Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ∼20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60-70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, including a variety of additional tumours (e.g. pancreatic and ampullary tumours) and most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies. Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community. This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored

Preoperative biliary drainage for biliary tract and ampullary carcinomas

We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for postdrainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned

Quadruple-peaked spectral line profiles as a tool to constrain gravitational potential of shell galaxies

Stellar shells observed in many giant elliptical and lenticular as well as a few spiral and dwarf galaxies, presumably result from galaxy mergers. Line-of-sight velocity distributions of the shells could, in principle, if measured with a sufficiently high S/N, constitute one of methods to constrain the gravitational potential of the host galaxy. Merrifield & Kuijken (1998) predicted a double-peaked line profile for stationary shells resulting from a nearly radial minor merger. In this paper, we aim at extending their analysis to a more realistic case of expanding shells, inherent to the merging process, whereas we assume the same type of merger and the same orbital geometry. We use analytical approach as well as test particle simulations to predict the line-of-sight velocity profile across the shell structure. Simulated line profiles are convolved with spectral PSFs to estimate the peak detectability. The resulting line-of-sight velocity distributions are more complex than previously predicted due to non-zero phase velocity of the shells. In principle, each of the Merrifield & Kuijken (1998) peaks splits into two, giving a quadruple-peaked line profile, which allows more precise determination of the potential of the host galaxy and, moreover, contains additional information. We find simple analytical expressions that connect the positions of the four peaks of the line profile and the mass distribution of the galaxy, namely the circular velocity at the given shell radius and the propagation velocity of the shell. The analytical expressions were applied to a test-particle simulation of a radial minor merger and the potential of the simulated host galaxy was successfully recovered. The shell kinematics can thus become an independent tool to determine the content and distribution of the dark matter in shell galaxies, up to ~100 kpc from the center of the host galaxy.Comment: 15 pages, 16 figures | v2: accepted for publication in A&A, minor language correction

The outer halos of elliptical galaxies

Recent progress is summarized on the determination of the density distributions of stars and dark matter, stellar kinematics, and stellar population properties, in the extended, low surface brightness halo regions of elliptical galaxies. With integral field absorption spectroscopy and with planetary nebulae as tracers, velocity dispersion and rotation profiles have been followed to ~4 and ~5-8 effective radii, respectively, and in M87 to the outer edge at ~150 kpc. The results are generally consistent with the known dichotomy of elliptical galaxy types, but some galaxies show more complex rotation profiles in their halos and there is a higher incidence of misalignments, indicating triaxiality. Dynamical models have shown a range of slopes for the total mass profiles, and that the inner dark matter densities in ellipticals are higher than in spiral galaxies, indicating earlier assembly redshifts. Analysis of the hot X-ray emitting gas in X-ray bright ellipticals and comparison with dynamical mass determinations indicates that non-thermal components to the pressure may be important in the inner ~10 kpc, and that the properties of these systems are closely related to their group environments. First results on the outer halo stellar population properties do not yet give a clear picture. In the halo of one bright galaxy, lower [alpha/Fe] abundances indicate longer star formation histories pointing towards late accretion of the halo. This is consistent with independent evidence for on-going accretion, and suggests a connection to the observed size evolution of elliptical galaxies with redshift.Comment: 8 pages. Invited review to appear in the proceedings of "Galaxies and their Masks" eds. Block, D.L., Freeman, K.C. & Puerari, I., 2010, Springer (New York

Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines

Diagnostic and therapeutic strategies for acute biliary inflammation/ infection (acute cholangitis and acute cholecystitis), according to severity grade, have not yet been established in the world. Therefore we formulated flowcharts for the management of acute biliary inflammation/ infection in accordance with severity grade. For mild (grade I) acute cholangitis, medical treatment may be sufficient/appropriate. For moderate (grade II) acute cholangitis, early biliary drainage should be performed. For severe (grade III) acute cholangitis, appropriate organ support such as ventilatory/circulatory management is required. After hemodynamic stabilization is achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. For patients with acute cholangitis of any grade of severity, treatment for the underlying etiology, including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has improved. For patients with mild (grade I) cholecystitis, early laparoscopic cholecystectomy is the preferred treatment. For patients with moderate (grade II) acute cholecystitis, early laparoscopic or open cholecystectomy is preferred. In patients with extensive local inflammation, elective cholecystectomy is recommended after initial management with percutaneous gallbladder drainage and/or cholecystostomy. For the patient with severe (grade III) acute cholecystitis, multiorgan support is a critical part of management. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy and/or drainage. Delayed elective cholecystectomy may be performed after initial treatment with gallbladder drainage and improvement of the patient's general medical condition. © Springer-Verlag Tokyo 2007.published_or_final_versio

Preoperative Y-90 microsphere selective internal radiation treatment for tumor downsizing and future liver remnant recruitment: a novel approach to improving the safety of major hepatic resections

<p>Abstract</p> <p>Background</p> <p>Extended liver resections are being performed more liberally than ever. The extent of resection of liver metastases, however, is restricted by the volume of the future liver remnant (FLR). An intervention that would both accomplish tumor control and induce compensatory hypertrophy, with good patient tolerability, could improve clinical outcomes.</p> <p>Case presentation</p> <p>A 53-year-old woman with a history of cervical cancer presented with a large liver mass. Subsequent biopsy indicated poorly differentiated carcinoma with necrosis suggestive of squamous cell origin. A decision was made to proceed with pre-operative chemotherapy and Y-90 microsphere SIRT with the intent to obtain systemic control over the disease, downsize the hepatic lesion, and improve the FLR. A surgical exploration was performed six months after the first SIRT (three months after the second). There was no extrahepatic disease. The tumor was found to be significantly decreased in size with central and peripheral scarring. The left lobe was satisfactorily hypertrophied. A formal right hepatic lobectomy was performed with macroscopic negative margins.</p> <p>Conclusion</p> <p>Selective internal radiation treatment (SIRT) with yttrium-90 (Y-90) microspheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio. We present this case report to suggest that the portal vein radiation dose can be substantially increased with the intent of inducing portal/periportal fibrosis. Such a therapeutic manipulation in lobar Y-90 microsphere treatment could accomplish the end points of PVE with avoidance of the concern regarding tumor progression.</p