Peripheral blood lymphocyte subset repertoires are biased and reflect clinical features in patients with dermatomyositis.

OBJECTIVE: Dermatomyositis (DM) is an idiopathic inflammatory myopathy which often involves the lungs. DM is likely to be associated with aberrant T- and B-cell activation in the pathogenesis because of the proven effectiveness of T- and B-cell-targeted treatments. Assuming that the aberrant activation is reflected by biases in the lymphocyte subset repertoires, we aimed to elucidate these biases, especially in relation to clinical features of DM. METHOD: Based on the immunophenotyping standardized by the Human Immunology Project Consortium, untreated 13 DM patients, including seven patients with interstitial lung disease (ILD), and 18 age-matched healthy donors (HDs) were examined for proportions of peripheral blood lymphocyte subsets. Six DM patients were examined before and after successful induction of remission. RESULTS: Naïve CD4+ T cells and naïve B cells were more abundant, while there were fewer naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, Th1 cells, Tfh cells, and memory B cells in DM patients than in HDs. When the patients were subgrouped according to the presence of ILD, the lymphocyte subset repertoires in the patients with ILD contributed to the statistical differences in all the biased lymphocyte subset proportions. After treatment, transitional B cells vanished and there was an increase in memory B cells. CONCLUSION: The lymphocyte subset repertoires in the DM patients were biased, and were associated with the presence of ILD and disease activity of DM.

Human membrane type-4 matrix metalloproteinase (MT4-MMP) is encoded by a novel major transcript: isolation of complementary DNA clones for human and mouse mt4-mmp transcripts.

Five distinct membrane-type matrix metalloproteinases (MT-MMP) have been reported by cDNA cloning. However, the mt4-mmp gene product (MMP-17) has not been identified yet in spite of the cDNA isolation [Puente et al. (1996), Cancer Res. 56, 944-949]. In this study, we re-examined the transcripts for human mt4-mmp by 5' RACE and identified two types of transcripts. The minor one corresponded to the cDNA reported by Puente et al. and failed to express protein, and the other is the major transcript that has an extended open reading frame and expressed 67 and 71 kDa translation products. Thus, functional mt4-mmp has been identified for the first time.

The role of radiotherapy in the management of extrahepatic bile duct cancer: an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy.

PURPOSE: To determine the feasibility of high dose radiotherapy and to evaluate its role in the management of extrahepatic bile duct (EHBD) cancer. METHODS AND MATERIALS: Between 1983 and 1991, 145 consecutive patients with EHBD cancer were treated by low dose rate intraluminal 192Ir irradiation (ILRT) either alone or in combination with external beam radiotherapy (EBRT). Among the primarily irradiated, 77 patients unsuitable for surgical resection, 54 were enrolled in radical radiotherapy, and 23 received palliative radiotherapy. Fifty-nine received postoperative radiotherapy, and the remaining 9 preoperative radiotherapy. The mean radiation dose was 67.8 Gy, ranging from 10 to 135 Gy. Intraluminal 192Ir irradiation was indicated in 103 patients, and 85 of them were combined with EBRT. Expandable metallic biliary endoprosthesis (EMBE) was used in 32 primarily irradiated patients (31 radical and 1 palliative radiotherapy) after the completion of radiotherapy. RESULTS: The 1-, 3-, and 5-year actuarial survival rates for all 145 patients were 55%, 18%, and 10%, for the 54 patients treated by radical radiotherapy (mean 83.1 Gy), 56%, 13%, and 6% [median survival time (MST) 12.4 months], and for the 59 patients receiving postoperative radiotherapy (mean 61.6 Gy), 73%, 31%, and 18% (MST 21.5 months), respectively. Expandable metallic biliary endoprosthesis was useful for the early establishment of an internal bile passage in radically irradiated patients and MST of 14.9 months in these 31 patients was significantly longer than that of 9.3 months in the remaining 23 patients without EMBE placement (p < 0.05). Eighteen patients whose surgical margins were positive in the hepatic side bile duct(s) showed significantly better survival compared with 15 patients whose surgical margins were positive in the adjacent structure(s) (44% vs. 0% survival at 3 years, p < 0.001). No survival benefit was obtained in patients given palliative or preoperative radiotherapy. Gastroduodenal complications increased in those receiving doses of 90 Gy or more, and serious biliary bleeding was experienced in three preoperatively irradiated patients. Complications in other patients was tolerable. CONCLUSIONS: High-dose radiotherapy, consisting of ILRT and EBRT, appears to be feasible in the management of EHBD cancer, and it offers a survival advantage for patients not suited for surgical resection and patients with positive margins in the resected end of the hepatic side bile duct. Expandable metallic biliary endoprosthesis assists the internal bile flow and may lengthen survival after high dose radiotherapy.

