Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer

Small guanosine triphosphatase RhoA has been known to re‐organize cytoskeletons and regulate cell migration. The present authors have previously reported that expression of RhoA is significantly increased in advanced ovarian carcinomas and also in the peritoneal disseminated lesions. The present study investigated whether overexpression of RhoA could alter the progressive behavior of ovarian cancer cells. The effect of various Rho inhibitors on the biological behavior of ovarian cancer cells in vitro and in vivo was also examined. A stable RhoA‐transfectant of an ovarian cancer cell line SKOV3 was generated and examined in vitro for alterations of proliferative activity and invasiveness, and also in the nude mice model for peritoneal dissemination. In addition, the effect of a specific Rho inhibitor (C3 exoenzyme), Rho kinase inhibitor (Y27632) and hydroxymethylglutaryl coenzyme A (HMG–CoA) reductase inhibitor (Lovastatin and Pravastatin) were studied in vitro and in vivo. Forced overexpression of RhoA did not alter proliferative activity but significantly increased the invasiveness in vitro, which was suppressed by addition of C3 exoenzyme, Y27834, Lovastatin and Pravastatin. In the nude mice model, the frequency of dissemination and the number of disseminated lesions were significantly increased in the RhoA transfectant than in the control. In addition, oral administration of Lovastatin significantly decreased the number of metastatic sites compared with the control. These findings suggest that upregulation and/or activation of RhoA play an important role in the peritoneal dissemination of ovarian carcinoma, and that Lovastatin might be a candidate for the possible, novel treatment for ovarian carcinoma patients with peritoneal dissemination. (Cancer Sci 2008; 99: 2532–2539)     

Heterogeneous prognoses of patients with tumors invaded within muscularis propria according to tumor depth in the layers of the muscularis propria

Background  The muscularis propria of the stomach is histologically divided into three layers; namely, the innermost oblique, the inner circular, and the outer longitudinal layers. In patients with gastric cancer the depth of tumor invasion has been reported to correlate with lymph node metastasis and prognosis. However, it is unclear whether the depth of tumor invasion in the muscularis propria has an effect on lymph node metastasis and prognosis. Methods  Fifty-nine gastric cancer patients with muscularis propria invasion were analyzed retrospectively. These patients were divided into two groups, the inner group, with invasion up to the inner circular layer; and the outer group, with invasion beyond the inner circular layer. The relationships between tumor invasion and clinicopathological factors and survival were evaluated. Results  Of the 59 patients, 34 were classified as the inner group, and 25 were classified as the outer group. The inner group had a significantly lower probability of lymph node metastasis (P = 0.0053) and a significantly better overall cancer-specific survival (P = 0.017) than the outer group. Conclusion  Gastric cancers with muscularis propria invasion had heterogeneous prognoses according to the tumor depth in the muscularis propria layers.     

Chronic α1 blockade in a patient with Eisenmenger syndromeblockade in a patient with Eisenmenger syndrome

Summary In an 18-year-old male with Eisenmenger syndrome cyanosis and erythrocytosis were increasing. The erythrocytosis diminished following oral bunazosin and phlebotomy was not needed during the treatment. When bunazosin was stopped, the erythrocytosis increased, but when it was resumed, the erythrocytosis and general fatigue diminished.     

Antitumor effects of human recombinant interferon-gamma and tumor necrosis factor on five cervical adenocarcinoma cell lines, in vivo and in vitro

We examined the antitumor effects of recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) on cervical adenocarcinoma cell lines, in vitro and in vivo. Four of five cell lines showed a high sensitivity to IFN-gamma, in vitro. One of five cell lines showed a remarkable sensitivity to TNF, in vitro. Only one cell line resistant to both IFN and TNF was derived from a well-differentiated adenocarcinoma of endocervical type. Experiments using nude mice bearing transplanted tumors revealed that these cytokines were also effective against tumors in vivo. All these observations suggest that IFN-gamma or TNF can have positive effects in the treatment of patients with adenocarcinoma of the uterine cervix.     

