive. A new amino acid PET compound, [18F]-fluciclovine, was recently authorized in suspected PCa recurrence but not yet included in the standard staging work-up of primary PCa. A prospective monocentric study was designed to evaluate [18F]-fluciclovine PET/CT diagnostic performance for preoperative LN staging in primary high-risk PCa. METHODS: Consecutive patients (pts) with biopsy-proven PCa, standard staging (including [11C]choline PET/CT), eligible for PLND, were enrolled to undergo an investigational [18F]-fluciclovine PET/CT. Nodal uptake higher than surrounding background was reported by at least two readers (blinded to [11C]choline) using a visual 5-point scale (1-2 probably negative; 4-5 probably positive; 3 equivocal); SUVmax, target-to-background (aorta-A; bone marrow-BM) ratios (TBRs), were also calculated. PET results were validated with PLND. [18F]-fluciclovine PET/CT performance using visual score and semi-quantitative indexes was analyzed both per patient and per LN anatomical region, compared to conventional [11C]choline and clinical predictive factors (to note that diagnostic performance of [18F]-fluciclovine was explored for LNM but not examined for intrapelvic or extrapelvic M1 lesions). RESULTS: Overall, 94 pts underwent [18F]-fluciclovine PET/CT; 72/94 (77%) high-risk pts were included in the final analyses (22 pts excluded: 8 limited PLND; 3 intermediate-risk; 2 treated with radiotherapy; 4 found to be M1; 5 neoadjuvant hormonal therapy). Median LNM risk by Briganti nomogram was 19%. LNM confirmed on histology was 25% (18/72 pts). Overall, 1671 LN were retrieved; 45/1671 (3%) LNM detected. Per pt, median no. of removed LN was 22 (mean 23 ± 10; range 8-51), of LNM was 2 (mean 3 ± 2; range 1-10). Median LNM size was 5 mm (mean 5 ± 2.5; range 2-10). On patient-based analyses (n = 72), diagnostic performance for LNM resulted significant with [18F]-fluciclovine (AUC 0.66, p 0.04; 50% sensitivity, 81% specificity, 47% PPV, 83% NPV, 74% accuracy), but not with [11C]choline (AUC 0.60, p 0.2; 50%, 70%, 36%, 81%, and 65% respectively). Briganti nomogram (OR = 1.03, p = 0.04) and [18F]-fluciclovine visual score (≥ 4) (OR = 4.27, p = 0.02) resulted independent predictors of LNM at multivariable analyses. On region-based semi-quantitative analyses (n = 576), PET/CT performed better using TBR parameters (TBR-A similar to TBR-BM; TBR-A fluciclovine AUC 0.61, p 0.35, vs choline AUC 0.57 p 0.54; TBR-BM fluciclovine AUC 0.61, p 0.36, vs choline AUC 0.58, p 0.52) rather than using absolute LN SUVmax (fluciclovine AUC 0.51, p 0.91, vs choline AUC 0.51, p 0.94). However, in all cases, diagnostic performance was not statistically significant for LNM detection, although slightly in favor of the experimental tracer [18F]-fluciclovine for each parameter. On the contrary, visual interpretation significantly outperformed PET semi-quantitative parameters (choline and fluciclovine: AUC 0.65 and 0.64 respectively; p 0.03) and represents an independent predictive factor of LNM with both tracers, in particular [18F]-fluciclovine (OR = 8.70, p 0.002, vs OR = 3.98, p = 0.03). CONCLUSION: In high-risk primary PCa, [18F]-fluciclovine demonstrates some advantages compared with [11C]choline but sensitivity for metastatic LN detection is still inadequate compared to PLND. Visual (combined morphological and functional), compared to semi-quantitative assessment, is promising but relies mainly on readers' experience rather than on unquestionable LN avidity. TRIAL REGISTRATION: EudraCT number: 2014-003,165-15.

Standardization of conventional chemoembolization for hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Conventional transarterial chemoembolization (cTACE) has several limitations due to the lack of standardization. The aim of this study was to evaluate the chemical and physical characteristics and behaviors over time of emulsions for cTACE and to assess intra- and inter-operator variabilities in the preparation processes. MATERIALS AND METHODS: This in vitro study involved evaluation of emulsions for cTACE prepared using two methods: water-in-oil (WiO) and chemotherapeutic-in-oil (CiO). Three emulsions were prepared with each method and obtained after 20, 50, and 100 pumping exchanges. A drop from each final mixture was analyzed via light microscopy (time 1) and after 5, 10, 15, and 20min since the end of preparation. After 20min, all preparations were re-mixed and new drops were re-evaluated. The intra- and inter-operator variabilities were analyzed. RESULTS: The mean droplet diameter decreased non-significantly when the number of pumping exchanges increased and increased significantly over time for both WiO and CiO. The droplets returned to their initial diameters after re-mixing. There were no significant differences in the intra- and inter-operator variabilities (P>0.01). CONCLUSIONS: Any interventional radiologist, regardless of their experience, may prepare these emulsions. These data may represent a set of instructions to standardize cTACE.

