Search

Cell membrane fluidity (CMF) and transferrin receptor (Tf-R) expression were investigated in K562 cells, a human chronic myelocytic leukemia cell line, treated by gamma-interferon (IFN-gamma). CMF was increased using spin-labeled electron spin resonance techniques, and Tf-R expression was measured by flow cytometric analysis with an EPICS-750 flow cytometer/cell sorter. Treatment of K562 cells in suspension culture with IFN-gamma for as long a time as 6 hr caused an increase in CMF, and then returned to the level of control cells at 12 hr. Conversely, by 24 hr after the beginning of treatment, the rigidity of CMF was increased. Thus, the changes of IFN-gamma-induced CMF was biphasic. While the early change of CMF is related to signal generation and transmission, the later change may reflect changes in lipid compositions and/or cytoskeletal complexes of the plasma cell membrane. A significant increase of Tf-R after 6 hr and 24 hr in number was obtained by treatment of K562 cells with IFN-gamma, but at 12 hr the number of Tf-R did not differ from the control. These results suggested that the early phase of upregulation of Tf-R induced by IFN-gamma was caused by increased CMF, and the late phase of upregulation of Tf-R was due to increased rigidity of CMF. In conclusion, the state of CMF associated with a certain receptor expression in cells is not rigid and can be modulated to some extent by exogenous influences. This may open possibilities of some adjuvant therapeutic measures in malignant diseases by increasing the antigenicity of tumor cells.

In this study, we investigated serum-soluble interleukin-2 receptor (sIL-2r) and neopterin (NPT) levels in five patients with severe postoperative infections. A total of 25 synchronous determinations of sIL-2r and NPT were performed. A marked increase in sIL-2r and NPT levels was observed, and the increase in sIL-2r was significantly correlated to that of NPT which is a marker of macrophage activity. These results suggest that macrophages are involved in the stimulation of sIL-2r release, representing a potentially negative biological effect. The results indicate that sIL-2r may be a useful indicator of the efficacy of antibiotics and of prognosis.

Endoscopical segmental piecemeal tumorectomy (ESPT) for nodular elevation of colorectal tumor is advantageous in terms of minimizing both surgical invasion and postoperative burden to the patients. Nodular elevation of colorectal tumors is said to occur when the body of the tumor is adenomatous and the surface of the focal cancer grows more horizontally into the lumen than vertically. We report here four cases of nodular elevation of colorectal tumors which were each treated by different surgical procedures.

The effects of tumour necrosis factor-alpha on transferrin receptor expression in a human chronic myelocytic leukaemia cell line, K 562 cells, were studied. Cytofluorometry studies showed that the numbers of transferrin receptors in exponentially growing K 562 cells were increased when the cells were incubated with tumour necrosis factor-alpha for 24 h. The induction of transferrin receptors by tumour necrosis factor-alpha may be mediated by a mechanism that is independent of growth since cell growth in treated cultures did not differ from that in the controls. The DNA contents of K 562 cells treated with tumour necrosis factor-alpha showed that after 24 h there were less cells in the G1 and S phases and more cells in the G2/M phase than in the control group. The phase of upregulation of transferrin receptors induced by tumour necrosis factor-alpha may be dependent on the cell cycle. This new evidence that tumour necrosis factor-alpha upregulates transferrin receptors suggests a cancer-anaemia cascade in which the cancer burden state activates macrophage release of tumour necrosis factor-alpha as a result of transferrin receptor expression.

Lateral lymph node dissection has been advocated for advanced low rectal tumours. However, its benefit is debatable because of the possibility of postoperative bladder and sexual impairment. To assess the role of lateral lymph node dissection 95 patients who underwent the procedure between 1981 and 1991 were reviewed and compared with 83 who had resection of rectal cancer without lateral node dissection. Only ten (11 per cent) of the 95 patients had lateral lymph node involvement; all had Dukes' C tumours. Lymphovascular invasion was present in 50.6 per cent of all patients and neural invasion in 27 per cent of 65 examined specimens. Local recurrence, distant metastasis and overall 5-year survival rates were 7, 9 and 76 per cent respectively in patients undergoing extended lymphadenectomy and 16, 7 and 72 per cent respectively in those who had resection alone. There were no statistically significant differences in survival between the two groups for any Dukes' stage. Recurrence, metastasis and survival were related more to venous or neural invasion and tumour spread than to node dissection. These results demonstrate that patients with Dukes' A tumours do not benefit from lateral lymph node dissection, and that local recurrence rates in those with Dukes' B and C lesions are not significantly decreased. It is concluded that extended lymphadenectomy is unlikely to provide significant benefit to patients with low rectal cancer.

