Natural killer cells prevent direct anterior-to-posterior spread of herpes simplex virus type 1 in the eye

PURPOSE: Anterior chamber (AC) inoculation of the KOS strain of herpes simplex virus type 1 (HSV-1) results in morphologic sparing of the ipsilateral retina, whereas the retina of the uninoculated contralateral eye becomes infected and undergoes acute retinal necrosis. Natural killer (NK) cells are an important component of the primary immune response to most virus infections. The purpose of this study was to determine whether NK cells are involved in preventing early direct anterior-to-posterior spread of HSV-1 after AC inoculation. METHODs: Normal BALB/c mice were inoculated with 4 X 10(4) plaque-forming units (PFU) of the KOS strain of HSV-1 using the AC route. NK activity was measured in the spleen, the superficial cervical and submandibular lymph nodes, and the inoculated eye by lysis of chromium-labeled, NK-sensitive YAC-1 target cells. Histopathologic scoring and immunohistochemical staining for HSV-1 were performed in NK-depleted (injected intravenously with anti-asialo GM1) or mock-depleted (injected intravenously with normal rabbit serum) mice. RESULTS: In mock-depleted mice, NK activity in the spleens, superficial cervical and submandibular lymph nodes, and inoculated eyes peaked at postinoculation (pi) day 5 and declined by pi day 7. Treatment with anti-asialo GM1 eliminated NK activity in the eye and at nonocular sites. The histopathologic scores at pi day 5 indicated more damage to the retinas of NK-depleted mice than to those of mock-depleted mice, and immunohistochemical staining for HSV-1 showed spread of the virus to the sensory retina only in NK-depleted mice. CONCLUSIONS: NK cells were activated within 5 days after AC inoculation of the KOS strain of HSV-1. Activation of NK cells appears to play a role in preventing direct anterior-to-posterior spread of the virus in the inoculated eye which, in turn, protects the retina of this eye and helps to explain why the architecture of the retina of this eye is spared.     

Transactivation of the vascular endothelial growth factor receptor KDR/Flk-1 by the bradykinin B2 receptor induces an angiogenic phenotype in human cultured coronary endothelial cells

BACKGROUND: Endothelial cells (ECs) are believed to be critical cellular elements responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of KDR/Flk-1 receptor, which is mainly expressed in ECs. Transactivation of KDR/Flk-1 receptor by bradykinin (BK) B2 receptor contributes to the activation of endothelial nitric-oxide (NO) synthase. Therefore, we examined whether transactivation by BK induced angiogenesis. METHODS AND RESULTS: We developed an in vitro model of human coronary artery ECs (HCECs) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK did not induce tube formation, the combination of a lower concentration of BK and VEGF did. These effects blocked specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NO synthase. In addition, BK induced the tyrosine phosphorylation of KDR/FlK-1 receptor (transactivation), as did VEGF itself. This transactivation was also blocked by Tki. CONCLUSIONS: Transactivation of KDR/Flk-1 by BK through B2 receptor is a potent signaling in angiogenic phenotype in HCECs.     

COX selectivity and animal models for colon cancer

Early experiments performed during 1980s and 1990s using carcinogen-induced rat intestinal tumor models demonstrated the inhibitory effects of non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal tumorigenesis. Furthermore, epidemiological studies and clinical trials for familial adenomatous polyposis (FAP) patients supported the possibility that NSAIDs can be used as chemopreventive agents. The major target molecules of NSAIDs are cyclooxygenases (COX), which catalyze the rate-limiting step of prostaglandin biosynthesis. Two isoenzymes of COX have been identified; COX-1 and COX-2. Whereas COX-1 is expressed constitutively in most tissues and responsible for tissue homeostasis, COX-2 is inducible and plays an important role in inflammation and intestinal tumorigenesis. A genetic study using compound mutant mice of COX-2(-)/(-), and Apc(Delta716) which is a model for human familial adenomatous polyposis (FAP), directly demonstrated that induction of COX-2 is critical for intestinal polyp formation. Numerous studies have also demonstrated that COX-2 selective inhibitors suppress intestinal polyp formation in Apc gene-mutant mice, and xenografted cancer cell growths. In addition, stimulation of angiogenesis is one of the major effects by COX-2 expression that is induced in the polyp stromal cells. On the other hand, another study indicated that COX-1 also plays an important role in the early stage of intestinal tumorigenesis. These data from animal model studies should be helpful in understanding the in vivo mechanism(s) of tumor suppression by NSAIDs or COX-2 inhibitors. Here, we review the animal studies that have been published as of August 2001, and reported to suppress intestinal tumor growths by NSAIDs or COX-2 inhibitors.     

