Purpose, use, and preparation of clinical practice guidelines for the management of biliary tract and ampullary carcinomas

Apart from periampullary carcinoma, the prognosis of biliary tract carcinomas, including hilar cholangiocarcinoma, extrahepatic biliary tract carcinoma, and gallbladder carcinoma, remains poor. Sophisticated diagnostic skills and treatment methods and their application are naturally required to achieve better treatment results for biliary tract carcinomas. However, it is not too much to say that, due to the paucity of high-level evidence for the management of these carcinomas, medical care by healthcare providers in clinics and at medical institutes throughout the world is currently delivered without common consensus and common standards. The clinical practice guidelines for the management of biliary carcinoma outlined here were produced with the aim that they could be used by physicians involved in the care of biliary tract carcinomas, as indicators that could help them provide their patients with the most appropriate care possible at this time. Also, the guidelines were prepared to provide measures that could assure patients with biliary tract carcinomas of safe medical care. The present guidelines are characterized by their clarification of clinical questions assumed to be often shared by healthcare professionals. For clarity, we divided the contents of the guidelines into eight areas. In each area, clinical questions are presented, together with recommendations of clinical actions in response to the question. As mentioned already, there is a paucity of high-level evidence in this area; therefore, the recommendations are classified into grades, of which there are five: A, strongly recommend performing the clinical action; B, recommend performing the clinical action; C1, the clinical action may be useful, although there is a lack of high-level scientific evidence; C2, clinical action not definitively recommended ecause of insufficient scientific evidence; D, recommend not performing the clinical action. The grading of the recommendations is based on the determination of the level of evidence in references on which the recommendation is based

Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy

Background Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. Methods Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/−). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. Results and discussion The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. Conclusions We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes

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

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment

Stenting and interventional radiology for obstructive jaundice in patients with unresectable biliary tract carcinomas

Together with biliary drainage, which is an appropriate procedure for unresectable biliary cancer, biliary stent placement is used to improve symptoms associated with jaundice. Owing to investigations comparing percutaneous transhepatic biliary drainage (PTBD), surgical drainage, and endoscopic drainage, many types of stents are now available that can be placed endoscopically. The stents used are classified roughly as plastic stents and metal stents. Compared with plastic stents, metal stents are of large diameter, and have long-term patency (although they are expensive). For this reason, the use of metal stents is preferred for patients who are expected to survive for more than 6 months, whereas for patients who are likely to survive for less than 6 months, the use of plastic stents is not considered to be improper. Obstruction in a metal stent is caused by a tumor that grows within the stent through the mesh interstices. To overcome such problems, a covered metal stent was developed, and these stents are now used in patients with malignant distal biliary obstruction. However, this type of stent has been reported to have several shortcomings, such as being associated with the development of acute cholecystitis and stent migration. In spite of these shortcomings, evidence is expected to demonstrate its superiority over other types of stent

Radiation therapy and photodynamic therapy for biliary tract and ampullary carcinomas

The purpose of radiation therapy for unresectable biliary tract cancer is to prolong survival or prolong stent patency, and to provide palliation of pain. For unresectable bile duct cancer, there are a number of studies showing that radiation therapy is superior to the best supportive care. Although radiation therapy is used in many institutions, no large randomized controlled trials (RCTs) have been performed to date and the evidence level supporting the superiority of this treatment is low. Because long-term relief of jaundice is difficult without using biliary stenting, a combination of radiation therapy and stent placement is commonly used. As radiation therapy, external-beam radiation therapy is usually performed, but combined use of intraluminal brachytherapy with external beam radiation therapy is more useful for making the treatment more effective. There are many reports demonstrating improved response rates as well as extended survival and time to recurrence achieved by this combination therapy. Despite the low level of the evidence, this combination therapy is performed at many institutions. It is expected that multiinstitutional RCTs will be carried out. Unresectable gallbladder cancer with a large focus is usually extensive, and normal organs with high radio sensitivity exist contiguously with it. Therefore, only limited anticancer effects are to be expected from external beam radiation therapy for this type of cancer. The number of reports on ampullary cancer is small and the role of radiation therapy in this cancer has not been established. Combination treatment for ampullary cancer consists of either a single use of intraoperative radiation therapy, postoperative external beam radiation therapy or intraluminal brachytherapy, or a combination of two or three of these therapies. Intraoperative radiation therapy is superior in that it enables precise irradiation to the target site, thereby protecting adjacent highly radiosensitive normal tissues from irradiation. There are reports showing extended survival, although not significant, in groups undergoing intraoperative or postoperative radiation therapy compared with groups without radiation therapy. To date, there are no reports of large RCTs focusing on the significance of radiation therapy as a postoperative adjuvant treatment, so its usefulness as a postoperative adjuvant treatment is not proven. An alternative treatment is photodynamic therapy. There is an RCT demonstrating that, in unresectable bile duct cancer, extended survival and improved quality of life (QOL) have been achieved through a combination of photodynamic therapy and biliary stenting, compared with biliary stenting alone. Results from large RCTs are desired