The records of 159 patients who underwent surgical resection of colorectal cancer were reviewed to assess the incidence of ovarian metastasis and to define the role of oophorectomy. Four of these patients presented with metachronous metastases, and one patient had synchronous ovarian involvement. The incidence of ovarian involvement was higher in younger patients. While most patients with ovarian involvement had the primary tumor located at the rectosigmoid region, a similar distribution of the primary tumor was observed in patients without ovarian metastasis. The histological type and degree of differentiation was similar regardless of whether or not ovarian metastasis was present. Of the patient without ovarian metastasis, 57% presented with nodal metastases and 3.2% with peritoneal dissemination, while all patients with ovarian metastasis had nodal and peritoneal involvement. Our results suggest that histological type and degree of differentiation of the primary tumor do not influence likelihood of ovarian metastasis. However, the exposure of the tumor to the serosal surface and the subsequent peritoneal dissemination may be an important route by which malignant tumor cells reach the ovaries. However, due to the wide lymphatic involvement in patients with ovarian metastasis, the lymphatic route may be important as well. Thus, we consider that oophorectomy should be performed in all postmenopausal women, when the ovaries are macroscopically affected, and in premenopausal patients with Astler-Coller B2 tumors or over.

Neural invasion may be one of the main causes of local recurrence, but its mechanism has not been sufficiently clarified. We previously reported that the expression of NCAM on cancer cells was correlated with neural invasion in pancreatic cancer. In this study, we examined the neural affinity of rectal cancer cells and the relationship between neural invasion and recurrence patterns of rectal cancers. A total of 64 rectal adenocarcinoma were examined. Specimens from 17 patients (27%) revealed perineural invasion. The incidence of neural invasion increased with the frequency of venous invasion and the degree of lymph node metastasis, but not significantly. The incidence of the expression of NCAM in rectal cancer cell was 45.3 percent. Neural invasion of rectal carcinoma was significantly related to the expression of NCAM (p < 0.05). NCAM immunocytolocalization was classified into the focal type, and the diffuse type. Concerning the recurrence type, 8 of 9 cases that developed local recurrence showed either presence of neural invasion or expression of NCAM. Liver metastasis was associated with absence of neural invasion or NCAM expression. The expression of NCAM may contribute to local recurrence, whereas the absence of NCAM may predict liver metastasis.

We investigated alterations in protein kinase C (PKC) activity of PANC-1 cells following treatment with tumour necrosis factor (TNF)-alpha or TNF-beta by an in vitro autoradiographic method. Binding studies performed on whole cells using [3H]phorbol-12,13-dibutyrate (PDBu) as a ligand revealed strong activation of PKC by TNFs within 30 min. The effect was similar to that seen after 30 min treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). After treatment for 24 h, TNF-beta caused a marked down-regulation of PKC similar to that seen after 24 h treatment with TPA; significant activation persisted, however, in the cells treated for 24 h with TNF-alpha. Our data suggest that PKC activation may play a more important role in the TNF-alpha signal transduction pathway than in that of TNF-beta.

We report a 62-year-old man with five primary cancers. He underwent nephrectomy for a right renal cell carcinoma and removal of malignant meningioma and 6 years later was diagnosed as having a rectal cancer and hepatocellular carcinoma. He died of respiratory failure and a gastric cancer was found at autopsy.

The anti-proliferative effects of tumour necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha), alone or in combination, on human pancreatic cancer cells lines (PANC-1, MIA PaCa-2 and BxPC-3) and human pancreatic cancer tumour (Exp-58), were investigated in vitro and in vivo. The anti-proliferative effect was determined using the dye uptake method and the subcutaneous tumour model. Combined TNF-alpha and IFN-alpha demonstrated marked synergistic and/or additive effects in comparison with their effects as single agents. These results suggest that combined cytokine therapy of TNF-alpha and IFN-alpha may make possible some improvement in the treatment of pancreatic carcinoma patients in the future.

