Kenneth K. Tanabe

Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.

BACKGROUND: Radiofrequency (RF)-induced tissue coagulation represents a new approach for the thermal destruction of tumors within the liver. The purpose of the current study was to 1) assess technique safety; 2) determine the extent and evolution of induced cellular damage; and 3) correlate the observed pathologic effects with radiologic studies. METHODS: Twenty-three tumors measuring </= 8 cm (19 colorectal metastases and 4 hepatomas) in 22 patients were treated with RF (range, 500-1550 milliamperes) using internally cooled electrodes. All treated tumors were resected to allow pathologic analysis. Eleven tumors were treated intraoperatively under ultrasonographic guidance and excised immediately. Twelve tumors were treated percutaneously using ultrasound or computed tomography (CT) guidance and subsequently were excised 3-7 days after ablation. Contrast-enhanced CT (n = 12) and magnetic resonance imaging (MRI) (n = 2) were performed after ablation of all percutaneously treated patients. RESULTS: Tumors treated intraoperatively did not demonstrate definitive coagulative necrosis. However, pathologic abnormalities suggestive of tissue injury were observed with hematoxylin and eosin staining, and absent cytosolic and mitochondrial enzyme activity suggested irreversible cellular damage. In contrast, specimens removed > 3 days after ablation showed definite, contiguous coagulative necrosis without intervening areas of viable tumor. CT and MRI scans demonstrated circumscribed hypodense, nonenhancing regions surrounding the electrode tract as early as 15 minutes after ablation. These corresponded within 2 mm to measurements of coagulation at pathology. CONCLUSIONS: RF ablation is a minimally invasive and safe approach to the treatment of tumors in the liver. Tumors treated with RF energy do not immediately demonstrate coagulative necrosis, but do show evidence of irreversible cellular damage. The extent of tumor necrosis correlates closely with findings at contrast-enhanced imaging.

We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction. These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

BACKGROUND Radiofrequency (RF)-induced tissue coagulation represents a new approach for the thermal destruction of tumors within the liver. The purpose of the current study was to 1) assess technique safety; 2) determine the extent and evolution of induced cellular damage; and 3) correlate the observed pathologic effects with radiologic studies. METHODS Twenty-three tumors measuring ≤ 8 cm (19 colorectal metastases and 4 hepatomas) in 22 patients were treated with RF (range, 500–1550 milliamperes) using internally cooled electrodes. All treated tumors were resected to allow pathologic analysis. Eleven tumors were treated intraoperatively under ultrasonographic guidance and excised immediately. Twelve tumors were treated percutaneously using ultrasound or computed tomography (CT) guidance and subsequently were excised 3–7 days after ablation. Contrast-enhanced CT (n = 12) and magnetic resonance imaging (MRI) (n = 2) were performed after ablation of all percutaneously treated patients. RESULTS Tumors treated intraoperatively did not demonstrate definitive coagulative necrosis. However, pathologic abnormalities suggestive of tissue injury were observed with hematoxylin and eosin staining, and absent cytosolic and mitochondrial enzyme activity suggested irreversible cellular damage. In contrast, specimens removed > 3 days after ablation showed definite, contiguous coagulative necrosis without intervening areas of viable tumor. CT and MRI scans demonstrated circumscribed hypodense, nonenhancing regions surrounding the electrode tract as early as 15 minutes after ablation. These corresponded within 2 mm to measurements of coagulation at pathology. CONCLUSIONS RF ablation is a minimally invasive and safe approach to the treatment of tumors in the liver. Tumors treated with RF energy do not immediately demonstrate coagulative necrosis, but do show evidence of irreversible cellular damage. The extent of tumor necrosis correlates closely with findings at contrast-enhanced imaging. Cancer 2000;88:2452–63. © 2000 American Cancer Society.