Radiation therapy for lymph node metastasis from extramammary Paget's disease.

BACKGROUND: Inoperable patients with lymph node metastasis from extramammary Paget's disease (EMPD) have limited curative treatment options. OBJECTIVE: The aim of this study was to review the efficacy and toxicity of radiation therapy for lymph node metastasis from EMPD. METHODS: Eight EMPD patients with pelvic and inguinal lymph node metastasis, representing a total of 43 metastatic lymph nodes, underwent radiation therapy. Of these eight patients, two received radiation therapy as an initial treatment for EMPD and six for recurrence only in the lymph nodes after they had undergone surgery. Total doses of 45-61.2 Gy (median, 59.4 Gy) were delivered to metastatic lymph nodes in 25-34 fractions (median, 33 fractions). RESULTS: Of the 43 metastatic lymph nodes in the eight patients, all but one had no progression at the median follow-up time of 22 months. The 2-year local control rates were 86% in all patients and 98% in all metastatic lymph nodes, respectively. No therapy-related toxicities of grade 3 or greater were observed. CONCLUSION: Radiation therapy is effective and safe, and appears to offer a curative treatment option for lymph node metastasis from EMPD.

Efficacy and toxicity of (chemo)radiotherapy for primary subglottic cancer.

BACKGROUND AND PURPOSE: Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer. PATIENTS AND METHODS: Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy. RESULTS: Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher. CONCLUSION: Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control.

Radiation therapy for primary carcinoma of the eyelid: tumor control and visual function.

BACKGROUND AND PURPOSE: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. PATIENTS AND METHODS: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). RESULTS: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. CONCLUSION: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid.

Interleukin-18 expression in pig salivary glands and salivary content changes during acute immobilization stress.

Interleukin-18 (IL-18) has recently been considered a promising marker of stress responses. In this study, to evaluate IL-18 as a noninvasive stress marker in pigs, we investigated the expression of IL-18 in porcine salivary glands and its presence in saliva, and its dynamics during acute immobilization stress in pigs. IL-18 mRNA was detected robustly in the pig salivary glands by RT-PCR. Immunohistochemical staining of IL-18 protein expression revealed that the expression patterns differed among the three types of salivary glands (parotid, submandibular, and sublingual gland). IL-18 was also detected in pig saliva by ELISA, and a diurnal rhythm with a peak in the afternoon was observed. The IL-18 concentration in saliva was significantly increased during a 60-min acute immobilization stress in thirteen 5-month-old pigs. These results are the first evidence of a stress-related change of IL-18 in pig saliva. Salivary IL-18 may thus become a useful noninvasive marker for the evaluation of acute stress in pigs.

Preparation-Free Measurement of Event-Related Potential in Oddball Tasks From Hairy Parts Using Candle-Like Dry Microneedle Electrodes.

This paper reports successful measurement of even-related potential (ERP) using candle-like dry microneedle electrodes, which can acquire high-quality electroencephalogram (EEG) from hairy parts without any pretreatment. In our previous work, we successfully measured spontaneous EEG activity and its application to assess the stress state of the subjects. ERPs originate from electrophysiological response to stimulus and are one of the most important indices to capture the cognitive and sensory activities. In this work, using the candle-like dry microelectrodes, we demonstrate successful measurement of ERPs elicited by oddball tasks. Two oddball tasks using pure tone stimuli and speech stimuli were assigned to the subjects, where EEG was acquired from the parietal region (Cz in international 10-20 system). Note that no pretreatment, such as removal of hairs and abrasion of the scalp, was applied. As a result, P300 and mismatch negativity (MMN) were successfully measured in the both oddball tasks from the averaged EEG after the stimuli. Based on these results and given the attractive natures of the candle-like dry microneedle electrodes; they do not need any skin treatment and conductive gels and they can measure EEG from the hairy parts, the developed electrodes will accelerate cognitive neuroscience research using ERPs.

Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer.

Cellular detoxification, such as that mediated by the glutathione (GSH) system, is involved in the metabolism of various cytotoxic agents. Little is known, however, about the clinical relevance of cellular detoxification in chemoresistance. To elucidate the relevance of the GSH system to the resistance to chemotherapy observed in patients with ovarian cancer, we assayed the expression of mRNA encoded by the multidrug resistance-associated protein (MRP) and gamma-glutamyl cysteine synthetase (gamma-GCS) genes, as well as the level of GSH protein in 32 patients with epithelial ovarian cancer after chemotherapy. Tumors of 14 of the 32 patients responded to chemotherapy, whereas 18 did not. The levels of MRP and gamma-GCS transcripts in tumors from nonresponders were each about 2-fold higher than in responders. In contrast, the level of GSH did not differ between the two groups. We observed coordinated expression of gamma-GCS mRNA and GSH protein levels, and between gamma-GCS and MRP in nonresponders, but not in responders. Expression of MRP-encoded mRNA did not correlate to GSH level, however, in either group. These results suggest that gamma-GCS may up-regulate GSH and MRP expression in tumors unresponsive to chemotherapeutic agents, and that the GSH system may be involved in the mechanism of chemoresistance in ovarian cancer.

