A Phase I Study of S-1 and Gemcitabine with Concurrent Radiotherapy in Patients with Non-Metastatic Advanced Pancreatic Cancer.

BACKGROUND/AIMS: To determine the recommended dose (RD) for full-dose S-1 and low-dose gemcitabine combined with radiotherapy in patients with non-metastatic advanced pancreatic cancer. METHODOLOGY: Adult patients with non-metastatic advanced pancreatic cancer (Union for International Cancer Control T stage 3 or 4) were eligible. The weekly intravenous gemcitabine (level 0-1: 200 mg/ml,level 2: 300 mg/m on Days 1, 8, 15, 22, 29, 36) dose was escalated starting from level 1 in a 3+3 design along with full dose twice-daily oral S-1 (level 0: 60 mg/m2/day, level 1-2: 80 mg/ml/day), and was administered on the same days as radiotherapy (1.8 Gy x 28 days). RESULTS: Eight patients were included in this study. A dose-limiting toxicity (DLT) (grade 4 neutropenia) was observed in one of the first three patients in level 1, and three additional patients received the level 1 dose without any severe adverse events. DLTs (grade 3/4 neutropenia) were then observed in the first two patients given level 2 dose. Therefore, level 1 was designated as the RD. Common grade 3/4 toxicities included neutropenia (62.5%), anorexia (37.5%), and pneumonitis (12.5%). CONCLUSIONS: The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Differentiating immunoglobulin g4-related sclerosing cholangitis from hilar cholangiocarcinoma.

BACKGROUND/AIMS: Few studies have differentiated immunoglobulin G (IgG) 4-related sclerosing cholangitis (IgG4-SC) from hilar cholangiocarcinoma (CC). Thus, we sought to investigate useful features for differentiating IgG4-SC from hilar CC. METHODS: We retrospectively compared clinical, serological, imaging, and histological features of six patients with IgG4-SC and 42 patients with hilar CC. RESULTS: In patients with hilar CC, obstructive jaundice was more frequent (p<0.01), serum total bilirubin levels were significantly higher (p<0.05), serum CA19-9 levels were significantly higher (p<0.01), and serum duke pancreatic monoclonal antigen type 2 levels were frequently elevated (p<0.05). However, in patients with IgG4-SC, the serum IgG (p<0.05) and IgG4 (p<0.01) levels were significantly higher and frequently elevated. The pancreas was enlarged in all IgG4-SC patients but only in 17% of hilar CC patients (p<0.01). Salivary and/or lacrimal gland swelling was detected in only 50% of IgG4-SC patients (p<0.01). Endoscopic retrograde cholangiography revealed that the hilar or hepatic duct was completely obstructed in 83% of hilar CC patients (p<0.01). Lower bile duct stenosis, apart from hilar bile duct stenosis, was more frequent in IgG4-SC patients (p<0.01). Bile duct wall thickening in areas without stenosis was more frequent in IgG4-SC patients (p<0.01). CONCLUSIONS: An integrated diagnostic approach based on clinical, serological, imaging, and histological findings is necessary to differentiate IgG4-SC from hilar CC.

Pancreaticoduodenectomy in portal annular pancreas: report of a case.

Portal annular pancreas (PAP) is a rare anatomical anomaly in which the pancreatic parenchyma surrounds the superior mesenteric vein and portal vein (PV) annularly. This anomaly requires careful consideration in pancreatic resection. A case is presented and the technical issues are discussed. A 61-year-old female was referred to the hospital for suspected papilla Vater adenocarcinoma. Preoperative computed tomography showed that the PV was annularly surrounded by pancreatic parenchyma. Surgery revealed the uncinate process extended extensively behind the PV and fused with the pancreatic body. The pancreas was first divided above the PV, and it was divided again in the body after liberating the PV from pancreatic annulation. The postoperative course was uneventful without pancreatic fistula. It is safer to divide the pancreatic body on the left of the fusion between the uncinate process and the pancreatic body to reduce the risk of pancreatic fistula in pancreaticoduodenectomy for PAP.

Importance of early diagnosis of pancreaticobiliary maljunction without biliary dilatation.

