Treatment by corticosteroid and plasma exchange in 5 cases of renal cholesterol embolic disease

Cholesterol arterial embolization is a systemic disease resulting from cholesterol crystal embolization to multiple organs, including the kidney, skin, brain, eye, gastrointestinal tract and extremities. In general, it is associated with high morbidity and mortality, but no optimal treatment has yet been developed. In this paper, we report five patients with cholesterol atheroembolic renal failure. In three of the five patients, combined therapy with corticosteroids and plasma exchange was performed. The three patients survived. On the other hand, the two remaining patients died of multifactorial causes. In this report, the literature on steroid therapy for cholesterol atheroembolic renal disease is reviewed and the efficacy of combined therapy by use of corticosteroids and plasma exchange is evaluated.     

An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker.

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.     

Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.

PURPOSE: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas. EXPERIMENTAL DESIGN: In this study, we examined HIF [HIF-1alpha (HIF1) and HIF-2alpha (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis. RESULTS: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant. CONCLUSIONS: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.     

Intensification of antitumor effect by T helper 1-dominant adoptive immunogene therapy for advanced orthotopic colon cancer.

PURPOSE: T helper (Th) 1/Th2 balance, controlled by Th1 or Th2 cells producing cytokines, plays important roles in antitumor immunity. Interleukin-18 (IL-18) can act together with IL-12 in promoting the generation of IFN-gamma producing Th1 cells. The goal of this study was to determine whether cytotoxic T lymphocyte (CTL) secreted in a murine IL-18-induced Th1-dominant state inhibited the development of primary tumors and synchronous liver metastases in orthotopic colon cancer model. EXPERIMENTAL DESIGN: Murine IL-18 gene was transduced into activated T lymphocytes by an adenovirus vector encoding IL-18 (AdIL-18) liposome complex method. Efficacy of adoptive immunogene therapy using AdIL-18 with or without IL-12 was tested in advanced orthotopic xenograft of murine colon cancer. To elucidate the mechanism responsible for the adoptive immunogene therapy, serum IL-4, IL-6, IFN-gamma, and tumor necrosis factor alpha production in Th1/Th2 cytokine balance and quantification of tumor vascularity were investigated. RESULTS: By a modified method of adenoviral gene transduction, T lymphocytes achieved efficient IL-18 production without cell toxicity. Against orthotopic colon cancer, when combined with low dose of recombinant (r) IL-12 (AdIL-18-CTL/rIL-12), the therapeutic efficacy showed much smaller tumors with no liver metastases and no disseminated tumors. There was a significant difference in the volume of primary tumors and the number of liver metastases compared with the group treated with AdIL-18-CTL alone or other group (P < 0.01). In addition, the median survival time of the group treated with AdIL-18-CTL was 53.7 +/- 5.8 days and that of AdIL-18-CTL/rIL-12 was 78.4 +/- 6.1 days, which was also a significant difference (P < 0.01). These antitumor mechanisms were involved with Th1-dominant response in serum Th1/Th2 cytokine balance and suppression of neovascularization at primary tumor site. CONCLUSION: These data suggest that a strategy of Th1/Th2 balance-based adoptive immunogene therapy might be useful for advanced cancer patients.     

Neck node metastasis after successful brachytherapy for early stage tongue carcinoma.

