Locoregional Ablative Therapies Research Articles

Role of Advanced Gastrointestinal Endoscopy in the Comprehensive Management of Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs), also called neuroendocrine tumors (NETs), are relatively uncommon, heterogenous tumors primarily originating in the gastrointestinal tract. With the improvement in technology and increasing use of cross-sectional imaging and endoscopy, they are being discovered with increasing frequency. Although traditionally considered indolent tumors with good prognoses, some NENs exhibit aggressive behavior. Timely diagnosis, risk stratification, and management can often be a challenge. In general, small NENs without local invasion or lymphovascular involvement can often be managed using minimally invasive advanced endoscopic techniques, while larger lesions and those with evidence of lymphovascular invasion require surgery, systemic therapy, or a combination thereof. Ideal management requires a comprehensive and accurate understanding of the stage and grade of the tumor. With the recent advancements, a therapeutic advanced endoscopist can play a pivotal role in diagnosing, staging, and managing this rare condition. High-definition white light imaging and digital image enhancing technologies like narrow band imaging (NBI) in the newer endoscopes have improved the diagnostic accuracy of traditional endoscopy. The refinement of endoscopic ultrasound (EUS) over the past decade has revolutionized the role of endoscopy in diagnosing and managing various pathologies, including NENs. In addition to EUS-directed diagnostic biopsies, it also offers the ability to precisely assess the depth of invasion and lymphovascular involvement and thus stage NENs accurately. EUS-directed locoregional ablative therapies are increasingly recognized as highly effective, minimally invasive treatment modalities for NENs, particularly pancreatic NENs. Advanced endoscopic resection techniques like endoscopic submucosal dissection (ESD), endoscopic submucosal resection (EMR), and endoscopic full-thickness resection (EFTR) have been increasingly used over the past decade with excellent results in achieving curative resection of various early-stage gastrointestinal luminal lesions including NENs. In this article, we aim to delineate NENs of the different segments of the gastrointestinal (GI) tract (esophagus, gastric, pancreatic, and small and large intestine) and their management with emphasis on the endoscopic management of these tumors.

Tumeurs neuroendocrines digestives bien différenciées: focus sur les tumeurs pancréatiques

Pancreatic neuroendocrine tumors are rare tumors showing a rising incidence. They are well-differentiated tumors, classified by grade according to their Ki67 index value (grade 1 to 3). Pancreatic neuroendocrine tumors are mainly sporadic tumors but about 10% arise within endocrine tumor syndromes such as multiple endocrine neoplasia type 1. They can be responsible for functional syndromes or non-specific clinical symptoms depending on tumor extension. However, there is also an increase of incidental diagnoses of nonfunctional pancreatic neuroendocrine tumors with the widespread use of high-quality imaging techniques. About 50% of pancreatic neuroendocrine tumors are diagnosed at a metastatic stage, with metastases often located in the liver. Chromogranin A, CT-scan and often an abdominal MRI, and functional imaging should be performed for tumor staging and follow-up. Imaging with PET/CT with68Ga-labeled somatostatin analogues has the highest sensitivity for the diagnosis of pancreatic neuroendocrine tumors, while 18fluorodeoxyglucose PET/CT can sometimes be useful. Overall, they are rather indolent tumors with prolonged survival. Surgery is the recommended treatment in the localized setting, with the exception of small<2cm nonfunctional tumors that can be monitored with imaging techniques. For advanced tumors, there are several available treatments such as somatostatine analogues, chemotherapy, targeted therapies (sunitinib, everolimus), locoregional ablative therapies and Peptide Receptor Radiolabelled Therapy. The treatment strategy will depend on the initial tumor staging, tumor grade, aggressiveness and patient's choice.

EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains &lt; 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

Combination of the gamma-glutamyltransferase-to-prealbumin ratio and other indicators may be a novel marker for predicting the prognosis of patients with hepatocellular carcinoma undergoing locoregional ablative therapies