AIM: To clarify the strategy for early diagnosis of pancreaticobiliary maljunction (PBM) without biliary dilatation and to pathologically examine gallbladder before cancer develops. METHODS: The anatomy of the union of the pancreatic and bile ducts was assessed by using endoscopic retrograde cholangiopancreatography (ERCP). Patients with a long common channel in which communication between the pancreatic and bile ducts was maintained even during sphincter contraction were diagnosed as having PBM. Of these, patients in which the maximal diameter of the bile duct was less than 10 mm were diagnosed with PBM without biliary dilatation. The process of diagnosing 54 patients with PBM without biliary dilatation was retrospectively investigated. Histopathological analysis of resected gallbladder specimens from 8 patients with PBM without biliary dilatation or cancer was conducted. RESULTS: Thirty-six PBM patients without biliary dilatation were diagnosed with gallbladder cancer after showing clinical symptoms such as abdominal or back pain (n = 16) or jaundice (n = 12). Radical surgery for gallbladder cancer was only possible in 11 patients (31%) and only 4 patients (11%) survived for 5 years. Eight patients were suspected as having PBM without biliary dilatation from the finding of gallbladder wall thickening on ultrasound and the diagnosis was confirmed by ERCP and/or magnetic resonance cholangiopancreatography (MRCP). The median age of these 8 patients was younger by a decade than PBM patients with gallbladder cancer. All 8 patients underwent prophylactic cholecystectomy and bile duct cancer has not occurred. Wall thickness and mucosal height of the 8 resected gallbladders were significantly greater than controls, and hyperplastic changes, hypertrophic muscular layer, subserosal fibrosis, and adenomyomatosis were detected in 7 (88%), 5 (63%), 7 (88%) and 5 (63%) patients, respectively. Ki-67 labeling index was high and K-ras mutation was detected in 3 of 6 patients. CONCLUSION: To detect PBM without biliary dilatation before onset of gallbladder cancer, we should perform MRCP for individuals showing increased gallbladder wall thickness on ultrasound.

Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease.

OBJECTIVE: Autoimmune pancreatitis (AIP) and Mikulicz's disease have recently been recognized as pancreatic or salivary gland lesions of IgG4-related systemic disease. These are frequently associated with elevated serum IgG4 levels. This study aimed to clarify clinical implications of serial changes of elevated serum IgG4 levels in IgG4-related systemic diseases. METHODS: Serial changes of elevated serum IgG4 levels were examined in patients with IgG4-related systemic diseases. Patients Serial changes of elevated serum IgG4 levels were examined in 44 patients: AIP (n=24), Mikulicz's disease (n=8), pancreatic cancer (n=5), bile duct cancer (n=1), sclerosing cholangitis (n=1), hypereosinophilic syndrome (n=1), chronic thyroiditis (n=1), hypophysitis (n=1), idiopathic pancreatitis (n=1), and Behcet's disease (n=1). RESULTS: The serum IgG4 levels decreased in all patients with AIP and Mikulicz's disease after steroid therapy. The serum IgG4 levels were normalized in 46% of AIP patients and 38% of Mikulicz's disease patients. The serum IgG4 levels were not normalized at remission in 3 of 4 relapsed AIP patients, and re-elevation of serum IgG4 levels was detected in all relapsed patients. Elevated serum IgG4 levels decreased in 3 patients with pancreatic cancer after resection or chemotherapy, and decreased in patients with hypereosinophilic syndrome, sclerosing cholangitis, and hypophysitis after steroid therapy. CONCLUSION: Measurement of serial serum IgG4 levels is useful to determine the disease activity of IgG4-related systemic diseases.

