Survival outcomes of lung metastases from colorectal cancer treated with pulmonary metastasectomy or modern systemic chemotherapy: a single institution experience.

BACKGROUND: Although pulmonary metastasectomy is an accepted treatment strategy for resectable lung metastases (LM) from colorectal cancer (CRC), its survival benefits are controversial. In contrast, recent advancements in chemotherapy have significantly improved metastatic CRC prognosis. This study aimed to evaluate survival outcome of LM from CRC in the age of newly developed chemotherapy. METHODS: We retrospectively reviewed 50 patients who underwent complete resection and 22 patients who received chemotherapy as definitive treatment for LM from resected CRC at our hospital. The present study was limited to patients who started treatment for isolated LM after molecular targeted drugs became available in Japan. RESULTS: Overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS) rates after pulmonary resection were 64.5%, 66.4%, and 32.6% at five years, respectively. OS and CSS rates of chemotherapy patients were 26.8% and 28.3% at five years, with a median progression-free survival time of 10.0 months. When compared the characteristics of surgical and chemotherapy patients, patients with pN factors of CRC (p = 0.013), smaller size (p < 0.001), larger number (p < 0.001), and bilateral (p < 0.001) LM received chemotherapy. Univariate analysis showed that multiple LM and rectal lesions were poor prognostic factors for OS (p = 0.012) and DFS (p = 0.017) in surgical patients, and rectal lesions were a poor prognostic factor for OS (p = 0.013) in chemotherapy patients. CONCLUSIONS: Pulmonary metastasectomy showed a favorable survival in patients with LM from CRC. Despite the high recurrence rate after metastasectomy and recent advances in chemotherapy, surgical resection could still be considered as a valid option among multidisciplinary treatments. TRIAL REGISTRATION: The research plan was approved by the Institutional Review Board of Shinko Hospital (No. 2142) on February 7, 2022.

[An Elderly Patient with Local Recurrence of Gastric Cancer Responding Completely to S-1 Monotherapy].

An 80-year-old man with a local recurrence of gastric cancer was treated with S-1 monotherapy leading to a complete response(CR).The patient was diagnosed with gastric cancer and underwent a distal gastrectomy with lymph node dissection. Pathological findings showed tub2>por1, pT3 (SS), pN2, pStage III A.Five months after surgery, the patient presented with redness of the abdominal skin.Computed tomography (CT) revealed massive tumors in the abdominal cavity with invasion to the abdominal wall. He was administered S-1, 80 mg/body/day for 14 days, followed by a 7-day rest.After 2 courses of treatment, CT showed a dramatic reduction of the tumors. After 6 months, the tumor tissue completely disappeared and he had a CR.Administration of S-1 was continued for 2 years and 6 months.There was no relapse for 3 years after discontinuation.S -1 monotherapy appears to be a feasible and effective therapy for elderly patients with recurrent gastric cancer.

[A Case of Ascending Colon Cancer Showing Marked Reduction of Ascites by Bevacizumab Combination Chemotherapy].

A 68-year-old woman presented to our hospital with abdominal fullness. Computed tomography(CT)revealed ascites and massive tumors in the abdominal cavity. She was diagnosed with ascending colon cancer with peritoneal dissemination and ovarian metastasis. After ileostomy, panitumumab plus mFOLFOX6 therapy was initiated, but it was discontinued due to adverse events. As the ascites rapidly increased, her chemotherapy was changed to bevacizumab(BV)plus FOLFIRI. BV combination therapy resulted in a dramatic decrease in ascites and improved her quality of life, whereas the therapy did not reduce the primary and metastatic lesions. Our case suggested that BV could decrease ascites by inhibiting vascular endothelial growth factor(VEGF)-induced vascular permeability.

Eosinophilia and bone lesion as clinical manifestations of aggressive systemic mastocytosis.

We report a patient with aggressive systemic mastocytosis (SM), who exhibited eosinophilia and unusual destructive bone lesions. A 43-year-old female was referred to our hospital because of a vertebral compression fracture, multiple lytic bone lesions, and eosinophilia in February 2011. A diagnosis of aggressive SM was made on the basis of abnormal mast cells in the bone marrow, high serum tryptase levels, and multiple lytic bone lesions including vertebral compression fractures. Polymerase chain reaction and subsequent sequencing of its products to identify mutations of c-kit yielded negative results and imatinib mesylate failed to improve the SM of the patient. She was then treated with interferon-α, with considerable improvement of the disease, although severe myelosuppression prevented the continued administration of a sufficient dose of this agent. In August 2011, the patient suddenly developed paraplegia of the lower extremities. Magnetic resonance imaging demonstrated epidural mass lesions at the levels from Th9 to Th11, compressing the spinal cord. Emergent laminectomy and subsequent irradiation of the tumors were performed without improvement of the paraplegia. Histopathologic examination of the epidural tumors, from samples obtained intraoperatively, confirmed the diagnosis of SM. She was further treated with dasatinib and then cladribine without obvious improvement, although the latter reduced the eosinophilia to some extent ; however, she died of sepsis in September 2011.