Sensitivity to paclitaxel is not related to p53-dependent apoptosis in ovarian cancer cells.

We conducted this study to determine whether the sensitivity of ovarian cancer cells to paclitaxel (PTX) relates to cells undergoing p53-dependent apoptosis. Human ovarian adenocarcinoma cell lines (SK-OV-3, KF and KP cells) were used in this study. In SK-OV-3 and KP cells, which have a homozygous deletion of the TP53 gene, wild-type TP53 gene-transduction markedly enhanced the sensitivity to cisplatin (CDDP), but did not enhance the sensitivity to PTX. In all cells, the apoptotic index was increased by CDDP or PTX. After exposure to CDDP, p53 and Bax protein expression increased and Bcl-xL expression decreased in the KF cells and TP53 gene-transducted SK-OV-3 cells. However, these proteins did not change in KP cells. Therefore, the role of p53 in CDDP-induced apoptosis depends upon the cell type. In contrast, TP53 gene status did not correlate with PTX-induced cytotoxicity in any of the cell lines with differing apoptotic pathways. In conclusion, the sensitivity to PTX may not be related to p53-dependent apoptosis in ovarian cancer cells.

A newly developed adenovirus-mediated transfer of a wild-type p53 gene increases sensitivity to cis-diamminedichloroplatinum (II) in p53-deleted ovarian cancer cells.

A new recombinant adenovirus carrying a wild-type p53 gene (AxCAp53) was developed and the combination effect of p53 gene transfer and cis-diamminedichloroplatinum (II) (CDDP) was examined in an ovarian cancer cell line, SK-OV-3, with deletion of the p53 gene. AxCAp53 showed a high efficiency of gene transduction and increased sensitivity to CDDP in the SK-OV-3 cells. It was found that the sensitivity of the cells to CDDP correlated with the amount of infectious units of virus per cell of AxCAp53 which correlated with p53 protein expression. The results suggest that the combination of CDDP and AxCAp53 may be a potential strategy for the therapy of CDDP-resistant ovarian cancer.

Tumor cell kinetics in elderly patients with cervical cancer.

OBJECTIVE: To determine whether cell kinetics in cervical cancer differ by patient age. METHODS: We analyzed specimens from 118 women who had been treated for cervical squamous cell carcinoma. In a preliminary study, labeling indices were determined in 16 patients using bromodeoxyuridine in vitro. Adjacent portions of the same specimens were analyzed by flow cytometry. Proliferation indices were calculated and compared with labeling indices for 12 diploid tumors. For the remaining 102 tumors, paraffin-embedded specimens were analyzed by flow cytometry to determine DNA ploidy and proliferation index. Using these findings, we examined the relationship between tumor cell kinetics and age. RESULTS: There was a significant correlation between the labeling index and age (r = 0.86, P < .001) and a weak but statistically significant correlation between the proliferation index and the labeling index (r = 0.58, P < .05). The proportion of aneuploid tumors increased with age. The cutoff point of highest statistical significance was 65 years (P = .025). The proliferation index showed an age-dependent shift, and the cutoff point of highest statistical significance was also 65 years. Aneuploid tumors were more common in elderly patients aged 65 or more years. Proliferation indices were also significantly larger in the elderly patients (P < .005). Although stage III tumors were more common in the elderly, stage was not related to ploidy pattern or to proliferation index. CONCLUSION: Tumor cell kinetics of cervical squamous cell carcinomas differ between elderly and younger women.

Transvaginal ultrasonographic diagnosis of bladder-wall invasion in patients with cervical cancer.

OBJECTIVE: To evaluate the use of transvaginal ultrasonography for diagnosing invasion of the bladder by cervical cancer. METHODS: Twenty-one women with stages Ib-IIIb cervical cancer underwent radical hysterectomy or staging laparotomy. All had computed tomography (CT) scans and cystoscopic examinations, and five also underwent magnetic resonance imaging (MRI). During transvaginal ultrasonography, a transvaginal transducer was inserted into the anterior fornix of the vagina and the bladder wall was studied in the sagittal plane. The moveability of the bladder wall was assessed by the ability of the bladder to slide along the uterine cervix when the probe was pushed up against the bladder from the anterior fornix. Moveability was considered to indicate an intact bladder wall. RESULTS: The accuracy of transvaginal ultrasonography was superior to that of the other methods for detecting bladder-wall invasion by cervical cancer. The accuracy was 95% for transvaginal ultrasonography, 76% for CT, 86% for cystoscopy, and 80% for MRI. CONCLUSION: Transvaginal ultrasonographic examination is useful for detecting invasion of the bladder wall by cervical cancer.

