Cryosurgery is an emerging treatment for human solid tumors, notably colorectal liver metastasis. Cryosurgical procedures generate a thermal gradient of from at least -50 degrees C at the center of the tumor being treated to about 0 degrees C at the periphery. Cell death occurs by necrosis in the center, while the peripheral zone of frozen tumor harbors a mix of viable and dead tissue. In order to understand the mechanisms of cell death and survival in this peripheral area at risk for tumor recurrence, we have established an in vitro freezing system that mimics in vivo conditions of sublethal injury. HT29 colon cancer cells were subjected to freezing temperatures from -6 degrees C to -36 degrees C, thawed at room temperature for 30 min and rewarmed at 37 degrees C for a period of time. Post-freeze-thaw, cryolytic cells were evaluated by trypan blue exclusive assay. We also identified apoptotic cells after rewarming by cell shrinkage, nucleic condensation, TUNEL assay, DNA fragmentation and PARP degradation. The intensity of cryolysis and apoptosis was increased by lowering the freezing temperature. At -36 degrees C, all cells were dead immediately after freeze-thaw. A kinetic analysis of cryo-induced apoptosis showed that the commitment to enter apoptosis occurred right after the freeze-thaw period and lasted less than 8 hr after rewarming. We further demonstrated that freezing triggers one of the caspase cascade involved in apoptosis: release of cytochrome c from mitochondria to cytosol, followed by activation of caspase-9 and degradation of PARP. These results indicate the death of cancer cells under cryo-treatment at sublethal freezing temperature can be attributed 2 different modes, cryolysis as well as apoptosis. HT29 cells carrying p53 mutant have very quick response for induction of apoptosis by cryo-treatment and contain an intact pathway of caspase cascade. Further studies will address if mechanisms in cells with wild-type p53 will differ.
Longevity of patients with unresectable synchronous liver metastases from colorectal cancer is affected adversely by the presence of nodal metastases and extent of liver metastases. This should be considered in the planning treatment.
Cardiac metastasis from colorectal cancer is rare. Such metastasis is usually discovered during autopsy; antemortem diagnosis is rare. A 76-year-old woman in whom we had performed right hemicolectomy for ascending colon cancer was noted to have elevated tumor markers during a follow-up examination 4 months after the surgery. Chest CT indicated a cardiac tumor that was approximately 6 cm in diameter, and we suspected a metastatic cardiac tumor. Subsequently, obstructive jaundice developed as a result of lymph node metastases around an extrahepatic bile duct, and a stent was placed. The patient refused aggressive treatment and was simply followed up clinically. Within 2 months, the cardiac tumor enlarged enough to cause cardiac failure, and death ensued 7 months after the surgery. Autopsy revealed a myocardial tumor, approximately 7 x 5 cm, that extended from the right atrium to the right ventricle. The histopathologic diagnosis was cardiac metastasis from ascending colon cancer. We describe in detail this case of rapidly progressive cardiac metastasis that was discovered after surgical treatment of ascending colon cancer. In searching the medical literature, we found only 14 cases of metastasis of colorectal cancer to the heart. We describe our case in detail and review our experience in light of the available literature.
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