Predictors of malignancy and natural history of main-duct intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVES: Because the prevalence of carcinoma is high in main-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, surgical resection is recommended for all main-duct type IPMNs. This study aimed to investigate the clinical predictors of malignancy and natural history of main-duct IPMNs. METHODS: Preoperative clinical characteristics reliably correlated with malignancy in 26 surgically resected patients with main-duct IPMN, and long-term outcome in 20 conservatively followed patients with main-duct IPMN was examined. RESULTS: Age at diagnosis was significantly older in conservatively followed IPMN patients than in surgically resected IPMN patients. Main pancreatic duct (MPD) dilatation 10 mm or greater and mural nodules were significantly more frequent in malignant IPMNs. Obvious progression of dilatation of the MPD was detected in all 4 conservatively followed patients who developed invasive pancreatic carcinoma. The histology of IPMN at autopsy of 4 conservatively followed patients who died of other causes 21 to 120 months later was adenoma. Seven conservatively followed without malignant findings did not show obvious progression of MPD dilatation. CONCLUSIONS: Although surgical resection is indicated for many main-duct IPMNs, conservative follow-up may be an option for elderly asymptomatic patients with main-duct IPMNs with the MPD less than 10 mm, no obvious mural nodule, and negative cytology.

Serum IgG4-negative autoimmune pancreatitis.

BACKGROUND: Autoimmune pancreatitis (AIP) is considered to be a pancreatic lesion of IgG4-related systemic disease, but about 20% of AIP patients do not have elevated serum IgG4 levels. This study aimed to clarify the pathophysiology of AIP patients without elevated serum IgG4 levels. METHODS: Fifty-eight AIP patients were divided into 2 groups: those with elevated serum IgG4 levels (>135 mg/dl; SIgG4-positive AIP) and those without (SIgG4-negative AIP). The 2 groups' clinical, serological, radiological, and histological findings, as well as salivary and lacrimal gland function, were compared. RESULTS: Serum IgG4 levels were elevated in 45 AIP patients and normal in 13 patients. In SIgG4-negative AIP patients, the female ratio tended to be high; obstructive jaundice was less likely; abdominal pain and acute pancreatitis were more likely; segmental swelling of the pancreatic body and/or tail was more common; sclerosing extrapancreatic lesions, salivary and lacrimal gland dysfunction, and abundant infiltration of IgG4-positive plasma cells in the gastric mucosa were less likely; and conservative follow-up was sometimes implemented. Histological examination of the pancreas of SIgG4-negative AIP showed lymphoplasmacytic sclerosing pancreatitis (LPSP) rather confined to the pancreas (n = 4), inadequate material (n = 2), and pancreatic fibrosis showing infiltration of lymphocytes without infiltration of IgG4-positive cells or neutrophils (n = 2). CONCLUSIONS: Clinicopathological features of SIgG4-negative AIP differed from those of SIgG4-positive AIP. Some SIgG4-negative AIP cases are LPSP rather confined to the pancreas. SIgG4-negative AIP may include idiopathic duct-centric pancreatitis (IDCP) or sclerosing pancreatitis other than LPSP or IDCP, but further studies are needed to clarify this issue.

Large cystic acinar cell carcinoma of the pancreas.

Acinar cell carcinoma of the pancreas is a rare neoplasm exhibiting pancreatic enzyme production by the neoplastic cells. It has a highly characteristic cellular arrangement reflecting its acinar derivation, and a definite diagnosis is made based on immunohistochemical and ultrastructural results. Such tumors are often large but rather well circumscribed. Some cases have a cystic appearance due to hemorrhage or necrosis, but a large cystic mass appearing as a pseudocyst is quite rare. We present a large cystic acinar cell carcinoma of the pancreas.

A case of a large cholangiolocellular carcinoma.

Cholangiolocellular carcinoma (CoCC) is a rare malignant primary liver tumor that is considered to originate from the canals of Hering, where hepatic progenitor cells are located. CoCC has various clinicopathological findings, therefore it is difficult to describe a clear diagnostic criteria for CoCC. Reported is a case of a large CoCC in a 45-year-old Japanese woman, which could not be preoperatively diagnosed as CoCC. The final diagnosis of CoCC was determined by pathological observation. Since both the biological behavior and diagnostic criteria of CoCC remain unclear, it is necessary to accumulate more information on CoCCs in order to elucidate these characteristic findings.

FDG-PET/CT findings of autoimmune pancreatitis.