Severe fetal supraventricular bradyarrhythmia without fetal hypoxia.

Cardiac anatomy and rhythm were evaluated in a fetus at 39 weeks' gestation in a pregnant woman referred because of severe fetal bradycardia with a persistent fetal heart rate of 50-60 beats per minute. M-mode echocardiograms revealed supraventricular bradyarrhythmia. Umbilical cord blood analysis did not, however, reveal fetal hypoxia. Diagnostic methods of fetal bradyarrhythmia are discussed, and the importance of differentiating bradyarrhythmia from bradycardia due to fetal hypoxia is emphasized.

Platinum concentrations in uterus and serum after internal iliac arterial infusion of platinum compounds in rabbits.

OBJECTIVE: To compare three platinum compounds, and study the pharmacokinetics of these compounds after systemic and intra-arterial infusion. METHODS: Adult female rabbits received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cisdiammine(glycolato)platinum (254-S) via the internal iliac artery or jugular vein. The doses were equitoxic. Platinum tissue concentration in uterus and platinum serum levels were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: Platinum uterine concentration after intra-arterial infusion was significantly higher than that after i.v. infusion for each drug (P < .05). The ratios of platinum uterine concentration after intra-arterial infusion to those after i.v. infusion were 2.24 for cisplatin, 1.83 for carboplatin, and 1.67 for 254-S measured 20 minutes after drug administration. The area under the curve of filtrated platinum (micrograms/mL.hours) was significantly lower for cisplatin compared with carboplatin and 254-S in both infusion methods (1.5 for cisplatin, 32.1 for carboplatin, and 16.0 for 254-S after i.v. administration, and 0.8, 30.9, and 15.2 after intra-arterial administration, respectively). CONCLUSION: Cisplatin produced the highest ratio of uterine to serum concentration of platinum after intra-arterial infusion.

Antitumor effects of internal iliac arterial infusion of platinum compounds in a rabbit cervical cancer model.

OBJECTIVE: To compare three platinum compounds for their antitumor effects on cervical cancer after systemic and intra-arterial infusion. METHODS: Adult female rabbits with squamous cell carcinoma of the uterine cervix received infusions of 1.7 mg/kg cisplatin, 10 mg/kg carboplatin, or 6 mg/kg cis-diammine (glycolato)platinum (254-S) via the internal iliac artery or ear vein. Platinum concentrations in the tumor and tumor size were measured after internal iliac arterial or intravenous (i.v.) infusion with these platinum compounds. RESULTS: The platinum concentration in the tumor after intra-arterial infusion was significantly higher than that after i.v. infusion for cisplatin. However, the tumor concentrations of platinum for carboplatin and 254-S did not differ between the infusion methods. The platinum concentration 20 minutes after i.v. infusion was significantly higher for 254-S than for cisplatin or carboplatin. The platinum concentration 7 days after intra-arterial infusion was significantly higher with cisplatin than with carboplatin or 254-S. Tumor size 7 days after intra-arterial infusion was significantly smaller than that after i.v. infusion for cisplatin (1.85 +/- 0.54 versus 5.60 +/- 2.60 cm2; P < .05). Tumor size was significantly smaller with 254-S than with cisplatin or carboplatin using the i.v. infusion method (2.40 +/- 0.21 cm2 for 254-S, 5.60 +/- 2.60 cm2 for cisplatin, and 5.13 +/- 1.59 cm2 for carboplatin, P < .05. CONCLUSIONS: Intra-arterial infusion seems to be a suitable route of administration for cisplatin, whereas i.v. infusion appears to have an advantage for 254-S in the treatment of cervical cancer.

Alteration of telomerase activity associated with development and extension of epithelial ovarian cancer.

OBJECTIVE: To assess telomerase activity associated with the development and extension of epithelial ovarian cancer and to investigate the relationship between p53 gene status and telomerase activity. METHODS: A total of 53 samples (41 epithelial ovarian cancers, five borderline epithelial tumors, four benign adenomas, and three surface epithelia) were examined for telomerase activity by the polymerase chain reaction (PCR) -based telomeric repeat amplification protocol assay. Mutations in the p53 gene were determined by PCR-single strand conformation polymorphism analysis. RESULTS: Telomerase activity was detected in 33 of 41 epithelial ovarian cancers and in three of five borderline malignancies but was not detectable in either benign tumors or normal surface epithelium. The mean (+/-standard deviation [SD]) intensity of telomerase activity in cancers was significantly higher than that in borderline malignancies (10.6+/-8.2 versus 3.6 4+/-1.3). The positivity of telomerase activity did not correlate with any clinical findings, but the intensity (+/-SD) of telomerase activity was significantly higher in tumors with lymph node involvement (12.2+/-8.3 versus 3.8+/-1.1). Mutations of the p53 gene were observed in 44% of ovarian cancers; p53 gene status did not relate to telomerase activity. Multivariate analysis showed that the intensity of telomerase activity was not an independent factor for prognosis of patients with ovarian cancer. CONCLUSION: Telomerase activity may be associated with development and extension of epithelial ovarian cancer.

