Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.

Contrast Enhanced EUS for Predicting Solid Pancreatic Neuroendocrine Tumor Grade and Aggressiveness.

Pancreatic neuroendocrine tumor (PNET) behavior assessment is a daily challenge for physicians. Modern PNET management varies from a watch-and-wait strategy to surgery depending on tumor aggressiveness. Therefore, the aggressiveness definition plays a pivotal role in the PNET work-up. The aggressiveness of PNETs is mainly based on the dimensions and histological grading, with sometimes a lack of specificity and sensibility. In the last twenty years, EUS has become a cornerstone in the diagnostic phase of PNET management for its high diagnostic yield and the possibility of obtaining a histological specimen. The number of EUS applications in the PNET work-up has been rapidly increasing with new and powerful possibilities. The application of contrast has led to an important step in PNET detection; in recent years, it has been gaining interesting applications in aggressiveness assessment. In this review, we underline the latest experiences and opportunities in the behavior assessment of PNETs using contact-enhanced EUS and contested enhanced harmonic EUS with a particular focus on the future application and possibility that these techniques could provide.

Stereotactic Radiotherapy after Incomplete Transarterial (Chemo-) Embolization (TAE\TACE) versus Exclusive TAE or TACE for Treatment of Inoperable HCC: A Phase III Trial (NCT02323360).

Background: Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization (TAE/TACE) has shown a disease response in 15-55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses. Methods: This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications. Results: At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months, p = 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded. Conclusions: SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.

Multidisciplinary Tumor Board in the Management of Patients with Colorectal Liver Metastases: A Single-Center Review of 847 Patients.

There is still debate over how reviewing oncological histories and addressing appropriate therapies in multidisciplinary team (MDT) discussions may affect patients' overall survival (OS). The aim of this study was to describe MDT outcomes for a single cancer center's patients affected by colorectal liver metastases (CRLMs). From 2010 to 2020, a total of 847 patients with CRLMs were discussed at our weekly MDT meeting. Patients' characteristics and MDT decisions were analyzed in two groups: patients receiving systemic therapy (ST) versus patients receiving locoregional treatment (LRT). Propensity-score matching (PSM) was run to reduce the risk of selection bias. The median time from MDT indication to treatment was 27 (IQR 13−51) days. The median OS was 30 (95%CI = 27−34) months. After PSM, OS for patients undergoing LRT was 51 (95%CI = 36−64) months compared with 15 (95%CI = 13−20) months for ST patients (p < 0.0001). In this large retrospective study, the MDT discussions were useful in providing the patients with all available locoregional options.

Thermal Ablation of Liver Tumors Guided by Augmented Reality: An Initial Clinical Experience.

Background: Over the last two decades, augmented reality (AR) has been used as a visualization tool in many medical fields in order to increase precision, limit the radiation dose, and decrease the variability among operators. Here, we report the first in vivo study of a novel AR system for the guidance of percutaneous interventional oncology procedures. Methods: Eight patients with 15 liver tumors (0.7−3.0 cm, mean 1.56 + 0.55) underwent percutaneous thermal ablations using AR guidance (i.e., the Endosight system). Prior to the intervention, the patients were evaluated with US and CT. The targeted nodules were segmented and three-dimensionally (3D) reconstructed from CT images, and the probe trajectory to the target was defined. The procedures were guided solely by AR, with the position of the probe tip was subsequently confirmed by conventional imaging. The primary endpoints were the targeting accuracy, the system setup time, and targeting time (i.e., from the target visualization to the correct needle insertion). The technical success was also evaluated and validated by co-registration software. Upon completion, the operators were assessed for cybersickness or other symptoms related to the use of AR. Results: Rapid system setup and procedural targeting times were noted (mean 14.3 min; 12.0−17.2 min; 4.3 min, 3.2−5.7 min, mean, respectively). The high targeting accuracy (3.4 mm; 2.6−4.2 mm, mean) was accompanied by technical success in all 15 lesions (i.e., the complete ablation of the tumor and 13/15 lesions with a >90% 5-mm periablational margin). No intra/periprocedural complications or operator cybersickness were observed. Conclusions: AR guidance is highly accurate, and allows for the confident performance of percutaneous thermal ablations.

Case Report: New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management.

Background: The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients' management. Case Presentation: The first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings. Conclusions: According to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.

Myosteatosis Is Not Associated with Complications or Survival in HCC Patients Undergoing Trans Arterial Embolization.