BACKGROUND AND PURPOSE: The accuracy of factors for predicting lymph node metastasis in patients with early-stage (stage I and II) mobile tongue carcinoma and prognostic factors associated with the clinical and pathological findings of lymph node metastasis were examined. MATERIAL AND METHODS: Between 1971 and 1998, 616 patients with early stage mobile tongue carcinoma were treated by brachytherapy with or without external irradiation. Neck lymph node metastasis occurred in a total of 237 cases, and 191 of them were not associated with primary failure. Neck dissection was performed in 169 of these 191 cases, and 16 cases were treated by radiotherapy. A pathological analysis was possible in 159 of the 169 neck dissection cases. RESULTS: There were 88 tongue cancer recurrences, and the incidence of neck metastasis was 38% (191/528) in the cases of primary controlled early tongue carcinoma, and 25% (38/151) and 41% (153/377), in stage-I and -II carcinoma, respectively. Neck metastasis was diagnosed within 12 months in 80% of cases, and within 24 months in 95%. Macroscopic appearance, tumor thickness and tumor length were identified as significant risk factors by a univariate analysis, but macroscopic appearance was the only significant risk factor identified by a multivariate analysis (P<0.001). The incidence of cervical lymph node metastasis was 62% among the invasive/ulcerative type tongue carcinomas, and was lower among the superficial type and exophytic/nodular type (20 and 35%, respectively). Regional and/or distant failure occurred in 75 of the 169 neck dissection cases (44%). The incidence of regional/distant failure was extremely high (49/68=72%) in the extra-nodal invasion group, and extra-nodal invasion was found even in small metastatic node less than 1 cm in length (20%). CONCLUSIONS: The macroscopic appearance of the primary tongue carcinoma has a major impact on the incidence of lymph node metastasis in patients with early tongue cancer, and extra-nodal invasion was the dominant risk factor for regional and distant failure. Treatment policy for clinically negative neck metastasis in early tongue cancer patients should be determined after considering the possibility of neck metastases and the morbidity associated with elective neck dissection.     

Reduced MLH1 expression after chemotherapy is an indicator for poor prognosis in esophageal cancers.

PURPOSE: Loss of function or expression of the mismatch repair gene MLH1 has been implicated in experimentally acquired resistance to cisplatin (CDDP) and other anticancer agents. The clinical significance of MLH1 expression was evaluated in advanced thoracic squamous cell carcinoma of the esophagus (ESCC) treated by neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: We investigated MLH1 and P53 expression by immunohistochemistry in the surgical specimens of 107 patients who had undergone preoperative chemotherapy using CDDP along with 5-FU and ADM. These findings were correlated with the clinical outcome for this treatment. Biopsy samples before chemotherapy in 20 of these patients, and another 43 surgical specimens without chemotherapy, were also examined as control samples. RESULTS: In surgical specimens of ESCC, low MLH1 expression was not frequent without chemotherapy, whereas it was commonly observed after chemotherapy (14 versus 37%, P = 0.0057). Comparison between samples before and after chemotherapy revealed that MLH1 expression was unchanged during chemotherapy in 12 of 20 patients (60%) but was from high to low in 8 of 20 patients (40%). In the surgical specimen after neoadjuvant chemotherapy, MLH1 expression was not correlated with any clinicopathological factors, including the response to chemotherapy. However, low MLH1 showed poorer prognosis than high MLH1 (5-year survival 40.6 versus 19.3%, P = 0.0393), and in multivariate analysis, MLH1 was an independent prognostic factor for this multimodal treatment, following lymph node metastasis and clinical response to chemotherapy. Positive p53 expression, which was not affected by chemotherapy, was weakly associated with a poor response and clinical outcome, although this trend was not significant. CONCLUSIONS: In advanced ESCC, expression of MLH1 is reduced during CDDP-based chemotherapy, and this may partly account for poor postoperative survival.     

Regression of a presumed meningioma with the antiestrogen agent mepitiostane. Case report

This 68-year-old woman underwent a distal gastrectomy for gastric cancer in August 1994. A presumed meningioma of the falx was found incidentally on a staging examination of the gastric cancer, but the meningioma was not treated with surgery. Instead, after gastrectomy the patient received tegafur as adjuvant chemotherapy until February 1996, when she was readmitted to the hospital because of loss of appetite and emaciation but with no recurrence of the gastric cancer. A computerized tomography scan obtained during this second admission showed no change in the meningioma. To improve her general condition, tegafur was discontinued and she was started on a course of the antiestrogen agent mepitiostane. Administration of mepitiostane for approximately 2 years resulted in a marked regression (73%) of the meningioma. This is the first reported case of a presumed meningioma that regressed as a result of use of the antiestrogen agent mepitiostane.