ObjectiveThe aim of this study was to investigate the prognostic significance of the serum γ-glutamyltransferase (γ-GT)-to-prealbumin ratio (GPR) and whether combining this ratio with other parameters can lead to an improved prognostic value for patients with hepatocellular carcinoma (HCC) undergoing transcatheter arterial chemoembolization (TACE) combined with local ablation therapy.MethodsA total of 235 HCC patients who were treated with combined therapies were retrospectively analyzed. The demographic data and clinicopathological data were collected. A fibrinogen (Fib)-GPR score of 2 was assigned to patients with elevated Fib and GPR values, and a score of 1 or 0 was assigned to patients with one or neither of these two markers, respectively. In addition, an N-score of 2 was assigned to patients with low neutrophil and high GPR values, and a score of 1 or 0 was assigned to patients with one or neither of these two markers, respectively. The optimal cutoff values and prognostic roles of GPR and other markers were identified according to the time-dependent receiver operating characteristic (ROC) curves and Youden’s index.ResultsMultiple tumors, high levels of α-fetoprotein (AFP) and Fib, as well as a high GPR, were found to be independent risk factors in recurrent patients, while multiple tumors, a low neutrophil count, and a high GPR were associated with reduced overall survival (OS) in patients with HCC who received combined therapies. Patients with a Fib-GPR score of 2 and N-GPR score of 2 had poor recurrence-free survival (RFS) and OS, respectively.ConclusionsFib-GPR and N-GPR scores may be helpful in predicting both recurrence and the prognosis of HCC patients, thereby assisting in the process to make a true clinical decision and optimize therapeutic options.

Novel biomarkers for hepatocellular carcinoma surveillance: has the future arrived?

Hepatocellular carcinoma (HCC) remains a major cause of mortality in patients with chronic liver disease worldwide. Early detection of HCC is critical to providing effective treatment and can have a significant impact on survival. In addition, effective surveillance following hepatic resection or locoregional ablative therapy can identify early recurrence and optimize long-term outcomes. Currently available serum tumor markers, including alpha-fetoprotein (AFP), are characterized by low sensitivity in the detection of HCC. Advances in genomic, proteomic, metabolomic, and glycomic profiling may provide a means to identify unique molecular signatures and characterization of complex processes associated with HCC incidence and recurrence. The development of highly sensitive and specific serum biomarkers for HCC may greatly enhance early detection rates, risk assessment in treatment candidates, and identification of potential new targets for anticancer therapy.

Technical and practical considerations for device selection in locoregional ablative therapy.

Percutaneous ablation therapy is an essential component of contemporary interventional oncologic therapy of primary and secondary malignancies. The growing armamentarium of available ablation technologies calls for thorough understanding of the different ablation modalities to optimize device selection in individual clinical settings. The goal of the current article is to provide direction on ablative device selection by reviewing device mechanisms of action, advantages and disadvantages, and practical considerations in real-life case scenarios.

Role of antiviral therapy in the management of hepatocellular carcinoma

Globally, hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection leads to liver fibrosis and cirrhosis, which in turn causes resultant hepatocellular carcinoma (HCC). Frequently, HCC recurs very soon even after a potentially curative treatment such as surgical interference or locoregional ablative therapies. Chronic HBV/HCV infection is often responsible for this recurrence, through secondary carcinogenesis. Antiviral therapy after a curative treatment of HCC plays an important role in preventing or delaying recurrence and improves survival in patients with HBV/HCV infection-related HCC. This article reviews the worldwide epidemiology of HBV/HCV infection, the association of viral infection with HCC, the mechanism of hepatitis virus-related hepatocarcinogenesis, and the paramount importance of antiviral therapy in the management of HCC.

Contemporary Strategies in the Management of Hepatocellular Carcinoma

Liver transplantation is the treatment of choice for selected patients with hepatocellular carcinoma (HCC) on a background of chronic liver disease. Liver resection or locoregional ablative therapies may be indicated for patients with preserved synthetic function without significant portal hypertension. Milan criteria were introduced to select suitable patients for liver transplant with low risk of tumor recurrence and 5-year survival in excess of 70%. Currently the incidence of HCC is climbing rapidly and in a current climate of organ shortage has led to the re-evaluation of locoregional therapies and resectional surgery to manage the case load. The introduction of biological therapies has had a new dimension to care, adding to the complexities of multidisciplinary team working in the management of HCC. The aim of this paper is to give a brief overview of present day management strategies and decision making.

Critical reappraisal of risk factors for occurrence of hepatocellular carcinoma in patients with hepatitis C virus

More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan are attributable to hepatitis C virus (HCV) infection. HCV is also the primary cause of death in patients with HCV-related cirrhosis, with annual incidences of 0.5%–5% in Europe and 4%–10% in Asia. Screening is based on serum alpha-fetoprotein determination and liver ultrasound scan, but the sensitivity of the former is far less than optimal, and screening intervals are still poorly defined for the latter. Risk factors related to the host or environment, or both, appear to be more relevant than viral factors, such as HCV genotype, in determining disease progression to cirrhosis and cancer, and include age, male gender, severity of liver disease at presentation, coinfection with hepatitis B virus or human immunodeficiency virus, and alcohol abuse. Early liver transplantation in selected cases can be curative, but most patients are not eligible for liver grafting and are treated with locoregional ablative therapies, after which recurrence is common. Recently, orally available inhibitors of the vascular endothelial growth factor receptor have shown a significant, albeit modest, increment of survival in patients with advanced hepatocellular carcinoma, thus paving the way for modern molecular approaches to treatment of this highly malignant tumor.