Alterations in nutritional status, in particular sarcopenia, have been extensively associated with a poor prognosis in cirrhotic patients regardless of the etiology of liver disease. Less is known about the predictive value of myosteatosis, defined as pathological fat infiltration into the skeletal muscle. We retrospectively analyzed a cohort of 151 cirrhotic patients with unresectable hepatocellular carcinoma (HCC) who underwent their first trans-arterial embolization (TAE) between 1 March 2011 and 1 July 2019 at our Institution. Clinical and biochemical data were collected. Sarcopenia was assessed using the L3-SMI method while myosteatosis with a dedicated segmentation suite (3D Slicer), using a single slice at an axial plane located at L3 and calculating the IMAC (Intramuscular Adipose Tissue Content Index). The sex-specific cut-off values for defining myosteatosis were IMAC > −0.44 in males and >−0.31 in females. In our cohort, 115 (76%) patients were included in the myosteatosis group; 128 (85%) patients had a coexistent diagnosis of sarcopenia. Patients with myosteatosis were significantly older and showed higher BMI than patients without myosteatosis. In addition, male gender and alcoholic- or metabolic-related cirrhosis were most represented in the myosteatosis group. Myosteatosis was not associated with a different HCC burden, length of hospitalization, complication rate, and readmission in the first 30 days after discharge. Overall survival was not influenced by the presence of myosteatosis.

Risk Stratification of Cholangiocarcinoma Patients Presenting with Jaundice: A Retrospective Analysis from a Tertiary Referral Center.

Cholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract. Jaundice is a common clinical presentation; however, the prognostic impact of this symptom is poorly understood, and current management recommendations lack solid evidence. We aim to assess the clinical outcomes and predictive factors of CCA patients presenting with jaundice in the Emergency Room (ER). We retrospectively analyzed all consecutive ER cases presenting with jaundice between January 2010 and December 2017. During the study period, 403,766 patients were admitted to the ER, 1217 (0.3%) presented with jaundice, and in 200 (0.049%), the diagnosis was CCA. CCA cases increased during the study period (p for trend 0.026). Most of them presented with advance disease (stage III 46.5%, stage IV 43.5%) and median survival was 4.5 months (95% CI 3.4-6.0). Factors associated with better survival were age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis. A nomogram was constructed that significantly predicts 1-month, 6-month, and 1-year survival after patients' admission. In conclusion, the majority of CCA patients presenting with jaundice to the ER have advanced disease and poor prognosis. Risk stratification of these patients can allow tailored management.

Percutaneous Treatment of Bronchobiliary Fistula: Report of a Successful Transhepatic Embolization and a Decision-Making Strategy Driven by Systematic Literature Review.

Bronchobiliary fistula is a rare condition characterized by bile leaking into the bronchial tree causing biliptysis. It may arise from liver infection or as a consequence of resection and thermal ablation of cancer. Currently, there is no consensus about the treatment strategy. Surgery is considered the main therapy by most authors. However, this systematic literature review shows that the success rate of percutaneous treatments may reach 75%. Adding to such evidence, we also report the case of a woman affected by iatrogenic bronchobiliary fistula secondary to liver thermal ablation, successfully treated with percutaneous drainage plus embolization. Summarizing these results, we encourage the percutaneous management of bronchobiliary fistula by providing a 3-step decision-making algorithm, aimed at reducing the need for major surgery.

Percutaneous ablation of post-surgical solitary early recurrence of colorectal liver metastases is an effective "test-of-time" approach.

Standard treatment of early recurrence of colorectal liver metastases (CLM) after liver resection (LR) is chemotherapy followed by loco-regional therapy. We reviewed the outcome of a different strategy ("test-of-time" approach): upfront percutaneous ablation without chemotherapy. Twenty-six consecutive patients with early solitary liver-only recurrence amenable to both resection and ablation (< 30 mm, distant from vessels) undergone "test-of-time" approach were analyzed. Early recurrence had a median size of 17 mm and occurred after a median interval from LR of 4 months. Primary efficacy rate of ablation was 100%. Five patients are alive and disease-free after a mean follow-up of 46 months. Five patients had local-only recurrence; all had repeat treatment (LR = 4; Ablation = 1) without chemotherapy. Local recurrence risk was associated with incomplete ablation of 1-cm thick peritumoral margin. The remaining 16 patients had non-local recurrence, 13 early after ablation. Overall, six (23%) patients had ablation as unique treatment and 13 (50%) avoided or postponed chemotherapy (mean chemotherapy-free interval 33.5 months). Ablation without chemotherapy of early liver-only recurrence is a reliable "test-of-time" approach. It minimized the invasiveness of treatment with good effectiveness and high salvageability in case of local failure, avoided worthless surgery, and saved chemotherapy for further disease progression.

Prognostic Value of Metabolic Imaging Data of 11C-choline PET/CT in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma.