Correction: PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

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

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

Assessment of Liver Fibrosis With Elastography Point Quantification vs Other Noninvasive Methods.

BACKGROUND & AIMS: Elastography point quantification (ElastPQ) is a non-invasive method for assessing liver fibrosis based on liver stiffness. We evaluated the accuracy of ElastPQ for the staging of liver fibrosis in patients with chronic liver disease (CLD) compared with aspartate transaminase to platelet ratio index, fibrosis-4 index, and transient elastography (TE), using liver biopsy as reference standard. METHODS: We performed a retrospective study of 406 patients with CLD of any etiology who underwent liver biopsy analysis from September 2012 through June 2017 at a clinic in Bologna, Italy. We obtained liver stiffness measurements, made by ElastPQ and TE, for 361 patients. Liver fibrosis stage was assessed by the METAVIR scoring system. Areas under the receiver operating characteristic curve (AUROC) were used to assess the diagnostic performance of ElastPQ. RESULTS: ElastPQ values correlated with histologic detection of fibrosis (r = 0.718; P < .001). The AUROC values were 0.856 for detection of significant fibrosis (F≥2), 0.951 for advanced fibrosis (F≥3), and 0.965 for cirrhosis. The best cut-off values identified for classifying patients with F≥2, F≥3, or cirrhosis were 6.0 kPa, 6.2 kPa, and 9.5 kPa, respectively: these were lower than those for TE. Comparison of ElastPQ with TE data resulted in superimposable diagnostic accuracy of both methods for each stage of liver fibrosis. Both elastography techniques performed better than aspartate transaminase to platelet ratio index or fibrosis-4 index scores (P < .05 for all AUROC comparisons). CONCLUSIONS: ElastPQ has good to excellent performance for the non-invasive staging of liver fibrosis in patients with CLD. ElastPQ identified patients with fibrosis or cirrhosis with levels of accuracy that were not inferior to those of TE, and outperformed serum fibrosis indexes in identifying each stage of liver fibrosis.

Histological Evidence of Diabetic Kidney Disease Precede Clinical Diagnosis.

BACKGROUND: In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD). METHODS: In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. RESULTS: All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR <60 mL/min/1.73 m2. CONCLUSIONS: The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.

Histopathology and Long-Term Outcome of Kidneys Transplanted From Donors With Severe Acute Kidney Injury.

BACKGROUND: Acute kidney injury is a treatable entity although difficult to recognize without diagnostic biopsy. We investigated the potential association between clinically defined deceased donors and acute kidney injury with preimplantation histological findings and recipient outcomes. METHODS: Kidney biopsies from donors were classified using the Acute Kidney Injury Network criteria and assessed for percentage glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular narrowing with the Remuzzi score and for acute tubular necrosis. Differences in incidence rates of delayed graft function (DGF) and cumulative rejection episodes were compared between recipients transplanted with normal and 3 levels of acute kidney injury using the analysis of variance with Bonferroni correction ( P = .0012). RESULTS: Sixteen out of 335 donors showed a severe acute kidney injury level 3 with a median serum creatinine of 458 µmol/L. Fourteen (88%) had 0-3 Remuzzi score and were used for single kidney transplantation and 2 (12%) were used for dual kidney transplantation (score: 4-6). Recipients who received a kidney from a donor with level 3 acute kidney injury had a higher percentage of DGF (47%) without statistical significance ( P = .008). The rate of cumulative rejection (45%) at 2 years was not significantly increased ( P = .09). CONCLUSIONS: Recipients receiving level 3 acute kidney injury kidneys, selected with Remuzzi histopathological score and acute tubular necrosis assessment, had a greater incidence of DGF but a similar long-term cumulative rejection compared to no injury and level 1 and level 2 acute kidney injury donors. The application of the histopathological examination allowed expansion of the kidney donor pool.