Recently, the treatment for hepatic metastasis has been performed by injection of chemotherapeutic agents via hepatic artery. Although this therapeutic procedure has been contributing to a relatively higher response rate, the resulting increased response has not significantly improved prognosis. So, we assessed the infusion of chemotherapeutic agents via portal vein in rabbits and compared the results with those from arterial infusion. Two weeks after inoculation of VX-2 tumor cells into the liver, subcapsularly, injection of chemotherapeutic agents as well as sampling of the livers was started. The rabbits were allocated into two groups, an arterial infusion group and a portal vein infusion group. They received a single shot of mitomycin C (MMC, 1.7 mg/kg), or 5-fluorouracil (5-FU, 9.5 mg/kg) or cisplatin (CDDP, 1.6 mg/kg) injected by infusion pump for 1 h. The drug concentration into the normal liver and intratumorally was measured by HPLC method for 5-FU and MMC, and by flameless atomic absorption spectrometry for CDDP. Either drug concentration in the liver or tumor did not substantially differ between the two groups. This experiment revealed that portal vein infusion can contribute as much drug concentration intratumorally as by arterial infusion.

Between November 1984 and August 1992 we used hyperthermotherapy in six cases of local recurrence of rectal cancer. Hyperthermotherapy was performed on the average 8.7 times (range: 3-18) for each patient for 60 min each. All patients underwent combined radiotherapy and received a mean radiation dose of 42.5 Gy (range: 9-60 Gy). Five patients underwent heating within 1 h after irradiation and one patient simultaneously with the irradiation. Four patients underwent combined chemotherapy and two patients immunotherapy. Before the treatment all patients had painful lesions, but pain decreased posttherapeutically in five patients. Performance status improved in two patients. High carcinoembryonic antigen levels prior to the therapy in four patients decreased in all cases after treatment. Posttherapeutical computed tomograms revealed only minor response or no changes. After the treatment, four patients died of exacerbations of recurrent tumors and one patient of distant metastases. The patient who underwent simultaneous radiohyperthermotherapy is presently alive, in August 1992, 38 months after initiation of the treatment. The 50% survival time after initiation of the treatment was 25 months (range: 10-38 months). Hyperthermotherapy combined with radiotherapy, chemotherapy and/or immunotherapy was useful for the alleviation of pain in patients who developed local recurrence after surgery, and improved survival after recurrences can be expected.

We studied the role of reactive oxygen intermediates (ROIs) in experimental liver metastasis induced in mice by the inoculation of COLON 26-M5 murine colon cancer cells, a highly metastatic variant of COLON 26 cells, and the effect of ROIs on the invasive capacity of the cells in an in vitro chemo-invasion assay model using reconstituted basement membrane matrigel. We also measured the release of ROIs from cells using electron spin resonance (ESR) spectrometry. Hydroxyl radicals (.OH) were constitutively released from the cells. This release was augmented by pre-treatment with phorbol 12-myristate 13-acetate (PMA). In experimental liver metastasis in CDF1 mice, the administration of recombinant human superoxide dismutase (r-hSOD) significantly increased the number of metastatic nodules, while administration of catalase significantly inhibited metastasis formation. In vitro pre-treatment of cells with PMA significantly increased the number of metastatic nodules. Invasive capacity of the cells was markedly augmented by pre-treatment with PMA. PMA-induced augmentation was significantly inhibited by the simultaneous addition of r-hSOD to the assay. Catalase had no significant effect. Our findings suggest that ROIs play an important role in tumor invasion and metastasis, and that hydrogen peroxide (H2O2) may contribute to the retention or extravasation of circulating tumor cells. Furthermore, the superoxide anion (O2-) released by tumor cells may play an important role in basement membrane degradation.

A 56 year-old rectal cancer patient who developed a chronic rectoabdominocutaneous fistula postoperatively was treated with fibrin clot, and the fistula healed completely. Occlusion of chronic postoperative fistulas with fibrin clot appears to be a useful technique.

