Enhancement by hyperthermia of the in vivo antitumour effect of doxorubicin hydrochloride (DOX) and buthionine sulfoximine (BSO)-hydroxyapatite (HAP) complex

We have developed a new type of drug delivery system (DDS) comprising a complex of porous hydroxyapatite (HAP) with the anticancer drug doxorubicin hydrochloride (DOX) and the glutathione inhibitor buthionine sulfoximine (BSO) (DOX and BSO-HAP complex). We then studied the antitumour effect of DOX and BSO-HAP combined with 44 degrees C hyperthermia for 40 min. It was found that in mice this combined treatment suppressed the growth of sarcoma 180 in terms of tumour volume to 36% in comparison viith mice given plain HAP, and was more effective than HAP + hyperthermia or DOX- and BSO-HAP. These results were also confirmed by histological observation.     

Ovarian tumor complicated by a colo-ovarian fistula

Although a fistula is a rare complication of ovarian tumor, we encountered four patients with cole-ovarian fistulas in three years. The first case was demonstrated by following barium enema by the extravasation of barium from the sigmoid colon, and by a gas-containing lesion in the tumor observed on computed tomography. Mature cystic teratoma was the pathological diagnosis in two cases. A mixed germ cell tumor and a serous cystadenoma of low malignant potential were diagnosed in the other two cases. The etiology and differential diagnosis of cole-ovarian fistula are reviewed.     

Evaluation of the accuracy of preoperative staging in thoracic esophageal cancer

Background. Exact clinical staging before treatment of esophageal cancer has become increasingly important in the evaluation and comparison of the results of different treatment modalities, including surgery, chemotherapy, and radiotherapy.

Methods. The accuracy of preoperative tumor staging by using an esophagography, esophagoscopy, percutaneous and endoscopic ultrasonography, and computed tomography was assessed in 224 patients with resectable esophageal cancer. The results of tumor staging by these tests were compared prospectively with the pathologic stage of the esophagectomy specimens with respect to the T and N categories defined by the International Union Against Cancer TNM classification.

Results. For the T category, the overall accuracy was 80%. For the N category, overall accuracy was 72%, with a sensitivity of 78%, a specificity of 60%, and a positive predictive value of 78%. Overall, the accuracy of stage grouping was 56%.

Conclusions. Either the T or N categories can be predicted reliably by clinical staging techniques. However, the preoperative stage grouping might not be valid in resectable, localized esophageal cancer.     

Reduction of tumorigenicity by an interferon-γ-gene-transduced tumor on another syngeneic tumor in a murine model

To evaluate the effect of interferon-γ-genetransduced cells, DS mice were inoculated into their footpads with syngeneic mammary adenocarcinoma SC42 admixed with interferon-γ producing mammary adenocarcinoma SC115Kγ, which had been established by an interferon-γ-gene transduction in another syngeneic mammary adenocarcinoma SC115 using retroviral vectors. These mice rejected both tumor cells and developed resistance to subsequent challenges with either SC115 or SC42 cells inoculated into their opposite posterior footpads. These results thus indicate that systemic immunological memory to each of the independent tumor cell lines developed in these mice. Although the SC42 cells admixed with irradiated SC115Kγ cells were rejected by these mice, the SC42 cells admixed with irradiated SC115neoR, in which the neo-gene had been transduced, were observed to proliferate. Tumor rejection was reversed by an in vivo administration of anti-interferon-γ antibody, thus suggesting that locally produced interferon-γ plays an important role in tumor elimination and immunological memory induction. In conclusion, interferon-γ-gene-transduced tumor cells are therefore considered to have a therapeutic potential for other types of malignant tumor cell lines.     

High-dose intraoperative radiotherapy for unresectable pancreatic cancer

PURPOSE: The results of high-dose intraoperative radiotherapy (IORT) and/or external beam radiotherapy (EBRT) for unresectable pancreatic cancer were analyzed to evaluate the possible advantages of IORT in combination with EBRT. METHODS AND MATERIALS: Between 1983 and 1993, 115 patients with unresectable adenocarcinoma of the pancreas (53 with non-Stage IV disease and 62 with Stage IV disease) were treated with EBRT + IORT (55 patients), EBRT alone (44 patients), or IORT alone (16 patients). In non-Stage IV patients, the use of EBRT alone was due to the unavailability of IORT and the use of IORT alone was due to refusal of EBRT. The IORT dose was 30-33 Gy and the EBRT dose was 40-60 Gy. A historical control group comprised of 101 patients undergoing palliative surgery alone was also analyzed. RESULTS: Both non-Stage IV and Stage IV patients receiving EBRT with or without IORT had a better prognosis than the nonirradiated historical controls. Among non-Stage IV patients, the median survival of the EBRT + IORT group (8.5 months) and the EBRT group (8 months) was similar, although survival from 12 to 18 months was higher in the former group (38% vs. 10% at 12 months, p = 0.018, and 19% vs. 0% at 18 months, p = 0.023). In Stage IV patients, the prognosis was not influenced by the type of radiotherapy. Multivariate analysis revealed that a pretreatment carbohydrate antigen (CA) 19-9 level < 1000 U/ml was associated with better survival. In non-Stage IV patients with a CA 19-9 level < 1000 U/ ml, EBRT + IORT appeared to produce a better survival than EBRT alone (p = 0.047). This was supported by multivariate analysis. CONCLUSION: High-dose IORT + EBRT may be more effective than EBRT alone in patients with unresectable but localized pancreatic cancer and a low CA 19-9 level.     

Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma

Summary The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( 25% of stained cells) or high (> 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3–58).Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analy-sis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 14–17, 1994, Dallas, TX, USA     

Curative Resection of Microgastrinomas Based on the Intraoperative Secretin Test

The intravenous secretin injection test (secretin test) has been used for the differential diagnosis of gastrinoma. In this study we report that the intraoperative secretin test (IOS test) is also useful for determining the extent of curability in patients with Zollinger-Ellison syndrome (ZES). Twelve patients with ZES underwent surgical exploration and the IOS test. The results of the IOS test were obtained by rapid radioimmunoassay of the serum gastrin level (IRG) within 60 minutes. The test was diagnosed as negative when the maximum increase of serum IRG was less than 80 pg/ml and also less than 20% of the basal serum IRG level. Three of the twelve patients underwent pancreatoduodenectomy (PD), and two patients underwent distal pancreatectomy. Extirpation of duodenal tumors with dissection of regional lymph nodes was performed in seven patients. In two of the seven patients the IOS test remained positive after extirpation of the duodenal tumors and the dissection of regional lymph nodes. In one patient PD was performed on the basis of the positive results, and the IOS test became negative after PD. In the other patient, two tiny metastatic liver tumors were identified and were resected, but the IOS test did not become negative. We closed the abdomen in 11 patients when we obtained negative results from the IOS test. The results of the IOS test were almost identical to the data obtained by the standard assay postoperatively. The serum IRG levels of all but one patient fell to the normal level, and the secretin test became negative postoperatively. The IOS test is thus useful and indispensable for curative resection of microgastrinomas in patients with ZES.     

SIALYL-Tn ANTIGEN DISTRIBUTION IN HELICOBACTER PYLORI CHRONIC GASTRITIS IN CHILDREN: AN IMMUNOHISTOCHEMICAL STUDY

Sialyl-Tn antigen (STn) is a mucin-type carbohydrate normally present in goblet cells of small and large bowel. STn expression has been demonstrated to occur in complete and incomplete intestinal metaplasia as well as in many carcinomas but in no normal gastric cell. The aim of our present study was to evaluate the distribution of STn in Helicobacter pylori chronic gastritis (HpCG) of pediatric patients. Eighteen gastric biopsies from 15 children (mean age: 11.5 years) with HpCG, 9 gastric biopsies from 9 children without H. pylori infection, and 1 heterotopic gastric mucosa in Meckel's diverticulum were immunostained using the anti-STn antibody STn1 (18/18), NCL-MUC-1 (7/18), and NCL-MUC-2 (18/18) antibodies. Also, sulfated mucosubstances were investigated with the Alcian Blue-Periodic Acid Schiff (AB-PAS), pH 1.0 stain. Although with different intensity (weak in 5/18, moderate 9/18, and intense 4/18) all cases with HpCG exhibited STn immunoreactivity. The expression of STn was found to be located mainly to the supranuclear region of the epithelial cells at the foveolae and glandular necks, with occasional cells showing diffuse cytoplasmic staining. When reactivity was intense, it was for the most part found in the cells at the neck of the glands. The mucus out of the luminal border above the positive cells was usually also stained. MUC-1 was negative (2/7) or weakly positive (5/7) in a few surface mucous cells. MUC-2 was negative (16/18) or occasionally detected in some foveolar and surface cells (2/18). AB-PAS pH 1.0 revealed the presence of sulfomucins in the cytoplasm of isolated cells of gastric pits and glands of most cases (11/15). None of these findings was observed in the control group. We conclude that STn can be identified in gastric cells of pediatric patients with HpCG and that this does not correlate with other mucosubtances markers. Thefindings could indicate that minimal intestinal metaplasia takes place in children with HpCG.     

Two cases of methicillin-resistant Staphylococcus aureus (MRSA) sepsis following craniotomy

We report here two cases of MRSA sepsis following craniotomy. In case 1, a petroclival meningioma was subtotally removed and lumbar drainage was inserted postoperatively to prevent cerebrospinal fluid leakage. Ventriculo-peritoneal shunt was performed after meningitis was treated with vancomycin and panipenem/betamipron. Two weeks after the procedure, the patient revealed continuous spiking fevers related to MRSA sepsis, which did not improve with vancomycin and arbekacin administration. The focus of infection was found by scintigraphy and CT by 67Ga to be spondylo-diskitis at the level of L2-L3. The lesion was removed and bone from the iliac crest grafted. In case 2, seven days after surgery for multiple meningioma, the patient exhibited spiking fevers and swelling in the left leg. The central venous catheter was removed from the left femoral vein and MRSA was found from blood culture. The patient was treated with arbekacin (200 mg/day). Venous thrombosis diagnosed by CT was treated with heparin. Symptoms related to the infection and laboratory data did not improve because the concentration of arbekacin in the blood did not reach an effective level. The symptoms markedly improved when the dose of arbekacin was doubled (400 mg/day).