Intraoperative radiotherapy for esophageal carcinoma--significance of IORT dose for the incidence of fatal tracheal complication.

PURPOSE: The feasibility of intraoperative radiotherapy (IORT) combined with modified regional lymphatic dissection (plus esophagectomy) for advanced esophageal carcinoma was tested. The quality of life in the patients was expected to improve by modified surgery, securing a good local control by additional IORT. METHODS AND MATERIALS: Total esophagectomy plus modified three-regional lymphatic dissection with upper mediastinal IORT followed by postoperative external beam irradiation was systematically given to 62 patients between August 1989 and June 1992. Sixty-five percent of the patients were age over 60, and 76% (47/62) of the patients were Stage III or IV by pTNM. Several techniques for the IORT were developed and used throughout this period, including a temporary collapse of the right lung by unilateral tracheal incubation (for the insertion of IORT applicator) and an in vivo dosimetry to know the appropriate range (energy) of electron beam. The method of surgical treatment, the dose of external beam irradiation were kept standardized, and only the dose of IORT was randomized either to 20 or 25 Gy. IORT-related complications and the pattern of failures were carefully monitored. RESULTS: (a) Most prominent IORT-related complication was the late tracheal damage, which occurred 6 of 44 patients who were at risk for more than a year. (b) The incidence of IORT-induced tracheal damage was sharply dependent on the dose of IORT; 6 out of 21 patients who received single dose of 25 Gy, and none out of 33 who were given 20 Gy or less. (c) 2-year cause-specific survival and actuarial 2-year survival were 75.0 +/- 14.5% and 62.5 +/- 13.2%, respectively. No loco-regional recurrence has been detected at the time of analysis. CONCLUSION: IORT in combination with modified total esophagectomy is an effective and safe method to obtain a local control in advanced esophageal carcinomas, if the dose of IORT does not exceed 20 Gy.

The value of treatment planning using CT and an immobilizing shell in radiotherapy for paranasal sinus carcinomas.

This article describes a method which uses CT scans and immobilizing shells radiation treatment planning (CT-assisted planning) for paranasal sinus carcinomas and the value of this method on the treatment outcome. Results of the treatment for 82 patients who had CT-assisted planning were compared with that of 88 patients who had no such treatment planning. It has been concluded that the combined use of CT and the shell in treatment planning permitted a 3-dimensional localization of both the tumor and critical normal structures with great accuracy, leading to an improved long-term survival and a reduced complication rate. The multivariate regression analysis for predicting significant prognostic factors also confirmed the valuable role of CT in terms of survival and primary tumor control. The actuarial 5-year survival rate was 51% in all patients, whereas, by using CT-assisted planning, it was improved to 61%. The improved survival was observed among the patients with tumors of the suprastructures where tumors were located adjacent to the critical organs (brain and eye). Major complications attributable to radiation have included instances of brain and ocular damage. CT-assisted planning, however, has been proven effective in avoiding brain necrosis and preserving eye sight.

Stereotactic irradiation without whole-brain irradiation for single brain metastasis.