This paper reports a case of complete regression of a liposarcoma in a 62-year-old Japanese man who, in August 1986, presented with a giant subcutaneous tumor of the right anterior chest wall. Local radiotherapy and conventional chemotherapy were initially performed; however, the tumor did not respond at all. He then received cytokine treatment (interferon-alpha and tumor necrosis factor-alpha). Nineteen months after cytokine treatment, the mass disappeared totally. The patient has been in complete remission for five years without recurrence and with no additional treatment. This suggests that the use of interferon-alpha and tumor necrosis factor-alpha in combination may be an effective and promising modality for liposarcomas which are refractory to the conventional anticancer treatments.

Basic investigation of inhibitory effect on metastasis of nafamostat mesilate (FUT-175) which is a kind of serine protease inhibitors, was performed. Colon 26 cells were injected to the portal vein of CDF1 mice. FUT-175 at doses of 0.3, 1.0, 3.0, 10.0 mg/kg was injected intravenously every 7 day. Mice were sacrificed on day 21, and metastasis of liver surface were measured. The dose dependent reduction of metastasis was observed and reduction of metastasis of mice treated at a dose of 10.0 mg/kg was significant. FUT-175 showed no cytotoxicity at doses of 10(-5) M or less in vitro, and blood concentration of mice, treated at a dose of 10.0 mg/kg, was 2.67 x 10(-7) M. The results showed that inhibitory effect of FUT-175 on metastasis was not caused by direct cytotoxicity. FUT-175 at 2.67 x 10(-7) M in vitro can inhibit only thrombin and plasmin at nearly 50%, and can not inhibit platelet aggregation and collagenase directly. Possible mechanism of inhibition of metastasis is that FUT-175 inhibited both thrombin-mediated platelet aggregation and plasmin-mediated collagenase activation, that arrest and extravasation in cancer cells were inhibited. If protease inhibitor is administered continuously and immediately after surgery, liver metastasis may be prevented.

Herein we report the case of an ampullary tumor in a 53-yr-old Japanese woman who presented in March 1988 with abdominal pain, weight loss, and jaundice. A pancreatoduodenectomy was carried out, and 3 months later, she presented with a Virchow's node. She was initially treated with cytokines plus 5-fluorouracil derivative, resulting in a complete remission lasting over a year. However, in July 1990, the Virchow's node reappeared and was surgically excised. Histology revealed a small-cell neuroendocrine carcinoma (SCNC) similar to the prior ampullary tumor, which was confirmed by immunohistochemical studies and electron microscopic examination. The patient was discharged within 1 month, remaining disease-free over a 18-month period following excision. We suggest that the use of cytokines can be effective, and can increase survival in gastrointestinal neuroendocrine tumors.

Acute superior mesenteric artery syndrome (SMAS) following a major surgical procedure is extremely rare, and represents an iatrogenic cause of postoperative upper gastrointestinal obstruction. In this report, the first documented case of acute SMAS following a left hemicolectomy is presented in an obese patient. Upper gastrointestinal roentgenographic series and conservative management remain to be the first line diagnostic and therapeutic modalities and were successful in our patient. Up to date no patient with SMAS reported to be obese but apparently obesity per se, can not be considered as an insurance. A postoperative acute SMAS is impossible to predict depending on the previous history, predisposing factors and the physique of the patient. Therefore, the surgeon should be aware of the SMAS and it is his task to secure all the precautions in order to preclude excessive traction on the mesenteric vasculature and vascular compression of the duodenum during surgery. In cases in which SMAS is suspected during extended colonic resections with lymph node dissection, duodenal mobilization seems to be selectively justifiable.

Although many agents that interfere with clotting mechanisms have been investigated for their potential to inhibit metastasis, their toxicity has prevented administration of sufficiently high doses to achieve inhibition of metastasis in clinical trials. Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, inhibited liver metastasis in a CDF1 mice model with colon 26 adenocarcinoma cells. The apparently dose-dependent inhibitory effect was seen 21 days after all of the doses tested (0.3, 1.0, 3.0 and 10.0 mg/kg for 7 days) but the effect was only statistically significant (P less than 0.01) at the highest dose. The blood concentrations 3 min after dosing were less than 10(-6) M for all of the doses tested. At a concentration of 10(-5) M or less nafamostat mesilate was not cytotoxic towards colon 26 cells in vitro. The results indicate that it may not be difficult to achieve blood nafamostat mesilate concentrations that inhibit metastasis in mouse liver. Possible mechanisms of nafamostat mesilate are inhibition of extravasation and invasion of cancer cells, inactivation of collagenase due to inhibition of plasmin activity and inhibition of the formation of the cancer cell thrombus, and arrest in the capillaries through inhibition of thrombin activity. These preliminary results suggest that peri-operative administration of nafamostat mesilate may prevent metastasis into the liver after surgery for gastrointestinal malignancies.