BACKGROUND/AIMS: This study aimed to evaluate the clinical utility in Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET)/ computed tomography (CT) in the management of patients with autoimmune pancreatitis (AIP), with special emphasis on differentiating AIP from pancreatic cancer (PC). METHODOLOGY: FDG-PET/CT findings of 10 AIP patients were compared with those of 14 PC patients. RESULTS: There were no significant differences between AIP and PC in early and delayed maximum standardized uptake value (SUV(max)), and in the ratio of delayed to early SUV(max). Abnormal extrapancreatic FDG uptake was observed in 5 AIP patients, in the hilar lymph nodes (n = 4), mediastinal lymph nodes (n = 2), abdominal lymph nodes (n = 2), and bilateral salivary glands (n = 2). After steroid therapy, the abnormal FDG uptake in the pancreas disappeared almost completely in two patients, and the FDG uptake in the hilar, mediastinal and abdominal lymph nodes decreased in one patient. CONCLUSIONS: FDG-PET/CT may be helpful to differentiate AIP from PC by assessing FDG-uptake patterns in the pancreas and extrapancreatic lesions, it may have the potential to assess the disease activity of AIP and its extrapancreatic lesions, and it may be useful as a monitoring marker for tapering or stopping steroid therapy.

Pancreatobiliary disorders associated with pancreaticobiliary maljunction.

AIM: To clarify the features of biliary carcinomas and pancreatic disorders associated with pancreaticobiliary maljunction (PBM). METHOD: A total of 107 PBM patients with biliary dilatation were reviewed (52 with and 55 without PBM). Clinicopathological findings of biliary carcinomas, and acute or chronic pancreatitis were examined in association with PBM. We also investigated pancreatographic findings in PBM patients and the relationship to their clinical findings in view of pancreatic juice flow. RESULTS: Gallbladder and bile duct carcinomas were seen in 11 (21%) and 8 (15%) of the 52 patients with PBM and biliary dilatation, respectively. In patients with PBM without biliary dilatation (n = 55), only gallbladder carcinoma was detected in 36 (65%) patients. At diagnosis, patients with gallbladder or bile duct carcinoma associated with PBM were younger than those without PBM (p < 0.01). Gallstones were detected only in 6% of the patients with PBM-associated gallbladder carcinoma. Multiple biliary carcinomas were detected in 3 patients (38%) with PBM-associated bile duct carcinoma. While 48 patients (60%) with biliary carcinoma and PBM had a normal pancreatic duct system, only 2 gallbladder carcinomas occurred in 11 dorsal pancreatic duct (DPD)-dominant patients (p < 0.05). Amylase concentration in the bile of DPD-dominant patients was significantly lower than that of patients with a normal pancreatic duct system (p < 0.05). Ten PBM patients had pancreatic disorders: acute pancreatitis (n = 3), chronic pancreatitis (n = 5), and pancreatic carcinoma (n = 2). CONCLUSIONS: In PBM patients, pancreatobiliary reflux frequently leads to biliary cancer, and biliopancreatic reflux often leads to acute or chronic pancreatitis. The biliary tract of PBM patients can be considered premalignant.

A new embryological theory of the pancreatic duct system.

BACKGROUND/AIMS: To clarify the anatomy of the pancreatic duct system and to investigate its embryology. METHODS: We reviewed pancreatograms of 256 patients with a normal pancreatic head and 36 cases of complete pancreas divisum. RESULTS: Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct (APD) forms a straight line and joins the main pancreatic duct (MPD) at the neck portion of the pancreas. The short-type APD joins the MPD near its first inferior branch. The short-type APD is less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the short- and long-type APD. The first long inferior branch from the long-type APD passes through the MPD near the origin of the inferior branch from the MPD. Immunohistochemically, in the short-type APD, the MPD between the junction of the short-type APD and the neck portion originated from the ventral pancreas. CONCLUSION: The long-type APD represents a continuation of the main duct of the dorsal pancreatic bud. The short-type APD is very likely formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch, with the main duct of the dorsal pancreatic bud at the point of connection with the main duct of the ventral pancreatic bud being obliterated and replaced by this additional communication.

Autoimmune pancreatitis and IgG4-related sclerosing disease.