PURPOSE: The effectiveness of stereotactic irradiation (STI) alone without whole-brain irradiation (WBI) for a single metastatic brain tumor was analyzed retrospectively. METHODS AND MATERIALS: Forty-four patients with this condition were treated using radiosurgery (RS) alone or fractionated stereotactic radiotherapy (FSR) without WBI. RESULTS: The initial response rate was 92% and the overall local control rate was 84% (37 of 44 patients). A total of 39% (18 of 44) of patients experienced intracranial relapse outside the initial target area. Forty-eight percent (21 of 44) of patients required salvage treatment for intracranial relapse. All 7 patients who received WBI as salvage treatment required no further salvage treatment, but 5 of the 14 patients who received salvage STI without WBI required three to four treatments for brain metastasis. Late radiation damage was not seen with initial treatment but was observed with retreatment. The overall median survival time was 261 days, with a standard error of 64 days. Actuarial survival at 12 and 24 months was 34% and 9%, respectively. The actuarial survival rate was significantly affected by the existence of active extracranial disease (p = 0.041). CONCLUSION: The high response rate and short treatment period of STI alone are advantageous in the treatment of single brain metastasis in patients with active extracranial disease with WBI reserved for relapse. Because of the low complication rate, STI alone may be also useful in patients with good prognosis, without extracranial disease.

High-dose-rate intracavitary irradiation using linear source arrangement for stage II and III squamous cell carcinoma of the uterine cervix.

PURPOSE: The purpose of this article is to evaluate fractionated high-dose-rate (HDR) intracavitary irradiation using linear source arrangement (LSA) for patients with squamous cell carcinoma of the uterine cervix. MATERIALS AND METHODS: The subjects consisted of 217 patients (71 patients with stage II and 146 with stage III disease) who received external beam therapy (EBT) followed by fractionated HDR intracavitary irradiation using LSA between January 1980 and June 1990. In EBT, 40 Gy in 20 fractions (40 Gy/20 Fr) or 39.6 Gy/22 Fr was delivered to the whole pelvis and an additional 10 Gy/5 Fr or 10.8 Gy/6 Fr was delivered to the parametrium. The intracavitary irradiation dose was 30 Gy/6 Fr or 35 Gy/7 Fr with a daily fraction size of 5 Gy and two fractions per week. During the intracavitary treatment, most patients were treated on an out-patient basis. RESULTS: Cause-specific 5-year survival rates were 77% for stage II and 50% for stage III. Pelvic failure rates were 13% for stage II and 36% for stage III. In multivariate analyses, improved cause-specific survival was significantly associated with stage II (P = 0.0003), higher pretreatment serum hemoglobin level (P = 0.0015), higher pretreatment serum total protein level (P = 0.0029), and shorter total treatment time (P = 0.0024). The rate of severe (grade 3 or 4) late complication was 2% for the rectum, 1% for the small intestine or sigmoid colon and 1% for the bladder. CONCLUSIONS: Fractionated HDR intracavitary irradiation using LSA is an effective treatment for patients with uterine cervical cancer without need for hospitalization.

Physicopharmaceutical characteristics of an oil-in-water emulsion-type ointment containing diclofenac sodium.

The oil-in-water (o/w) emulsion-type ointment was prepared with food additives containing diclofenac sodium. The oil phase and the emulsifier used were 1,2,3- propanetriyl trioctanoate (caprylic acid glyceryl ester) and sugar wax, and sugar ester, respectively. The emulsion stability of the o/w emulsion-type ointment as well as the diclofenac sodium release profile were investigated and compared with those from conventional ointments. The emulsion stability was evaluated in terms of the viscosity of the emulsion product, the particle size distribution of oil droplets, and the zeta potential of the droplets. It was found that sugar esters have excellent properties as emulsifiers, based on the results of viscosity and zeta potential measurements. The in vitro release test revealed that the amount of diclofenac sodium released from o/w emulsion-type ointment was greater than from the hydrophilic and absorptive ointment. Accordingly, it was concluded that o/w emulsion-type bases are suitable for pharmaceutical use in ointment products.

Study of intravenous hyperalimentation: effect of selected amino acids on the stability of intravenous fat emulsions.