Twenty-four patients seen between 1978 and 1990 with early colorectal carcinoma were reviewed to determine the outcome of surgical treatment. The mean age was 62 (range 35-79) years; there were 16 men and eight women. The site of the tumour was the ascending colon in two patients, sigmoid colon in ten and rectum in 12. The polypoid and flat-elevated ulcerated (IIa+IIc) subtypes were detected in 14 and nine lesions respectively. Restorative colectomy was carried out in 19 patients, and five required Mile's operation. There were no postoperative complications or deaths at a mean follow-up of 71 (range 12-151) months. Neither recurrence nor distant metastasis was found during follow-up. There was a close relationship between the depth of submucosal invasion and presence of flat-elevated ulcerated subtype lesions with lymphatic infiltration. This association may play an important role in the mechanism of metastasis. Major surgical resection is probably required if longer disease-free intervals and better cure rates are desired.

Inherited metabolic diseases resulting in urolithiasis secondary to urinary excretion of insoluble substances are rare but often present as urinary obstruction of renal insufficiency. We herein report a case of partial adenine phosphoribosyltransferase deficiency associated with 2,8-dihydroxyadenine urolithiasis. In family members the propositus and his younger brother are homozygotes for defective APRT genes, and who exhibits the type II phenotype designated APRT*J (Japanese type).

The anti-proliferative effects of natural cytokines, human tumour necrosis factor-beta, natural human interferon-alpha and natural human interferon-gamma, on three human pancreatic cancer cell lines (PANC-1, MIA PaCa-2 and BxPC-3) were investigated in vitro. The anti-proliferative effect was determined using the dye uptake method and analysed for synergism by the median effect principle. Tumour necrosis factor-beta, as a single agent, had little anti-proliferative effect on any of the three cell lines, whereas interferon-alpha and interferon-gamma exhibited a strong anti-proliferative effect against two cell lines (MIA PaCa-2 and BxPC-3) and one cell line (BxPC-3), respectively. When tumour necrosis factor-beta and interferon-alpha were administered together (ratio 1:1), a synergistic effect was observed against PANC-1 cells. The combination of tumour necrosis factor-beta and interferon-gamma (ratio 10:1) was synergistic against both PANC-1 and MIA PaCa-2 cells. A synergistic anti-proliferative effect of tumour necrosis factor-beta and interferons was, therefore, observed even for cell lines that showed little biological response to each cytokine alone. The data suggest that some future improvement in the treatment of pancreatic cancer may be obtained by using combination cytokine therapy.

Thirteen patients with rectal carcinoma seen between December 1980 and December 1990 have been reviewed to determine the risk of lymph node metastasis and its implication for subsequent treatment. The mean age was 64 years (from 38 to 79; 9 males, 4 females). The site of the tumor was predominantly in the lower rectum (53.8 percent). The polypoid (I) and flat-elevated ulcerated (IIa + IIc) subtypes were detected in seven and six lesions, respectively. Sphincter-saving techniques were carried out in eight cases, and five cases required Miles' operation. Neither postoperative complications nor deaths were noted. The mean follow-up period was 57 months (6 to 133 months). No recurrence or distant metastasis was found during this follow-up. IIa + IIc subtype lesions with deep submucosal invasion at or beyond Smlc level were closely related with lymphatic and vascular invasion. Although this association was not necessarily accompanied by an increased number of involved lymph nodes, major surgical resection is suggested in such IIa + IIc cases due to an increased possibility for lymph node metastasis.