Laparoscopic surface scanning and subsurface targeting: Implications for image-guided laparoscopic liver surgery

Segmental liver resection and locoregional ablative therapies are dependent upon accurate tumor localization to ensure safety as well as acceptable oncologic results. Because of the liver's limited external landmarks and complex internal anatomy, such tumor localization poses a technical challenge. Image guided therapies (IGT) address this problem by mapping the real-time, intraoperative position of surgical instruments onto preoperative tomographic imaging through a process called registration. Accuracy is critical to IGT and is a function of: 1) the registration technique, 2) the tissue characteristics, and 3) imaging techniques. The purpose of this study is to validate a novel method of registration using an endoscopic Laser Range Scanner (eLRS) and demonstrate its applicability to laparoscopic liver surgery. Six radiopaque targets were inserted into an ex-vivo bovine liver and a computed tomography (CT) scan was obtained. Using the eLRS, the liver surface was scanned and a surface-based registration was constructed to predict the position of the intraparenchymal targets. The target registration error (TRE) achieved using our surface-based registration was 2.4 +/- 1.0 mm. A comparable TRE using traditional fiducial-based registration was 2.6 +/- 1.7 mm. Compared to traditional fiducial-based registration, laparoscopic surface scanning is able to predict the location of intraparenchymal liver targets with similar accuracy and rate of data acquisition.

Staging Hepatocellular Carcinoma by a Novel Scoring System (BALAD Score) Based on Serum Markers

Previously proposed staging systems for hepatocellular carcinoma (HCC) involve clinical, imaging, or pathologic factors in the evaluation. We established and validated a novel staging system for HCC that is based on simply serum markers. The new scoring system is based on 5 serum markers: bilirubin, albumin, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) and thus is termed the BALAD score. The system was validated in 2600 HCC patients from 5 institutions. The power of our system to predict patient survival and its discriminative ability were compared with those of previously reported staging systems. The best tumor marker cutoff values were 400 ng/dL for AFP, 15% for AFP-L3, and 100 milli-arbitrary unit/mL for DCP. The patients were classified into 6 categories on the basis of 5 laboratory values. The categories reflected patient survival well. The discriminative ability was comparable to that of previously reported staging systems. The new staging system for HCC combining serum albumin, serum bilirubin, and 3 tumor markers predicts patient outcomes with excellent discriminative ability. The system is easy to use and objective. In addition, stage can be evaluated with the use of only 1 serum sample. It also allows global comparison of patients with HCC or comparison of patients from different time periods with the same standard.

Impact of Surveillance on Survival of Patients With Initial Hepatocellular Carcinoma: A Study From Japan

We investigated trends in the prediagnostic surveillance of patients in whom hepatocellular carcinoma (HCC) was diagnosed, and evaluated the impact of these trends on early detection of HCC and on patient survival. We evaluated 1641 patients in whom HCC initially was diagnosed during the period of 1968 to 2004. Patients were grouped by the year of diagnosis: 1968-1980 (n = 151), 1981-1990 (n = 409), 1991-2000 (n = 754), and 2001-2004 (n = 324). They also were classified according to whether they were in surveillance and its context before the diagnosis of HCC: patients undergoing follow-up evaluation in our center (group A), those followed up and referred by a primary care physician (group B), and those not in surveillance (group C). The percentage of patients in groups A and B increased markedly over time. Early stage HCC was significantly more prevalent in groups A and B than in group C, and the frequency of early stage HCC increased sequentially. The patient survival rate was highest in group A, followed by that in groups B and C in that order; patient survival improved sequentially. The percentage of patients undergoing in-center surveillance or referred by a primary care physician increased, resulting in increased early detection of HCC and improved patient survival.