In an attempt to resolve the conflicts relevant to intravenous fat emulsion compatibility two amino acids, L-valine and L-histidine monohydrochloride monohydrate, were chosen as intravenous additives, and these substances were investigated as to whether they could induce significant changes in the physicochemical properties of an intravenous soybean oil emulsion. The stability of the fat emulsion was evaluated in terms of gross visual observation, particle size distribution, surface tension, pH, and the zeta potential. It was found that (a) no significant difference was produced on the particle size distribution up to 7 d after admixing, (b) the mean diameter of oil globules was approximately 0.21-0.24 micron, and (c) the fat emulsion was sufficiently stable, with a zeta potential ranging between -30 and -60 mV. The relationship of the isoelectric point (pI) of the amino acids and the pH of the buffer solutions was determined to be one of the most important factors in the stability of the fat emulsion.

Compatibility of intravenous fat emulsions with prodrug amino acids.

Three prodrugs, N-alpha-acetyl-L-arginine, N-alpha-acetyl-L-histidine and N-alpha-acetyl-L-lysine have been examined to see if they could induce significant changes in the stability of an intravenous fat emulsion, the stability being evaluated in terms of physicochemical measurements such as particle size distribution, surface tension, pH and zeta potential. The acetyl amino acids had an excellent stabilizing effect on the emulsion compared with amino acids without acetyl groups.

[Preparation of freeze-thaw poly(vinylalcohol) emulsion gel suppository].

Poly (vinylalcohol) (PVA) emulsion gel suppositories were prepared by a given cycle of freezing and thawing. Oil phase and emulsifying agent used were Panacete 800 and a series of Pluronic L-44, respectively. The effects of polymerization degree of PVA on the gel strength and the drug release were investigated. Drug release from PVA emulsion gel suppository was compared with that from a conventional suppository. The structure of gel was observed by using a scanning electron microscope. The gel strength increased when PVA emulsion gel suppository was prepared with Panacete 800 and Pluronic L-44. The drug release of hydrophilic and hydrophobic drugs from the suppository was in agreement with a zero-order release profile. When oil phase was added into PVA gel suppository, PVA fiber became thin and the network of PVA fiber became dense.

[Stereotactic irradiation for brain metastases using linear accelerator].

A stereotactic irradiation (STI) system using a linear accelerator was developed and its effectiveness for brain metastasis was investigated. The system consisted of a conventional linear accelerator, invasive fixation head frame (RADFRAME, Mizuho Ika Kogyo), and a tungsten collimator. The RADFRAME was developed to be used with any linear accelerators and with any dose planning systems. The accuracy of the irradiation was assured to be within +/-1.5mm. Fifty-one patients with metastatic brain tumors were treated using the system. The overall median survival time was 10 months. No difference in survival was observed between patients with a single lesion and patients with two or three lesions. Complete, partial, and minimal responses were obtained in 16 (39%), 18 (41%), and 7 (16%) lesions. These were comparable to the reported results of gamma knife treatment. A maximum dose of 25 Gy was suggested to be more effective than lower doses. Local control rate was higher in tumors with a diameter of less than 2.0cm (87.5%) than in larger tumors (60%). No difference in tumor response was observed among various histopathologic types. In a patient with a 25mm cerebellar metastasis from an adenocarcinoma of the lung, autopsy at 5 months after STI showed fibrinoid degeneration and hyaline deposition without residual tumor at the Gd-enhanced region on MRI. The efficacy of linac stereotactic irradiation was equal to that of gamma knife radiotherapy for metastatic brain tumors.

[Benefits of totally implanted central venous access in patients with cancer].

A totally implanted system for improved central venous access has been investigated during 44 procedures in 38 patients (37 with cancer and one with cerebral infarction). Most of them lacked peripheral venous sites, and ten per cent of the patients had a prior chronic external central venous catheter. This system is implanted using local anesthesia and consists of a port connected to a central venous catheter threaded through the subclavian vein into the superior vena cava. The system was used mainly for intermittent administration. Injections and infusions of virtually all classes of antineoplastic drugs or antibiotics (81%), blood components (26%), hyperosmolar total parenteral nutrition (47%), and intravenous solutions (53%) were administered through the system. Twenty-one patients died with the system still functioning. Ten of the systems were eventually removed, either after completion of therapy (1) or because of a complication (9). In another 13 cases the devices were working at the completion of the study. Infections accounted for nine per cent of port complications. Four systems became occluded and two of them were replaced. Overall patient acceptance was excellent. This system can be assigned to an appropriate setting that facilitates management of the cancer patient.