We investigated the antitumor activities of 5-fluorouracil (5-FU), 5'-deoxy-5-fluorouridine (5'-DFUR), 1-hexylcarbamoyl-5-fluorouracil (HCFU) and 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207) in combination with hyperthermia in vitro. The antitumor effect of 5-FU (10(-4) M) was slightly enhanced by combination with hyperthermia (42 degrees C) for 2h, and the effect was determined to be additive. Synergistic enhancement of antitumor activity was obtained by the concurrent use of hyperthermia (42 degrees C, 2h) and 5'-DFUR (10(-4) M) or HCFU (10(-5) M). However, the antitumor effect of FT-207 (10(-4) M) in combination with hyperthermia was comparable that of hyperthermia alone. The synergistic enhancement of antitumor activity was not obtained for all drugs when the cells were preheated at 42 degrees C for 2h. On the other hand, when cells were pretreated with drugs before heat exposure, weak interactions were obtained after 5-FU and 5'-DFUR treatment, and a synergistic interaction was obtained after HCFU treatment. It is speculated that the metabolites of 5'-DFUR and HCFU enhance the cytotoxicity of 5-FU, or might change the threshold concentration for a cytotoxic effect of 5-FU in cancer cells.

We present herein a case of a young woman who experienced lower intestinal hemorrhage caused by ischemic necrosis of the small intestine induced by the compression of a Fallopian tube hematoma in an ectopic pregnancy. All accessible preoperative attempts to clear the site of the bleeding were unsuccessful and an exploratory laparotomy was indicated seventeen days after the development of melena. An ileocecal resection and right salpingectomy finally had to be performed.

The hydroxyl radicals produced by two adherent cell lines, a human cancer cell and a mouse fibroblast, and six suspended human leukemia cell lines at different stages of differentiation were measured by electron spin resonance (ESR) spectrometry. The concentration of hydroxyl radicals detected in these tumor cells increased in proportion to temperature and cell number. The addition of the enzymes superoxide dismutase (SOD) and catalase (which do not permeate the cell membrane), reduced the amount of hydroxyl radicals detected. SOD decreased hydroxyl radicals somewhat but catalase eliminated hydroxyl radicals almost completely. These findings suggest that hydroxyl radicals are produced extracellularly consisted primarily of H2O2 but partially from superoxide radicals. Using the human leukemia cell lines at different stages of differentiation we demonstrated that cell differentiation may correlate with hydroxyl radical production. The earlier the stage of leukemic cell differentiation the more the greater the production of hydroxyl radicals. Moreover, the ability of SOD or catalase to eliminate hydroxyl radical activity correlated inversely with leukemic cell differentiation.

Among the cytokines which show an antiproliferative effect on certain tumor cells, we investigated the free radical scavenging properties of tumor necrosis factor-alpha, interferon-alpha, and interferon-gamma. The scavenging properties were determined in vitro by the ability to reduce DPPH free radicals. All of these cytokines exhibited marked DPPH free radical scavenging ability.

A rare gastrointestinal tract neoplasm, primary non-Hodgkin's B-cell lymphoma in a 39-year-old, asymptomatic woman is described. The tumor was originally localized in the rectum without evidence of any other lymphoma-involved organ and treated by curative surgical procedure associated with postoperative chemotherapy.

The positively charged rhodamine analog rhodamine 123 accumulates specifically in the mitochondria of living cells. Mitochondria-specific interaction of this molecules is apparently dependent on the high transmembrane potential maintained by functional mitochondria (1, 2, 3). The application of such potential-dependent probes in conjunction with flow cytometry allows the monitoring of mitochondrial membrane potential in living cells (4, 5, 6). In the present work, the uptake of rhodamine 123 by Molt 16 cells stimulated by IFN-gamma or IFN-beta was measured by flow cytometry. Marked elevations in mitochondria-associated probe fluorescence have been observed in cells as early as 30-60 min after exposure of IFN-gamma but not observed by IFN-beta exposure. This results suggest that the IFN-gamma and -beta induced biological functions are different in the control of energy metabolism and energy requirements at the cellular level.

We report herein, a rare case of a 32 year old man who presented with a massive sacrococcygeal tumor found by digital examination. A transrectal biopsy was performed, however, as massive anal bleeding occurred 1 day later, an abdominal perineal resection was carried out. Histologic examination subsequently revealed the giant tumor to be pure seminoma. Residual masses of seminoma were detected by CT examination 1 month postoperatively and, despite irradiation, the patient died 26 months after the operation. Although there have been reports of extragonadal seminoma being located in the retroperitoneum, mediastinum and pineal body, this is the first reported case of it being found in the sacrococcygeal region.