Autoimmune pancreatitis (AIP) is a unique form of pancreatitis in which the pathogenesis is suspected to involve autoimmune mechanisms. AIP sometimes mimics pancreatic cancer in its presentation, but as AIP responds dramatically to steroid therapy, accurate diagnosis is necessary. AIP is currently diagnosed on the basis of a combination of characteristic clinical, serological, morphological and histopathological features. However, its diagnosis remains a clinical challenge and there are no internationally agreed diagnostic criteria. Another type of AIP called 'idiopathic duct-centric chronic pancreatitis' or 'AIP with granulocytic epithelial lesion' has been reported in Western countries. IgG4-related sclerosing disease is a systemic disease in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs. Organs with tissue fibrosis and obliterative phlebitis, such as the pancreas, salivary gland and retroperitoneum, show clinical manifestations; AIP seems to represent one manifestation of IgG4-related sclerosing disease. As a mass is formed in most cases of IgG4-related sclerosing disease, a malignant tumor is frequently suspected on initial presentation. Clinicians should consider IgG4-related sclerosing disease in the differential diagnosis to avoid unnecessary surgery.

K-ras mutation in the major duodenal papilla and gastric and colonic mucosa in patients with autoimmune pancreatitis.

BACKGROUND: Pancreatic cancer occurs in some patients with autoimmune pancreatitis (AIP). Significant K-ras mutations are frequently detected in the pancreas of AIP patients. AIP may be a pancreatic lesion of IgG4-related systemic disease. Gastric and colonic cancer can occur during the follow up of AIP patients. We examined K-ras mutations in the major duodenal papilla and gastric and colonic mucosa of AIP patients. METHODS: K-ras analysis and/or immunohistochemical study was performed on the tissues of the major duodenal papilla (n = 8), gastric mucosa (n = 5), colonic mucosa (n = 3), pancreas (n = 5), common bile duct (n = 5), and gallbladder (n = 4) of 12 AIP patients. RESULTS: Significant K-ras mutations were detected in the major duodenal papilla of 4 of 8 cases [GAT (n = 4)], in the gastric mucosa of 2 of 4 cases [AGT (n = 2)], and in the colonic mucosa of 2 of 3 cases [GAT (n = 2)]. Significant K-ras mutations were detected in the pancreas of all 5 cases [GAT (n = 5), in the common bile duct of 4 cases (GAT (n = 2), TGT (n = 1), and GCT/TGT (n = 1)], and in the gallbladder epithelium of 3 cases [GAT (n = 1), GCT (n = 1), and GTT (n = 1)]. K-ras mutations were detected in the organs associated with IgG4-related fibroinflammation with abundant infiltration of T lymphocytes and forkhead box P3-positive cells. CONCLUSIONS: Significant K-ras mutations were frequently detected in the major duodenal papilla and gastric and colonic mucosa of AIP patients. AIP patients may have risk factors for gastric and colonic cancer, but the mechanisms of K-ras mutation and its clinical implications are not clear.

[A case report-neoadjuvant chemoradiotherapy with combination of S-1 and gemcitabine in a patient with locally advanced pancreatic cancer].

A 63-year-old woman was pointed out pancreatic tumor by a follow up CT after operation for the corpus uteri cancer. She was diagnosed as having locally advanced pancreatic cancer which involved the superior mesenteric vein (SMV). She was treated with radiation (1.8 Gyx28 Fr) and the combination chemotherapy of S-1 plus gemcitabine (S-1: 80 mg/m2/dayx28 days, gemcitabine 200 mg/m2/dayx6 fr, 1 fr a week). Indeed, grade 3 leukopenia and neutropenia were occurred by this treatment, she could be treated on schedule. Four weeks later from completion date, a reduction of the tumor size and an improvement of involving SMV were observed by diagnostic imaging. Subsequently, pylorus-preserving pancreatoduodenectomy (PpPD) with a partial resection of SMV and intraoperative radiation were undergone. She was discharged 19 days after the operation without any surgical complications, and is undergoing adjuvant chemotherapy.

Hemosuccus pancreaticus due to intraductal papillary-mucinous carcinoma of the pancreas.