New hallmark of hepatocellular carcinoma, early hepatocellular carcinoma and high-grade dysplastic nodules on Gd-EOB-DTPA MRI in patients with cirrhosis: a new diagnostic algorithm.

OBJECTIVE: Many improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging. DESIGN: Our study population included 420 nodules >1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology. RESULTS: A classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules ≤2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P<0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN. CONCLUSION: Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN.

Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study.

Donation after circulatory death (DCD) is a potential source of reducing organ demand. In Italy, DCD requires a 20-min no-touch period that prolongs warm ischemia and increases delayed graft function (DGF) risk and graft loss. We report here our preliminary experience of sequential use of normothermic regional perfusion (NRP), as standard procedure, and hypothermic oxygenated perfusion (HOPE), as an experimental technique of organ preservation, in 10 kidney transplants (KT) from five DCD Maastricht III with extensive functional warm ischemia time (fWIT) up to 325 min. During NRP, renal function tests were evaluated to accept organs which were retrieved according to standard fashion with biopsy. While waiting for pathology and cross-match results, organs were preserved with HOPE through pressure- and temperature-controlled arterial pulsatile flow. All grafts with Karpinski score ≤4 were used for conventional single KT with mean cold ischemia time of 584 ± 167 min and mean fWIT of 151 ± 132 min. At the end of HOPE, lactate levels increased significantly in all cases with DGF (P = 0.0095), which were 3/10 (30%). No primary nonfunctions were recorded, and all patients had sCr < 1.5 mg/dl at 6-month post-KT. NRP and HOPE for DCD may overcome fWIT limits safely, and lactate during HOPE predicts DGF.

Ten-Year Survival after Liver Resection for Breast Metastases: A Single-Center Experience.

BACKGROUND: The role of liver resection for metastatic breast carcinoma is still debated. METHODS: Fifty-one resected patients were reviewed. All patients received adjuvant chemotherapy after resection of the primary tumor. Clinicopathological characteristics and immunohistochemistry expression of estrogen (ER), progesterone (PR), human epidermal growth factor (HER2), or Ki67 were evaluated. RESULTS: The median number of metastases was 2; single metastases were present in 24 (47%) patients. The median tumor diameter was 4 cm. Major hepatectomies were performed in 31 (61%) patients. Postoperative mortality was null. Postoperative morbidity was 13.7%. The 1-, 5-, and 10-year survival rates were 92, 36, and 16% respectively. Eleven (21.6%) patients survived longer than 5 years and 8.9% are alive without recurrence 10 years after surgery. At the univariate analysis, tumor diameter, lymph node status, PR receptor status, and triple positive receptors (ER+/PR+/Her2+) were significantly related to survival. At the multivariate analysis, tumor diameter, PR receptor, and triple negative status were significantly related to the long-term outcome. CONCLUSION: Liver resection seems to be a safe and effective treatment for metastases from breast cancer, and encouraging long-term survival can be obtained with acceptable risk in selected patients. Tumors less than 5 cm and positive hormone receptor status are the best prognostic factors.

A New Two-Dimensional Shear Wave Elastography for Noninvasive Assessment of Liver Fibrosis in Healthy Subjects and in Patients with Chronic Liver Disease.

PURPOSE: To assess the performance of two-dimensional shear wave elastography (2D-SWE) on the GE LOGIQ E9 ultrasound system in a cohort of healthy subjects and to investigate its accuracy in the staging of liver fibrosis in patients with chronic liver disease (CLD) using liver biopsy as a reference standard. MATERIALS AND METHODS: From October 2014 to June 2016, 54 healthy subjects and 174 patients with CLD were consecutively enrolled. Liver fibrosis stage was assessed by the METAVIR scoring system. 18 (10.3 %) and 17 (9.8 %) patients had advanced fibrosis and cirrhosis, respectively. The correlation of liver stiffness measurement (LSM) and continuous variable was assessed using the Spearman rank correlation. The accuracy of 2D-SWE was evaluated with areas under the receiver operating characteristics curves (AUROC). RESULTS: Reliable LSMs were obtained in all subjects. The interobserver agreement ICC was excellent: 0.847. In healthy subjects, gender, but not anthropometric and biochemical data, were correlated with LSM. In patients with CLD, LSM had a strong positive correlation with fibrosis stage (rho = 0.628; p > 0.001). The AUROC was 0.724 for mild fibrosis (F≥ 1), 0.857 for moderate fibrosis (F≥ 2), 0.946 for severe fibrosis (F≥ 3), and 0.935 for cirrhosis (F4). Likewise, good accuracy was observed in the HCV subgroup. The optimal cut-off value in differentiating healthy subjects from CLD patients with any fibrosis was 5.47 kPa with an AUROC of 0.875. CONCLUSION: 2D-SWE is a reliable and reproducible method to assess LSM with good diagnostic accuracy to assess liver fibrosis in patients with CLD.