The histopathologic changes following chemotherapy treatment of fresh human tumors implanted under the renal capsule of normal immunocompetent mice were evaluated. On the basis of the histopathologic profile of the xenografts, four parameters were recognized: (1) cancer area (C), (2) necrosis area (N) (each measured by image analysis), (3) pathologic effect of cancer cells (P) (assessed histopathologically), and (4) number of mitoses (M) (counted microscopically), and were scored in a semiquantitative fashion from 0 to 2 or 4. The drug sensitivity (S) was scored using the following formula: S = C + P + M - N; this score varied from -4 to 10. Histopathologic changes represent a sensitive indicator of the response of implanted human tumors under the renal capsule to anticancer drugs. Availability and correct interpretation of the post-treatment histopathologic picture is of importance in selecting the proper combination treatment which would maximize tumor response.

Fresh surgical explants of solid tumors obtained from 50 patients were tested against six chemotherapeutic agents in the in vivo subrenal capsule assay. Control growth adequate to meet evaluable assay criteria was obtained in 36 of 50 tumors (72.0%). With activity criteria set at current drug screening levels as a change in modifidd PAPAN score in less than or equal to -2.0 for the SRC assay, 36.1% of the human tumors evaluable and 11.6% of drugs tested were sensitive, respectively. Our research reveals that gastric cancers respond to drugs about 2.5-fold higher than colorectal cancers. Comparisons were made of the drug sensitivity in terms of histologic differentiation, and it was strongly suggested that the sensitivity of the poorly differentiated type was higher than that of well or moderately differentiated type.

HLA-A, B and DR typing was performed on a total of 236 patients with chronic glomerulonephritis (CGN) which were diagnosed by renal biopsies evaluated by light microscopy, direct immunofluorescent staining and whenever indicated electron microscopy. The interrelationship between the HLA system and the histopathologic classification of CGN was examined. There were 20 patients with benign recurrent hematuria (BRH), 82 with IgA nephropathy (IgA-N), 24 with proliferative glomerulonephritis (PGN), 47 with minimal change nephrotic syndrome (MCNS), 4 with membranous nephropathy (MN), 43 with membranoproliferative glomerulonephritis (MPGN) and 16 with focal glomerulosclerosis (FGS). The following results were obtained: 1) Antigens from different loci were associated with different subgroups of CGN. There were three types of associations; a) HLA-A locus associated as found in PGN, b) HLA-B locus associated as found in BRH and c) HLA-DR locus associated as found in MCNS. IgA-N, MPGN and FGS seemed to be included in this group. 2) The association of HLA-A locus antigens with MCNS could be subdivided by age o onset suggesting that in MCNS HLA-A antigens are linked to disease expression. 3) A heterogeneity in IgA-N is suggested by its association with different HLA antigens; a) a HLA-B37 associated group, b) a HLA-DR4 or DYT associated group and c) a HLA-DEn (Dw 6.1) or B12 associated group. These data suggest differences in the mechanisms of HLA and disease association in each histopathologic subtype of CGN.

The tumor lysis syndrome, consisting of severe hyperkalaemia, hyperphosphatemia and hypocalcemia, occurs after the effective induction chemotherapy of rapidly growing responsive tumors. The metabolic abnormalities are thought to be secondary to the release of intracellular products. For the purpose to examine quantitative relation between cellular potassium release and drug sensitivity, we compare the inhibition of valinomycin (K-ionophore)-induced-hyperpolarization (MPR Test) with that of succinate dehydrogenase activity (SDI test). Our present research revealed a high correlation of MPR test and SDI test, and suggested the significant association of drug sensitivity with potassium release from cancer cells. Therefore, it seems appropriate to monitor potassium levels when therapy of a responsive tumor is initiated.

Laser is an effective, simple and harmless clinical procedure used for the treatment of hemorrhoids, as an alternative to medical therapy or surgery. In this report, we describe our experience of applying carbon dioxide laser to hemorrhoids in a total 1816 consecutive patients. The results lead us to conclude that the laser treatment of hemorrhoids is effective in pain alleviation from the first session and that patients so treated have a much more comfortable postoperative course.