Improved outcome of chronic hepatitis B after heart transplantation by long‐term antiviral therapy

Chronic hepatitis B progresses to cirrhosis in the majority of immunosuppressed patients. The outcome of long-term antiviral therapy in HBV-infected organ transplant recipients is unknown. In 1996, we included 20 heart transplant (HT) recipients in a pilot trial to treat chronic hepatitis B with famciclovir. At that time, bridging fibrosis or cirrhosis was evident in 15 individuals (75%). From 1998 onwards, patients were switched to lamivudine in case of primary or secondary virological nonresponse to famciclovir. Adefovir or tenofovir became available at our centre for HT recipients in 2002. After 103 months, one patient was still on famciclovir showing a complete virological response. Sixteen patients were switched to lamivudine after 0.5-4 years of famciclovir therapy. Six of those showed a long-term response to lamivudine therapy lasting for up to 7 years. Lamivudine resistance developed in the remaining 10 patients (63%), in 4 of them successful rescue therapy (adefovir n = 3, tenofovir n = 1) could be initiated. Only one hepatocellular carcinoma developed, which was successfully treated by locoregional ablative therapy. Nine patients died (45%), with lamivudine-resistance-related liver failure as the cause of death in five cases. Significant improvement of Ishak fibrosis scores could be demonstrated in six of the seven patients with more than two sequential liver biopsies available. Long-term antiviral therapy of chronic hepatitis B can lead to regression of liver cirrhosis in patients after organ transplantation, unless viral resistance occurs. This study demonstrates the urgent need for further antivirals to overcome antiviral resistance.

Prognostic Significance of Simultaneous Measurement of Three Tumor Markers in Patients With Hepatocellular Carcinoma

We conducted a prospective study to evaluate the significance of simultaneous measurement of 3 currently used tumor markers in the evaluation of tumor progression and prognosis of patients with hepatocellular carcinoma (HCC). Three tumor markers for HCC, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), were measured in the same serum samples obtained from 685 patients at the time of initial diagnosis of HCC. Positivity for AFP >20 ng/dL, AFP-L3 >10% of total AFP, and/or DCP >40 mAU/mL was determined. In addition, tumor markers were measured after treatment of HCC. Of the 685 patients, 337 (55.8%) were positive for AFP, 206 (34.1%) were positive for AFP-L3, and 371 (54.2%) were positive for DCP. In a comparison of patients positive for only 1 tumor marker, patients positive for AFP-L3 alone had a greater number of tumors, whereas patients positive for DCP alone had larger tumors and a higher prevalence of portal vein invasion. When patients were compared according to the number of tumor markers present, the number of markers present clearly reflected the extent of HCC and patient outcomes. The number of markers present significantly decreased after treatment. Tumor markers AFP-L3 and DCP appear to represent different features of tumor progression in patients with HCC. The number of tumor markers present could be useful for the evaluation of tumor progression, prediction of patient outcome, and treatment efficacy.

An Intensive Surveillance Program Detected a High Incidence of Hepatocellular Carcinoma Among Hepatitis B Virus Carriers With Abnormal Alpha-Fetoprotein Levels or Abdominal Ultrasonography Results

To study the incidence and treatment outcomes of hepatocellular carcinoma (HCC) detected in an intensive surveillance program (ISP) of hepatitis B virus (HBV) carriers. We screened 1,018 HBV carriers by serum alpha-fetoprotein (AFP) measurement and abdominal ultrasonography (AUS). Patients with an abnormal AFP level or AUS result were enrolled in an ISP that included Lipiodol computed tomography followed by AFP measurement/AUS every 3 months for 2 years and then every 6 months thereafter. The rest were on routine surveillance for 2 years. A total of 9,849 serum AFP measurements and 3,053 AUSs were performed. After a median follow-up of 4.12 years, we diagnosed 24 HCCs among 78 patients with abnormal screening test results at enrollment (group A); 23 HCCs among 93 patients with only abnormal surveillance test results during follow-up (group B); and nine HCCs among 847 patients with 2 years of normal surveillance (group C). Annual incidence of HCC in the ISP was 760.2 (95% CI, 538.4 to 1,073.7) per 100,000. Mean tumor sizes were 3.02, 2.91, and 4.82 cm in groups A, B, and C, respectively (P = .01). Tumor resection rate of the ISP was 36.2%, although another 29.8% of the patients were eligible for locoregional ablative therapy. This study illustrated that a high incidence of relatively small HCCs may be detected by using intensive surveillance of high-risk HBV carriers. However, the surgical resection rate was low, and we were not able to demonstrate clinical benefit with the early detection. Future surveillance studies should consider incorporation of therapy aimed at long-term control of small-sized tumors.