Flowcharts for the management of biliary tract and ampullary carcinomas

No strategies for the diagnosis and treatment of biliary tract carcinoma have been clearly described. We developed flowcharts for the diagnosis and treatment of biliary tract carcinoma on the basis of the best clinical evidence. Risk factors for bile duct carcinoma are a dilated type of pancreaticobiliary maljunction (PBM) and primary sclerosing cholangitis. A nondilated type of PBM is a risk factor for gallbladder carcinoma. Symptoms that may indicate biliary tract carcinoma are jaundice and pain in the upper right area of the abdomen. The first step of diagnosis is to carry out blood biochemistry tests and ultrasonography (US) of the abdomen. The second step of diagnosis is to find the local extension of the carcinoma by means of computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP). Because resection is the only way to completely cure biliary tract carcinoma, the indications for resection are determined first. In patients with resectable disease, the indications for biliary drainage or portal vein embolization (PVE) are checked. In those with nonresectable disease, biliary stenting, chemotherapy, radiotherapy, and/or best supportive care is selected

A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

<p>Abstract</p> <p>Background</p> <p>Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of <it>KRAS </it>are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells.</p> <p>Methods</p> <p>DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for <it>KRAS </it>amplification by quantitative PCR, and investigated <it>KRAS </it>amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of <it>KRAS </it>knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively.</p> <p>Results</p> <p>DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the <it>KRAS </it>gene locus. Amplification of the <it>KRAS </it>locus was detected in 15% (3/20) of gastric cancer cell lines (8–18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8–50-fold amplification). <it>KRAS </it>mutations were identified in two of the three cell lines in which <it>KRAS </it>was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased <it>KRAS </it>copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type <it>KRAS</it>, but not in cells with amplified mutant <it>KRAS</it>. Knock-down of <it>KRAS </it>in gastric cancer cells that carried amplified wild-type <it>KRAS </it>resulted in the inhibition of cell growth and suppression of p44/42 MAP kinase and AKT activity.</p> <p>Conclusion</p> <p>Our study highlights the utility of DGS for identification of copy-number alterations. Using DGS, we identified <it>KRAS </it>as a gene that is amplified in human gastric cancer. We demonstrated that gene amplification likely forms the molecular basis of overactivation of KRAS in gastric cancer. Additional studies using a larger cohort of gastric cancer specimens are required to determine the diagnostic and therapeutic implications of <it>KRAS </it>amplification and overexpression.</p

Diagnosis of biliary tract and ampullary carcinomas

Diagnostic methods for biliary tract carcinoma and the efficacy of these methods are discussed. Neither definite methods for early diagnosis nor specific markers are available in this disease. When this disease is suspected on the basis of clinical symptoms and risk factors, hemato-biochemical examination and abdominal ultrasonography are performed and, where appropriate, enhanced computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) is carried out. Diagnoses of extrahepatic bile duct cancer and ampullary carcinoma are often made based on the presence of obstructive jaundice. Although rare, abdominal pain and pyrexia, as well as abnormal findings of the hepatobiliary system detected by hemato-biochemical examination, serve as a clue to making a diagnosis of these diseases. On the other hand, the early diagnosis of gallbladder cancer is scarcely possible on the basis of clinical symptoms, so when this cancer is found with the onset of abdominal pain and jaundice, it is already advanced at the time of detection, thus making a cure difficult. When gallbladder cancer is suspected, enhanced CT is carried out. Multidetector computed tomography (MDCT), in particular — one of the methods of enhanced CT — is useful for decision of surgical criteria, because MDCT shows findings such as localization and extension of the tumor, and the presence or absence of remote metastasis. Procedures such as magnetic resonance imaging, endoscopic ultrasonography, bile duct biopsy, and cholangioscopy should be carried out taking into account indications for these procedures in individual patients. However, direct biliary tract imaging is necessary for making a precise diagnosis of the horizontal extension of bile duct cancer