The efficacy and limitations of transarterial embolization for severe hepatic injury

BACKGROUND: The efficacy of transarterial embolization (TAE) for severe blunt hepatic injury has been reported. We performed a prospective study evaluating the efficacy and the limitation of TAE from January 1996 to December 2000. METHODS: All patients with blunt abdominal injury who could be stabilized by fluid resuscitation underwent computed tomographic (CT) scan examinations. Patients with CT scan evidence of hepatic injury were classified into five grades according to CT scan findings on the basis of the injury scale of the American Association for the Surgery of Trauma (Mirvis classification). All patients with CT scan grade 3 to 5 injury underwent angiography. When angiography showed extravasation of contrast medium extending from hepatic arterial branches, TAE was performed. RESULTS: Of 612 patients with blunt abdominal trauma, 51 had CT scan grade 3 to 5 injury. Thirty-seven of these patients had a CT scan grade 3 injury and 18 underwent TAE. One of 19 patients who did not undergo TAE developed a delayed hemorrhage on day 6 and required a laparotomy. All 13 patients with a CT scan grade 4 injury had angiographic findings of the extravasation. TAE was successful in 11 patients and unsuccessful in 2. Five patients with a CT scan grade 4 injury required laparotomy. One developed a delayed hemorrhage on day 4. The remaining four patients had a major venous injury (a right lobectomy was performed in two with inferior vena cava injury, and a gauze packing in two with hepatic venous injury). One patient with a CT scan grade 5 injury underwent immediate laparotomy after TAE. Laparotomy revealed inferior vena cava injury and a right lobectomy was performed. Only two patients who underwent a lobectomy died of an uncontrollable hemorrhage. All CT scans of patients with hepatic venous or inferior vena cava injury showed a large low-density area (> or = 10 cm) with involvement of these vessels. The volumes of fluid resuscitation needed from admission until TAE ranged from 2,109 to 2,638 mL/h. CONCLUSION: It was considered that the combination of the presence of a CT scan grade 4 or 5 lesion and the fluid requirements of more than 2,000 mL/h to maintain normotension indicated the absolute necessity of surgery. We felt that these patients were not candidates for TAE, and should undergo immediate laparotomy.     

Comparative study of various biological parameters,including expression of survivin,between primary and metastatic human colonic adenocarcinomas

BACKGROUND: Hepatic metastasis of colorectal carcinomas is the most important factor in prognosis. We examined the level of apoptosis and proliferation, the expression of survivin, bcl-2, p53 and intratumoral microvessel density (IMVD) in paired tissue specimens of primary human colon tumors and hepatic metastases and determined the molecular biological changes of the tumor cells in liver metastasis. MATERIALS AND METHODS: We examined, immunohistochemically, the level of apoptosis and proliferation, the expression of survivin, bcl-2 p53 and intratumoral microvessel density in 37 paired tissue specimens of primary colon tumors and hepatic metastases. RESULTS: The mean apoptotic index (AI) was 0.60+/-0.45 for the primary colon tumors and 1.22+/-0.73 for the hepatic metastases. The mean proliferative index (PI) was 37.4+/-15.8 for the primary colon tumors and 29.4+/-14.1 for the hepatic metastases. Significantly higher AI and lower PI were observed in the hepatic metastases as compared to the primary colon tumor (p<0.0001 and p=0.0049, respectively). The mean-weighted survivin score was 4.32+/-2.78 for primary colon carcinomas, and 1.54+/-1.77 for the hepatic metastases. The mean-weighted bcl-2 score was 2.62+/-2.62 for the primary colon carcinomas and 0.81+/-1.56 for the hepatic metastases. There were significantly decreased scores of immunostaining for both survivin and bcl-2 in the hepatic metastases as compared to the primary carcinomas (p<0.0001 and p<0.0002, respectively). Nuclear accumulation of p53 was demonstrated in 25 cases (67.6%) of the primary carcinomas and 24.cases (64.9%) of the hepatic metastases, without significant differences. The IMVD was 89.9+/-37.5 for primary colon tumors, while it was 55.1+/-32.5 for hepatic metastases. A statistically significant decrease in the IMVD was observed in the hepatic metastases as compared to the primary colon tumors (p<0.0001). CONCLUSION: These data suggest that the tissue kinetics of colorectal carcinoma cells in hepatic metastases are biologically quite different from those of primary tumors, probably because of co-operative effects of both internal (AI, survivin, bcl-2) and external (IMVD) regulation factors.     