Actual Risk of Using Very Aged Donors for Unselected Liver Transplant Candidates: A European Single-center Experience in the MELD Era.

OBJECTIVE: To evaluate the whole experience of liver transplantation (LT) with donors ≥70 years in a single center not applying specific donor/recipient matching criteria. BACKGROUND: LT with very old donors has historically been associated with poorer outcomes. With the increasing average donor age and the advent of Model for End-stage Liver Diseases (MELD) score-based allocation criteria, an optimal donor/recipient matching is often unsuitable. METHODS: Outcomes of all types of LTs were compared according to 4 study groups: patients transplanted between 1998 and 2003 with donors <70 (group 1, n = 396) or ≥70 years (group 2, n = 88); patients transplanted between 2004 and 2010 with donors <70 (group 3, n = 409), or ≥70 years (group 4, n = 190). From 2003, graft histology was routinely available before cross-clamping, and MELD-driven allocation was adopted. RESULTS: Groups 1 and 2 were similar for main donor and recipient variables, and surgical details. Group 4 had shorter donor ICU stay, lower rate of moderate-to-severe graft macrosteatosis (2.3% vs 8%), and higher recipient MELD score (22 vs 19) versus group 3. After 2003, median donor age, recipient age, and MELD score significantly increased, whereas moderate-to-severe macrosteatosis and ischemia time decreased. Five-year graft survival was 63.6% in group 1 versus 59.1% in group 2 (P = 0.252) and 70.9% in group 3 versus 67.6% in group 4 (P = 0.129). Transplants performed between 1998 and 2003, recipient HCV infection, balance of risk score >18, and pre-LT renal replacement treatments were independently associated with worse graft survival. CONCLUSIONS: Even without specific donor/recipient matching criteria, the outcomes of LT with donors ≥70 and <70 years are comparable with appropriate donor management.

Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal, recessive disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzymatic activity, toxic nucleoside accumulation, and secondary mitochondrial DNA damage. Thymidine phosphorylase replacement has been achieved by allogeneic hematopoietic stem cell transplantation, a procedure hampered by high mortality. Based on high thymidine phosphorylase expression in the liver, a 25-year-old severely affected patient underwent liver transplantation. Serum levels of toxic nucleosides rapidly normalized. At 400 days of follow-up, the patient's clinical conditions are stable. We propose liver transplantation as a new therapy for MNGIE. Ann Neurol 2016;80:448-455.

Accuracy of elastography point quantification and steatosis influence on assessing liver fibrosis in patients with chronic hepatitis C.

BACKGROUND & AIMS: Elastography point quantification is a novel non-invasive method for the assessment of liver fibrosis by measuring liver stiffness. The aim of this study was to evaluate the accuracy of elastography point quantification for the diagnosis of liver fibrosis and to assess impact of steatosis on liver stiffness measurement, in a cohort of patients with chronic hepatitis C. METHODS: In this single-centre cross-sectional study, 211 consecutive patients with chronic hepatitis C, scheduled for liver biopsy, were examined with the elastography point quantification technology. On the same day, all patients underwent clinical examination, laboratory tests and abdominal ultrasound. RESULTS: The best cut-offs of liver stiffness measurement were 6.16 kPa for the diagnosis of significant fibrosis (≥S3) and 6.79 kPa for advanced fibrosis (≥S4). Areas under the receiver operating characteristic curve were 0.831 (CI: 0.773-0.880) for significant fibrosis, and 0.954 (CI: 0.916-0.978) for advanced fibrosis. Among patients within the same fibrosis stages (S0-S2 and S3-S6; S0-S3 and S4-S6), mean liver stiffness measurement values were similar in patients with steatosis (≥10% at liver biopsy or detected by ultrasound) compared to those without. Discordance between elastography point quantification and histology were affected by the presence of BMI>30 kg/m2 (P=.047, CI: 0.136-0.988 and P=.020, CI: 0.083-0.812 respectively). CONCLUSIONS: In patients with chronic hepatitis C, elastography point quantification is an accurate non-invasive method for the diagnosis of significant and advanced fibrosis. The presence of obesity is a risk factor for misclassification of significant and advanced liver fibrosis.