A 72-year-old female was referred to our hospital for evaluation of a hyperechoic mass in the pancreatic head with ultrasound sonography. She had no symptom expect slight anemia (Hb 11.3 g/dl). On endoscopy, blood was expelled from the orifice of the major duodenal papilla, but excretion of mucus was not detected. Endoscopic retrograde pancreatography revealed an irregular defect in the main pancreatic duct at the head of the pancreas. Computed tomography revealed a 2-cm mass with a low density lesion in the pancreas head. On suspicion of malignant tumor of the pancreas, pylorus-preserving pancreaticoduodenectomy was performed. Histological diagnosis was intraductal papillary-mucinous carcinoma without mucin hypersecretion. It grew within the inferior branch of the main pancreatic duct, and the top of the tumor stood out into the main pancreatic duct. As the causes of hemosuccus pancreaticus, pancreatic benign diseases, for example, chronic pancreatitis, pseudocyst, arterial aneurysm and pseudoaneurysm, are known, but pancreatic tumors are rare. In particular, this may be the first report of hemosuccus pancreaticus induced by intraductal papillary-mucinous carcinoma of the pancreas without mucin hypersecretion.

Metachronous Carcinomas of the Biliary Tract in a Patient Treated Three Times with Curative Surgery.

We here report on a case of metachronous multicentric carcinomas of the biliary tract treated 3 times with curative surgery over 23 years. A 28-year-old woman underwent cholecystectomy because of papillary carcinoma of the gallbladder. After 17 years, 3 carcinomas developed in the biliary tract: intrahepatic cholangiocarcinoma of the left liver, common bile duct carcinoma, and remnant cystic duct carcinoma. They were successfully removed via left hepatectomy combined with pylorus-preserving pancreatoduodenectomy. Furthermore, another intrahepatic cholangiocarcinoma developed 6 years after the second surgery, which was removed again via partial resection of the posterior segment of the liver. Histological findings of carcinomas represented various grades of cell differentiation. No predisposition toward carcinogenesis was found, since neither pancreaticobiliary maljunction nor primary sclerosing cholangitis was present, and the overexpression of cyclooxygenase-2 was negative in all resected specimens. Close monitoring for recurrence is warranted for early detection of metachronous carcinoma that might be effectively treated with repeated resection.

Rectal cancer metastasis to the head of the pancreas treated with pancreaticoduodenectomy.

We report a case of a 50-year-old man who developed metastatic pancreatic cancer from a primary rectal cancer that had been curatively removed 3 years previously. The patient presented with a tumor that occupied the head of the pancreas, associated with obstructive jaundice, but the main pancreatic duct was not dilated. The patient was initially diagnosed as having primary pancreatic cancer. Cytological examination of the bile was conclusive for the presence of adenocarcinoma. The patient refused surgical treatment and chose to have gemcitabine therapy (1000 mg/body), which was given 27 times over 10 months. For 1 year, local disease progression was slow and no distant metastases developed; therefore, the initial diagnosis of pancreatic cancer was questioned. At that time, the patient asked for the tumor to be removed, and pancreaticoduodenectomy was performed. On histology, including immunohistochemical staining for cytokeratin 20 (positive) and cytokeratin 7 (negative), the tumor was shown to be a metastatic pancreatic carcinoma that had originated from the original rectal cancer.

Tumor size significantly correlates with postoperative liver metastases and COX-2 expression in patients with resectable pancreatic cancer.

BACKGROUND/AIM: Local treatment often fails in patients with resectable pancreatic cancer due to the postoperative development of distant metastases, especially liver metastases. We determined the prognostic factors for postoperative liver metastases in pancreatic cancer patients following surgical resection with combined radiotherapy. METHODS: Sixty-four patients with nonmetastatic, resectable pancreatic cancer were entered into this study. All of these patients had pancreatic resection surgery combined with radiotherapy. The development of postoperative liver metastases was carefully followed, and the survival ratio was evaluated using the Kaplan-Meier method. The prognostic importance of clinicopathological factors and molecular characteristics was analyzed by the Cox proportional hazards model. The correlation study was performed using Fisher's exact test. RESULTS: Tumor size, curability, and histological type of differentiation were statistically significant independent prognostic factors. On multivariate analysis, curability and histological type of differentiation were statistically significant. Only tumor size (> or = 3 cm) was significantly correlated with postoperative liver metastases, as well as cyclooxygenase-2 expression. CONCLUSIONS: There were three significant prognostic factors in patients with resectable pancreatic cancer who had local therapy. Patients who have a large tumor require particularly careful follow-up for postoperative liver metastases.