Treatment of advanced cervical cancer by a combination of peplomycin, vincristine, mitomycin-C, and cisplatin

Eighteen patients with advanced or recurrent carcinoma of the cervix were treated with a combination of peplomycin, vincristine, mitomycin-C, and cisplatin (POMP). Ten of the 16 evaluable patients (63%) responded, including 4 with a complete response. Median duration of the response was 7 months. Two of 6 with intrapelvic recurrent tumors responded to some extent following intraarterial infusion. The subcutaneous infusion of peplomycin was well accepted by the patients. Toxicity was tolerable. This regimen seemed to be one of the regimens which should be considered for the advanced or recurrent cervical cancer.     

Epididymis Metastasis from Colon Carcinoma: A Case Report and a Review of the Japanese Literature

A 56-year-old Japanese man in whom a descending colon carcinomahad been resected underwent a high orchitectomy for metastaticepididymis from the colon. Metastatic carcinoma from the digestiveorgans to the spermatic cord (SC) and/or the intrascrotal contents(ISC) is rare. Fifty-four Japanese patients with metastasisfrom the digestive organs to the SC and/or the ISC were analyzed.The most frequent primary site was the stomach and the mostfrequent metastatic site was the spermatic cord. Our patientwas the first to exhibit metastasis from the colon to the epididymis.A primary site was identified in 24 patients subsequent to themetastatic tumor. Twenty patients had other organ metastatis.The prognosis for SC and/or ISC metastasis patients is poor.Our patients has survived for 18 months following his orchitectomywith no other organ metastasis (31 months after the primaryoperation). In our patient, monoclonal estrogen receptor stainingwas negative; however, further study must be undertaken.     

Comparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer.

A comparative study of a new tumour marker, CA242, and CA19-9 was conducted with special reference to their diagnostic usefulness in pancreatic cancer. CA242 showed sensitivity similar to that of CA19-9 for overall cases and early cases (stage I tumour) of pancreatic cancer. For other malignancies, the positive rates of CA242 were lower than those of CA19-9 except for colorectal cancer. An important characteristics of CA242 was that it was only slightly and infrequently elevated in the sera of patients with benign diseases such as chronic pancreatitis, chronic hepatitis and liver cirrhosis. This characteristic was more apparent in the patients with benign obstructive jaundice, indicating that the serum level of this marker was scarcely affected by cholestasis. Using cut-off levels corresponding to a 90% specificity, the clinical results obtained with CA242 in the diagnosis of pancreatic cancer were similar to those obtained with CA19-9, except that CA19-9 was falsely negative in some patients with early-stage pancreatic cancer. These findings suggest the usefulness of this marker for screening pancreatic cancer in patients on their first hospital visit. However, CA242 was found to be influenced by the Lewis blood group system. This unfavourable result is attributed to the C241 catcher antibody of this assay system, which has almost the same epitope specificity as the C50 and the NS19-9 monoclonal antibodies. In conclusion, CA242 is superior to CA19-9 in diagnosing pancreatic cancer by virtue of its higher specificity.     

Evidence for ras gene mutation in 2-amino-3-methylimidazo[4,5-f]quinoline–induced colonic aberrant crypts in the rat

Aberrant crypt foci (ACF) are putative peneoplastic lesions that develop after treatment of animals with colon carcinogens, including cooked-meat heterocyclic amines such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 rats given IQ by gavage on alternating days for 2 wk (130 mg/kg body weight) and killed 12 wk after the final carcinogen dose had an average of 4.4 ACF/colon and an average of 3.2 crypts/focus. The DNA from these ACF was amplified by the polymerase chain reaction and analyzed by 3′-primer mismatch and direct sequencing methods for mutations in the Ki-ras proto-oncogene. Of the 37 IQ-induced ACF screened, three contained a GGT→GAT mutation in codon 12 and one contained a GGC→GCC mutation in codon 13. The approximately 11% frequency of mutation in IQ-induced ACF is within the range of previous ACF studies of azoxymethane, which reported a 7–37% incidence of Ki-ras mutaion. These findings suggest that for both compounds, ras mutations occur during early stages of colorectal tumorigenesis. However, while ras mutations can be detected with increasing frequency in azoxymethane-induced adenomas and carcinomas, they are reportedly absent in IQ-induced colon tumors. Thus, for IQ and related compounds additional factors (possibly increased cell proliferation) may be important in the later stages of colorectal tumorigenesis. © 1995 Wiley-Liss Inc.