Hepatic follicular dendritic cell sarcoma favorably controlled by transcatheter arterial chemoembolization.

A 78-year-old woman with multiple tumors in the liver and spleen was diagnosed with follicular dendritic cell (FDC) sarcoma based on the histological picture of splenectomized specimen and its expression of CD21 and CD 23. As a paraneoplastic immune disorder, Coombs' test was positive although hemolysis was not obvious. Since systemic chemotherapies were ineffective for residual liver tumors, transcatheter arterial chemoembolization (TACE) was performed with subsequent tumor reduction. Currently, the patient is alive 27 months after the diagnosis with residual hepatic tumors favorably controlled by repeated TACE. Our experience suggests that TACE is useful for the management of hepatic FDC sarcoma.

[A case of sarcomatoid malignant peritoneal mesothelioma responding to combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine(CYVADIC)].

A 66-year-old woman was seen at our hospital because of abdominal fullness. A computed tomography(CT)revealed massive tumors in abdominal cavity. The patient underwent surgery consisting of tumorectomy, segmental gastrectomy, partial resection of small intestin, transverse colectomy, left oophorectomy and gastrostomy. By using immunohistochemical staining, the patient was diagnosed as sarcomatoid malignant peritoneal mesothelioma. Rapidly abdominal fullness occurred as of 22 days after the operation, and an abdominal CT revealed the massive recurrent tumors. We started a combination chemotherapy of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). The recurrent tumors showed remarkable reduction after the two courses of CYVADIC chemotherapy. Although we next started carboplatin and paclitaxel combination chemotherapy, she died due to rapidly progression of the disease with disseminated intravascular coagulation after 132 days of the operation. Malignant mesothelioma, especially sarcomatoid mesothelioma, is known to have a poor prognosis. However, our case suggests that we could improve the prognosis of sarcomatoid malignant mesothelioma by aggressive chemotherapy.

Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylgeranylation of Rho.

Rho family GTPases are frequently overexpressed in breast cancers, which regulate cancer cell migration and invasion. They require prenylation, a lipid post-translational modification, for full biological functions. We examined the effects of 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (fluvastatin), a selective farnesyltransferase inhibitor (FTI-277) and a selective geranylgeranyltransferase type I inhibitor (GGTI-298) on in vitro invasive capacity of MDA-MB-231 human breast cancer cells into the endothelial cell monolayer in a transendothelial migration assay. Although, at a maximal dose of 5 microM, fluvastatin did not affect the integrity of endothelial cell monolayer, the transendothelial migration of MDA-MB-231 cells was inhibited potently by fluvastatin in a dose-dependent manner. The transendothelial migration of MDA-MB-231 cells was also inhibited potently by GGTI-298 in a dose-dependent manner but weakly by FTI-277. The inhibitory effects of fluvastatin, GGTI-298 and FTI-277 on MDA-MB-231 cell invasion were shown to correlate well with inhibition of the membrane localization of RhoA and RhoC, but not with Ras. These results suggest that geranylgeranylation step of RhoA and RhoC could be a good therapeutic target for the prevention of invasion and metastasis of breast cancer cells.

Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis.

A number of small GTPases are involved in cancer cell proliferation, migration and invasion, acting as molecular switches that cycle between GTP- and GDP-bound states. GTPase-activating proteins (GAPs) have been established as a major class of negative regulators of Rho GTPase signaling. To investigate the biological function of p190 RhoGAP toward RhoA in cancer cell invasion and metastasis, we generated a chimera made of the RhoGAP domain of p190 and the C-terminus of RhoA (p190-RhoA chimera), and transfected it into human pancreatic cancer cells, AsPC-1. Epidermal growth factor (EGF)-induced activation of RhoA, as well as RhoB and RhoC, to a lesser extent, was significantly inhibited in p190-RhoA chimera-transfected AsPC-1 cells compared with that of control cells (mock-infected), when assessed by pull-down assay for GTP-bound RhoA, RhoB, and RhoC, respectively. EGF-induced invasion of p190-RhoA chimera transfectants was significantly inhibited compared with that of mock-infected cells in a modified Boyden chamber assay. Furthermore, the mice injected intrasplenically with AsPC-1 cells that overexpressed the p190-RhoA chimera had a marked reduction in the number and size of metastatic nodules in the liver. These data suggest that the inhibitory action of p190 RhoGAP toward RhoA offers a novel approach to the treatment of invasion and metastasis of cancer cells.

Cross talk between apoptosis and invasion signaling in cancer cells through caspase-3 activation.