[Concomitant arterial infusion chemotherapy with tamoxifen therapy for hepatic metastases from pancreatic adenocarcinoma--a preliminary report].

The prognosis for hepatic metastasis from pancreatic adenocarcinoma is generally poor. Estrogen receptors have recently been demonstrated in pancreatic adenocarcinoma, and it has been suggested that tamoxifen increases patient survival. We have tried tamoxifen therapy combined with intermittent intraarterial infusion chemotherapy using mainly 5-FU for 4 patients with hepatic metastasis from pancreatic adenocarcinoma. Clinical evaluation of initial response was available for these 4 patients. Although the number of the patients in this study was small, we obtained a response rate of 50%; CR in one case, PR in one case. No patients showed progressive disease (PD). Median survival period was 4.6 months; 3 of 4 patients died with carcinomatous peritonitis at 2.5 to 6 months from the initiation of the therapy. No severe complication was observed. It is believed that this new concomitant therapy is effective in controlling hepatic metastasis from pancreatic adenocarcinoma. But additional therapy for carcinomatous peritonitis, which often develops after achieving hepatic control, is necessary to achieve long-term survival benefit.

[Combined chemotherapy and radiotherapy in recurrent tumors of the head and neck region].

Over the past four years, 27 patients with recurrent tumors of the head and neck region have been treated with chemotherapy. The regimens used were BCMF (bleomycin 15 mg i.v. for 3 days, cyclophosphamide 500 mg i.v., methotrexate 50 mg i.v. and 5-fluorouracil 500 mg i.v.) and CMU (cyclophosphamide 350 mg/m2 i.v., methotrexate 30 mg/m2 i.v. and UFT 600 mg p.o. for 14 days). Of the 27 patients, eight were treated with combined radiation and chemotherapy, and either CR or PR was obtained. Nineteen patients were treated with chemotherapy alone, for which the response (CR + PR) rates were 8% (1/12) for BCMF and 43% (3/7) for CMU, respectively. No serious toxicities were observed as a result of these regimens. It was thus demonstrated that the CMU regimen was of great value in terms of improved response and minor toxicity in the treatment of head and neck tumors.

[Management of hilar bile duct carcinoma with high-dose radiotherapy and expandable metallic stent placement].

This article describes our experience with high-dose radiotherapy in combination with the placement of expandable metallic stents (EMS) in the management of hilar bile duct carcinoma. Between 1988 and 1999, 107 consecutive patients with hilar bile duct carcinoma were treated with EMS placement either alone or in combination with high-dose radiotherapy. External beam radiotherapy (EBRT) was indicated in 101 patients, and in 86 this was combined with intraluminal 192Ir irradiation (ILRT, 59-98Gy). EMS were placed after the completion of radiotherapy. The 1-, 2-, 3-, and 5-year actuarial survival rates for the radiotherapy group were 66.4%, 23.4%, 15.6%, 7.8%, respectively, and the 1- and 2-year actuarial survival rates for the nonradiotherapy group were 66.4% and 0%, respectively. The placement of EMS was useful for the early establishment of an internal bile passage in radically irradiated patients and the 1-, 2-, 3-, and 5-year actuarial patency rates for the radiotherapy group were 56.3%, 45.3%, 35.2%, and 23.4%, respectively, and the 1- and 2-year actuarial patency rates for the non radiotherapy group were 50.0% and 0% respectively. High-dose radiotherapy, consisting of ILRT and EBRT, appears to be feasible in the management of hilar bile duct carcinoma, and it offers a survival advantage for patients not suited for surgical resection. The placement of EMS assists the internal bile flow and lengthens survival after high-dose radiotherapy.