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.

Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion.

Activation of proMMP-2 by MT1-MMP is considered to be a critical event in cancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP-2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study, we demonstrate that MT1-MMP forms a homophilic complex through the hemopexin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, abolished the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex formation of the full-length enzymes and activation of pro MMP-2. Furthermore, expression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion activity of invasive human fibrosarcoma HT1080 cells. These findings elucidate a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.

[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.

Practical protective tools for occupational exposure: 1) double focus spectacles for the aged with highly refracted glass lens 2) remodeled barrier for radiation protection.

SUMMARY: Two practical protective tools for occupational exposure for neurointerventional radiologists are presented. The first purpose of this study was to investigate the effectiveness of double focus spectacles for the aged with a highly refracted glass lens (special spectacles for the aged) for radiation protection of the crystalline lens of the eye in comparison with other spectacles on the market, based on the measurement of film density which was obtained by exposure of X-ray through those spectacles. As a result of the film densitometry mentioned above, the effectiveness of special spectacles for the aged in radiation protection was nearly equal to the effectiveness of a goggle type shield which is made with a 0.07 mm lead-equivalent plastic lens. The second purpose of this study was to investigate the effectiveness of the protective barrier, which we remodeled for cerebral angiography or neuroendovascular therapy, for radiation exposure, based on the measurement in a simulated study with a head phantom, and on the measurement of radiation exposure in operaters during procedures of clinical cases. In the experimental study radiation exposure in supposed position of the crystalline lens was reduced to about one third and radiation exposure in supposed position of the gonadal glands was reduced to about one seventh, compared to radiation exposure without employing the barrier. The radiation exposure was monitored at the left breast of three radiologists, in 215 cases of cerebral angiography. Employing the barrier in cerebral angiography, average equivalent dose at the left breast measured 1.49mu Sv during 10 min of fluoroscopy. In three kinds of neuroendovascular therapy in 40 cases, radiation exposure in an operator was monitored in the same fashion and the dose was recorded less than the result reported in previous papers in which any protective barrier have not been employed in the procedure (1,2). As a result, the two above mentioned protective tools are considered practical in clinical usage and very effective to reduce radiation exposure in an operator of interventional neuroradiolgy which may sometimes require many hours to complete the therapy under extended fluoroscopic time. 1) The first topic of this report is double focus spectacles for the aged with a highly refracted glass lens (special spectacles for the aged).

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.

Intraoperative radiation therapy to the upper mediastinum and nerve-sparing three-field lymphadenectomy followed by external beam radiotherapy for patients with thoracic esophageal carcinoma.

BACKGROUND: In patients with thoracic esophageal carcinoma, radical dissection of the upper mediastinal lymph nodes often leads to complications such as recurrent laryngeal nerve palsy and subsequent pulmonary disorders. Intraoperative radiation therapy (IORT) to the upper mediastinum and nerve-sparing three-field lymphadenectomy followed by external beam radiotherapy has been developed to improve the locoregional control rate without resulting in these major postoperative complications. METHODS: Three-field lymphadenectomy, including cervical, mediastinal, and abdominal lymph node dissection, was performed. Dissection of the upper mediastinum was conservative to preserve recurrent laryngeal nerve function. IORT of 12-25 grays (Gy) was applied to the upper mediastinum. Postoperative radiation therapy (PORT) of 45 Gy in 16 fractions over 4 weeks was applied to the entire neck and upper mediastinum using an external X-ray beam. Between 1989-1996, 121 patients with thoracic esophageal carcinoma underwent surgery and received IORT, and 103 of these patients underwent PORT as part of their treatment schedule. RESULTS: The surgical mortality rate was 0.8% (1 of 121 cases). The overall 5-year survival rate was 34.4% and the cause specific 5-year survival rate was 54.8%. The cause specific 5-year survival rate for pN0 tumors was 79.4% and was 43.8% for pN1 tumors. No patients died with locoregional recurrence in the mediastinal lymph nodes. Recurrent laryngeal nerve palsy was observed in 25 patients (21%), but the palsy remained for > 1 month in only 13 patients (11%). Mechanical ventilation support for > 48 hours was required for 22 patients (18.2%). Fatal tracheal ulcers occurred in 4 of 18 patients who received the highest IORT dose of 25 Gy. CONCLUSIONS: Three-field lymphadenectomy to preserve recurrent laryngeal nerves and IORT using 12-20 Gy followed by 45-Gy PORT effectively reduced locoregional recurrence, recurrent laryngeal nerve palsy, and pulmonary complications caused by radical surgical dissections. The minimally effective dose of IORT appears to be < or = 15 Gy, a factor that will be further evaluated with longer follow-up.

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.

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.

[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.

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.

[Biliary endoprosthesis using Gore-Tex covered expandable metallic stents: preliminary clinical evaluation].

Six patients with biliary obstruction caused by pancreatic carcinoma were treated with Gore-Tex covered EMS. In all cases cholangioscopy revealed massive tumor in the bile duct lumen, but all stents expanded well and equalled the caliber of the bile duct. Slipping migration was observed in 2 patients, in whom external drainage catheters could not be removed. In the remaining 4 patients, re-obstruction was not observed during 1-12 months follow-up. Covered stents can avoid rapid obstruction and prevent early occlusion of bile duct by tumor ingrowth into the lumen.

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.

[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.

Is postoperative radiotherapy beneficial in the management of stage I-II squamous-cell carcinoma of the uterine cervix with negative metastatic nodes and positive parametrial involvement?: A retrospective review of 70 patients.

Seventy patients having squamous-cell carcinoma of the uterine cervix FIGO Stage I-II with negative lymph nodes and positive parametrial involvement received postoperative radiotherapy following radical hysterectomy and pelvic lymphadenectomy. In 48 patients with microscopic parametrial invasion, the 5-year survival rate was 92%. The other 22 patients with macroscopic parametrial involvement had a 5-year survival rate of 75%. The overall recurrence rate was 13% (9 of 70). The sites of failure were 3 pelvic alone, 5 distant metastases alone, and 1 combined pelvis and para-aortic lymph node. All of those with recurrence were Stage-II cases. The absolute pelvic-control rate was 94.3% (66/70). Fifty-six percent of the patients experienced mild-to-moderate lymphedema. Severe complications requiring surgical intervention were observed in 6 patients (5 bowel obstructions and 1 femoral head fracture). A review of the literature suggests that early carcinoma can be successfully treated by surgery alone. Taking into consideration the risk and benefits involved, postoperative radiotherapy is not recommended for most cases with cervical carcinoma with negative lymph nodes and positive parametrial involvement in the present form, despite excellent local control. However, no definite conclusion can be drawn from this retrospective analysis.

[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.

[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.