In solid tumors, cancer cells are exposed to various microenvironmental stresses such as hypoxia, nutritional depletion, and low pH. Cancer cells adapt to these stresses and circumvent cell death. When the antiapoptotic signals overcome the stress, cancer cells might acquire physiologic functions, such as invasiveness, instead of cell death. Here, we report that tumor cells acquire an invasive capacity from apoptotic signals through caspase activation. We treated rat ascites hepatoma MM1 cells with an apoptosis-inducing drug, etoposide, or hypoxia, and assessed the invasion capacity with an in vitro bioassay. Although MM1 cells hardly showed invasiveness in serum-free medium, under stress conditions, invasive capacity accompanied with morphologic change was induced with caspase-3 activation. Such stress-induced invasion as well as morphologic change was suppressed by blocking caspase-3 activity with caspase inhibitors or by RNA interference of caspase-3. In contrast, lysophosphatidic acid-induced invasiveness was not affected by caspase-3 inhibition. These results suggest that caspase-3 activation contributes to the stress-induced invasive capacity of these cancer cells.

Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor.

A number of small GTPases are involved in cancer cell proliferation, migration and invasion. They need to be prenylated for full biological functions. We have recently reported that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which block the biosynthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate, inhibit in vitro invasion of human pancreatic cancer cells. In the present study, we examined the effects of two selective inhibitors of prenylation, a farnesyltransferase inhibitor (FTI-277) and a geranylgeranyltransferase type I inhibitor (GGTI-298), on in vitro invasion of cancer cells in a modified Boyden chamber assay. The invasion of COLO 320DM human colon cancer cells was inhibited potently by HMG-CoA reductase inhibitor lovastatin and GGTI-298 but weakly by FTI-277. The treatment of cancer cells with GGTI-298 markedly caused RhoA to decrease in the membrane fraction and accumulate in the cytosolic fraction, whereas it had almost no effect on the translocation of Ras. FTI-277 markedly inhibited membrane localization of Ras, but its inhibitory effect on cancer cell invasion occurred only at doses that affected membrane localization of RhoA. FTI-277 and GGTI-298 decreased the growth potential of COLO 320DM cells, but the inhibitory effect of GGTI-298 was rather selective toward invasion in association with changes in cell morphology and RhoA localization. These results suggest that geranylgeranylation of RhoA by geranylgeranyltransferase type I is critical for cancer cell invasion, and inhibition of geranylgeranyltransferase type I activity should offer a novel approach to the treatment of invasion and metastasis of cancer cells resistant to farnesyltransferase inhibitors.

Inhibition of lysophosphatidic acid-induced RhoA activation and tumor cell invasion by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.

The mevalonate metabolic pathway is necessary for the isoprenylation of a number of small GTPases. We have previously presented that Rho plays a pivotal role in 1-oleoyl-lysophosphatidic acid (LPA)-induced invasion of rat ascites hepatoma MM1 cells. Herein we report the effect of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on the in vitro invasion of MM1 cells. Fluvastatin and lovastatin inhibited LPA-induced MM1 cell invasion in a dose-dependent manner. Fluvastatin inhibited LPA-induced translocation of RhoA protein from the cytosol to the membrane and RhoA activation which was measured by pull-down assay for GTP-bound RhoA. Fluvastatin also inhibited the translocation of both endogenous and dominant-active RhoA from the cytosol to the membrane, actin stress fiber assembly and in vitro invasion of the cells expressing dominant-active RhoA (Val14-RhoA). These results indicate that HMG-CoA reductase inhibitors have the potential to reduce RhoA activation and cancer cell invasion by targeting the Rho protein isoprenylation.

3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis.

BACKGROUND & AIMS: Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase blocks the mevalonate metabolic pathway, which is necessary for the isoprenylation of a number of small guanosine triphosphatases. We examined the effects of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on human pancreatic cancer cell invasion in vitro and experimental liver metastasis in vivo. METHODS: Cell invasion was studied in a modified Boyden chamber assay. The translocation of RhoA was assessed by immunoblotting. Experimental liver metastases were induced in nude mice by intrasplenic inoculation of ASPC-1 human pancreatic cancer cells. RESULTS: Fluvastatin and lovastatin inhibited the in vitro cancer cell invasion induced by epidermal growth factor (EGF) in a manner sensitive to C3 transferase, a specific inhibitor of Rho. Treatment of ASPC-1 cells with fluvastatin markedly attenuated the EGF-induced translocation of RhoA from the cytosol to the membrane fraction and caused cell rounding. The effects of fluvastatin could be reversed by the addition of all-trans-geranylgeraniol. Administration of fluvastatin to nude mice reduced both metastatic tumor formation in the liver and the growth of established liver metastases at doses recommended for the treatment of hypercholesterolemia in humans. CONCLUSIONS: HMG-CoA reductase inhibitors can be antimetastatic agents with the potential for useful clinical applications.