11C-choline positron emission tomography/computed tomography (PET/CT) has been used for patients with some types of tumors, but few data are available for hepatocellular carcinoma (HCC). We queried our prospective database for patients with HCC staged with 11C-choline PET/CT to assess the clinical impact of this imaging modality. Seven parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), liver standardized uptake value (SUVliver), metabolic tumor volume (MTV), photopenic area, metabolic tumor burden (MTB = MTVxSUVmean), and SUVratio (SUVmax/SUVliver). Analysis was performed to identify parameters that could be predictors of overall survival (OS). Sixty patients were analyzed: fourteen (23%) were in stage 0-A, 37 (62%) in stage B, and 9 (15%) in stage C of the Barcelona classification. The Cox regression for OS showed that Barcelona stages (HR = 2.94; 95%CI = 1.41-4.51; p = 0.003) and MTV (HR = 2.11; 95%CI = 1.51-3.45; p = 0.026) were the only factors independently associated with OS. Receiver operating characteristics curve analysis revealed MTV ability in discriminating survival (area under the curve (AUC) = 0.77; 95%CI = 0.57-097; p < 0.001: patients with MTV ≥ 380 had worse OS (p = 0.015)). The use of 11C-choline PET/CT allows for better prognostic refinement in patients undergoing hepatectomy for HCC. Incorporation of such modality into HCC staging system should be considered.

Correction: Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0232371.].

Hepatic uptake index in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced magnetic resonance imaging estimates functional liver reserve and predicts post-hepatectomy liver failure.

BACKGROUND: Recent evidence suggests that gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance imaging may be used to evaluate liver function. The aim of this study was to assess whether the signal intensity of Gd-EOB-DTPA magnetic resonance imaging may be used to predict functional liver reserve and posthepatectomy liver failure in patients undergoing hepatectomy for liver tumors. METHODS: This is an observational retrospective study on 137 preoperative Gd-EOB-DTPA magnetic resonance imaging of patients undergoing hepatectomy between 2015 and 2018. Mean signal intensity of liver (L20) and spleen (S20) were measured on T1-weighted single-breath-hold 3-dimensional fat-saturated gradient echo sequences acquired 20 minutes after Gd-EOB-DTPA administration. The hepatocellular uptake index of liver volume (VL) was calculated with the formula VL([L20/S20] - 1) and was tested with several score systems for liver diseases and to the occurrence of post-hepatectomy liver failure. RESULTS: Patients with diseased liver had significantly lower values of hepatic uptake index in comparison with those with normal function. This was found for a Model for End-Stage Liver Disease score ≤9 versus >9 (P = .04), combination of bilirubin and cholinesterases levels score ≤2 versus >2 (P = .02), albumin to bilirubin grades (P = .03), and Humanitas score ≤6 versus >6 (P = .03). Twenty-two patients (16%) developed posthepatectomy liver failure, and 2 (1.4%) died within 90 days. The hepatocellular uptake index was significantly lower in those patients with posthepatectomy liver failure (P < .01). Receiver operating characteristics curve analysis revealed valuable hepatocellular uptake index ability in predicting post-hepatectomy liver failure (area under the curve = 0.84; 95% confidence interval, 0.71-0.92; P < .01), with a cutoff value of 574.33 (98% sensitivity; 83% specificity). CONCLUSION: The hepatocellular uptake index hepatocellular uptake index measured on preoperative Gd-EOB-DTPA magnetic resonance imaging identifies patients with diseased liver and predicts posthepatectomy liver failure. This index could be used to discern those patients at higher risk of complications after hepatectomy.

Liver Metastases-directed Therapy in the Management of Oligometastatic Breast Cancer.

INTRODUCTION: In the context of metastatic breast cancer, dissemination to the liver is a frequent occurrence. We aimed to evaluate the outcome and toxicity of metastatic breast cancer with liver oligometastases treated with metastases-directed therapies (MDTs), including surgery, stereotactic body radiation therapy, or thermal ablation (radiofrequency or microwaves). PATIENTS AND METHODS: We included patients with diagnosis of 1 to 5 liver metastases. Selection criteria included also age > 18 years; Eastern Cooperative Oncology Group performance status 0 to 2; absence of extra-hepatic disease or other controlled metastatic sites. Endpoints were liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival. RESULTS: A total of 72 patients were included. Previous local treatments were performed in 13 (18.1%) patients, whereas systemic therapy was used in 81.9% of cases. Treatment of choice was stereotactic body radiation therapy in 54 (75%) patients followed by surgery (13 patients; 18%) and thermal ablation (5 patients; 7%). With a median follow-up of 26.2 months, LPFS at 1 and 2 years was 52.4% and 38.8%, respectively. The number of metastases predicted LPFS (hazard ratio [HR], 1.70; P = .004). Rates of PFS were 38.7% and 22% at 1 and 2 years, respectively. Systemic therapy before MDT (HR, 2.89; P = .016) was correlated with PFS. Overall survival at 1 and 2 years was 95.5% and 76.9%, respectively. Human epidermal growth factor receptor 2 status correlated with survival (HR, 1.82; P = .010). CONCLUSION: Combination of systemic therapy with liver MDT in oligometastatic breast cancer results in durable disease control in a significant proportion of patients. Tumor biology, prior treatment, and extent of disease may be useful to guide the decision to add MDT to standard therapy.