A new regimen for TS-1 therapy designed to minimize adverse reactions by introducing a one-week interval after each two-week dosing session

It has been reported that the response rate to TS-1 of advanced recurrent gastric cancer was the highest rate (46.5%) of effectiveness among anti-cancer agents, but the incidence of adverse reactions to this drug has been found to be as high as 83.2%, with grade 3 or severer reactions occurring in 20.3% of patients. Taking into consideration the post-marketing survey finding that adverse reactions to the drug first appear 2-3 weeks after the start of oral TS-1 therapy, we attempted a new dosing regimen for this drug, wherein each session of therapy lasted for 2 weeks, with a one-week interval between two consecutive sessions (herein-after called "the 2-week regimen"). This regimen was employed based on the expectation that the adverse reactions to the drug would be minimized and that the consecutive dosing period could be prolonged, while keeping the anti-cancer potency at a level similar to that expected with the 4-week dosing regimen with a 2-week interval between sessions (the 4-week regimen). The subjects were 38 patients with advanced or recurrent stomach cancer who were treated with TS-1 at our center between September 1999 and November 2001. Twenty-four patients treated using the 4-week method until January 2001 were taken as a historical control, and compared with 14 patients treated using the 2-week method from February 2001 and afterwards. The incidence of adverse reactions was 71% in the 2-week regimen group against 92% in the 4-week regimen group. The incidence of grade 3 or severe adverse reactions was 8% in the 2-week group and 21% in the 4-week group. Thus, the incidence of adverse reactions was lower in the 2-week group. The percentage of patients who complied with the dosing instructions completely during a 6-month period, as evaluated by the Kaplan-Meier method, was 86% in the 2-week group and 58% in the 4-week group. The response rate, as calculated in patients whose lesions could be evaluated, was 25% in the 2-week group and 19% in the 4-week group. These results suggest that the 2-week regimen may allow safer outpatient drug therapy using TS-1 and merits a trial when considering the QOL of patients. We propose conducting a phase-II multi-center clinical study of this regimen in the near future.     

A case of recurrent rectal cancer responding to weekly low-dose CPT-11/isovorin/5-fluorouracil

We report the case of 66-year-old male with recurrent rectal cancer which responded to chemotherapy using CPT-11, Isovorin, and 5-fluorouracil (5-FU). CPT-11 was administered at 40 mg (90 min i.v.) x 3 day/week, and Isovorin and 5-FU were administered at 25 mg (bolus) and 250 mg (continuous) x 5 day/week by intraarterial infusion. Three cycles of this weekly regimen resulted in regression of tumors in the iliac region with remission of the lameness caused by iliac pain. The serum CEA level decreased from 13.1 ng/ml to 0.5 ng/ml. The patient has undergone 13 cycles of the regimen modified for outpatients (CPT-11 at 40 mg x 3 day/week plus Isovorin at 25 mg and 5-FU at 250 mg 1 day/week) with inhibitions of tumor regrowth and improved serum CEA level for more than 12 months. The current case suggests that weekly low-dose CPT-11/Isovorin/5-FU may have a potent therapeutic effect against recurrent rectal cancer.     

A gastric cancer patient with marked para-aortic lymph node metastasis surviving more than 10 years after aggressive operation and repeated EAP chemotherapy

The high incidence of side effects for EAP (etoposide, adriamycin, cisplatin) combination chemotherapy led to the recent decline in its use. However, we report herein the long-term disease-free survival of a woman following postoperative EAP therapy. A 57-year-old woman was referred to our hospital because of general malaise. X-ray and endoscopic examination revealed a Borrmann type 3 gastric cancer. Preoperative computed tomography and ultrasonography revealed multiple para-aortic lymph node swellings. The patient simultaneously underwent subtotal gastrectomy and splenectomy, and complete para-aortic lymph node dissection. Histopathological tests revealed that the tumor was a poorly differentiated adenocarcinoma with 35 metastatic para-aortic lymph nodes. The patient was treated with 2 cycles of EAP therapy. After discharge, swelling in one para-aortic lymph node was detected. Following three subsequent cycles of EAP therapy, the swollen lymph node disappeared and the patient has remained disease free for 10 years. This case illustrates that aggressive surgery followed by repeated courses of EAP therapy can produce excellent clinical outcomes.     

A case of liver metastasis of breast cancer successfully treated with paclitaxel infusion into the hepatic artery: an attempt of once weekly regimen

On October 21, 1995, a 45-year-old woman underwent mastectomy (Kodama's procedure), preserving the thoracic muscles, based on the diagnosis of right breast cancer (T2aN1bM0). After surgery, she received 3 cycles of adjuvant chemotherapy (CAF) using anthracycline and other drugs. Thereafter she was orally treated with UFT for 2 years. She developed tumor recurrence in her liver 3 years after surgery. At that time, she was initially scheduled to undergo partial hepatectomy (including the tumor-affected area), but it was later judged that radical surgery was impossible due to the presence of multiple lesions in both lobes of the liver. A reservoir was therefore installed in the hepatic artery. Ten days after reservoir installation, intra-arterial infusion of paclitaxel (80 mg/m2), dissolved in 100 ml of physiological saline, was performed for one hour, using the installed reservoir. This treatment was administered once weekly for 3 consecutive weeks, followed by one week of rest. After 3 cycles of this regimen, the liver metastases had disappeared completely. At present, 2 years after the beginning of this therapy, the patient remains in a state of CR (complete response). Grade 2 alopecia and grade 1 peripheral neuropathy were the only adverse reactions observed.