The same chemotherapeutic agents were tested against fresh surgical explants of solid tumors obtained from 50 patients using the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test in comparison. Control growth adequate to meet evaluable assay criteria was obtained in 36 of the 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at a change of less than or equal to -2.0 in the drug sensitivity score for the SRC assay and greater than or equal to 50.0% inhibition of succinate dehydrogenase activity for the SDI test, 12.5% of the drugs tested were active in the SRC assay and 22.3% were active in the SDI test. Correlations of tumor response between the two test systems were 31.7% for sensitivity (13/41) and 95.1% for resistance (98/103). In spite of the fundamental difference between the SRC assay and SDI test, meaningful correlations between the test results and clinical tumor responses in both test systems were obtained. This fact suggests that the two methods are complementary to each other.

Fresh surgical explants of solid tumors obtained from 50 patients were tested against the same chemotherapeutic agents in both the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test. Control growth adequate to meet evaluable assay criteria was obtained in 36 of 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at current drug screening levels as a change of less than or equal to -2.0 in modified PAPAN score (S) for the SRC and an inhibition of greater than or equal to 50.0% in succinate dehydrogenase activity (SD) for the SDI, 12.5% of the drugs tested were active in the SRC and 22.3% were active in the SDI. Correlations of tumor response between the two test systems were 31.7% for sensitive (13/41) and 95.1% for resistant (98/103).

This study demonstrates that the cytotoxicity of FT-207 was potentiated with elevated temperatures. This result leads us to the hypothesis that the heat-produced superoxide radicals could metabolize and degradate FT-207 to 5FU at membrane or cytoplasm.

When the plasma membrane capacity to maintain an ionic gradient is correlated with the cell viability, the anticancer drug-induced-cation (K+, Ca2+) mobilization, an early event associated with cell death, might be used as a rapid in vitro drug sensitivity test. A cyanine dye, dis-C3-5, was used to determine the membrane potential (Em), which was calculated as the following formula; Em = -RT/F In ([K+] in/[K+] out) in cancer cell lines. The change in cytoplasmic free calcium ion ([Ca2+]i) mobilization induced by the drugs was measured by fluorescent dye Fura2-AM. The results suggest that the sensitive drug, which showed greater than or equal to 50% inhibition of succinate dehydrogenase activity in SDI test, induced greater than or equal to 30% fall of membrane potential after 2 hour exposure to the drugs and also induced [Ca2+]i mobilization. On the other hand, the resistant drug showed no change of Em and [Ca2+]i.

Interferon (IFN) increases cytoplasmic free calcium ([Ca2+]i) in RPMI 4788 cells, a human colon cancer cell line. Addition of IFN to the cells loaded with Fura-2, a fluorescent Ca2+ indicator, causes an immediate increase in [Ca2+]i, which is the earliest event after IFN stimulation. A cyanine dye, dis-C3- (5) was used to determine the effects of IFN on the membrane potential in cancer cells. The depolarization was seen with IFN-gamma, but not with IFN-beta. These results taken together, suggest that the IFN-gamma and -beta induced [Ca2+]i mobilization are clearly different in their dependence on Ca2+ entry through voltage-gated Ca2+ channels.

From a series of 152 renal biopsy specimens examined by light, immunofluorescence, and electron microscopy, nine specimens were identified as being from patients with BRH. Histopathologic changes in renal biopsy specimens from most of the 9 patients consisted of either normal or slightly proliferative glomerulonephritis. Characteristic alterations were observed by electron microscopy, which showed the presence of small amounts of electron-dense deposits within the mesangium. In addition, immunofluorescent staining of peripheral blood lymphocytes from patients with BRH and their family members showed an increase of IgA-bearing peripheral blood lymphocytes, and the emergence of microhematuria among the families of patients with BRH indicates that some familial factors may be involved in the development of BRH and IgA nephropathy, which suggests that these two disorders may be closely related.

Immunoglobulin-bearing peripheral blood lymphocytes were examined in 20 children with Kawasaki disease and in 13 healthy control children. Routine laboratory tests were also performed. IgG-bearing lymphocytes, IgA-bearing lymphocytes, and IgM-bearing lymphocytes increased in children with Kawasaki disease when compared with those of controls. Measurement of immunoglobulin-bearing cells in peripheral blood may be used as a clinical test in the diagnosis of Kawasaki disease.