Further characterization of a human sperm coating antigen (gp12).

In our previous paper, we identified a novel sperm-coating antigen with molecular weight of approximately 12,000 daltons that is highly specific to sperm, seminal plasma, and milk from the plasma membrane fraction of human spermatozoa by using rabbit antiseminal plasma antiserum. In the present study, this 12,000-daltons component, termed gp12, has been investigated for its tissue distribution and antigenic stability. The largest amounts of the antigen are found in seminal plasma, although individual variation is rather high. In seminal plasma, the gp12 molecule presents in a large form with a molecular weight of approximately 50,000 daltons. Its antigenicity is stable when treated with acid, alkali, heat, and various protein denaturants.

A human sperm coating antigen isolated from sperm cell membrane.

A human sperm cell membrane antigen that is highly specific to sperm and seminal plasma was isolated from plasma membrane fraction of spermatozoa using rabbit antiserum against human seminal plasma. In addition to the high specificity to sperm and seminal plasma, the isolated antigen showed the following characteristics: (1) It is a glycoprotein of approximately 12,000 daltons that has an affinity to lentil lectin; (2) it is distributed in human milk other than in sperm and seminal plasma, but is not found in any other organs and tissues including testis; (3) seminal plasma contains the largest amount of the antigen activity, 60-fold greater than spermatozoa and 900-fold greater than milk, suggesting that this antigen could be a sperm-coating seminal plasma antigen.

Evaluation of cytoreductive surgery with lymphadenectomy including para-aortic nodes for advanced ovarian cancer.

The prognosis of 84 patients with advanced ovarian cancer who received the same regimen of postoperative chemotherapy but who received different surgical procedures, was evaluated retrospectively. Of those patients, 41 underwent cytoreductive surgery with lymphadenectomy, including removal of the para-aortic nodes (group A). The other 43 patients received hysterectomy, bilateral salpingoophorectomy and omentectomy (group B). Overall the patients in group A showed a significantly greater survival than those in group B. The performance of lymphadenectomy in patients with positive nodes improves the prognosis to equal that of patients with negative nodes. It is suggested that cytoreductive surgery with lymphadenectomy may be useful for the improvement of the prognosis of patients with advanced ovarian cancer.

Prognosis and clinicopathological characteristics of Ib-IIb adenocarcinoma of the uterine cervix in patients who have had radical hysterectomy.

AIMS: The aim of the present study was to evaluate the outcome of patients with stage lb-IIb cervical adenocarcinoma treated with radical hysterectomy, and to determine the clinicopathological characteristics of those patients. METHODS: A total of 255 patients with cervical carcinoma stage Ib-IIb (57 adenocarcinoma and 198 squamous cell carcinoma) who had undergone radical hysterectomy were included in this study. Patient survival distribution was calculated using the Kaplan-Meier method. RESULTS: The estimated 5-year survival rate for patients with adenocarcinoma was significantly poorer than that for patients with squamous cell carcinoma (77.9% vs 91.7%). The survival rate in stage Ib patients did not differ between two groups (95.8% vs 94.4% respectively). The incidence of lymph node involvement was significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma (31.6% vs 14.8%). Among patients receiving post-operative radiotherapy, the survival rate for adenocarcinoma (71.1%) was significantly poorer than that for squamous cell carcinoma (90.0%). When patients underwent radical hysterectomy, the survival rate for stage II patients with adenocarcinoma was significantly poorer than that for patients with squamous cell carcinoma. CONCLUSIONS: The higher incidence of lymph node involvement and lower response to post-operative radiotherapy are considered to be factors of poorer prognosis in cervical adenocarcinoma.

Response rate and cell-cycle changes due to intra-arterial infusion chemotherapy with cisplatin and bleomycin for locally recurrent uterine cervical cancer.

Intra-arterial infusion with cisplatin (CDDP) and bleomycin (BLM) was carried out in 21 patients with locally recurrent uterine cervical cancer who were previously treated with irradiation alone. Patients were treated with a bolus infusion into both internal iliac arteries of 50 mg/m2 of CDDP and 30 mg/m2 of BLM. Two to four courses of the infusion therapy were given to each patient, and the response rate, the tumor and serum drug concentrations, and the cell kinetics in tumor tissue were evaluated. The response rate (CR+PR) was 71.4% according to the WHO criteria. There was no difference, in the tumor tissue concentrations of CDDP and BLM between responders and nonresponders. Although the DNA ploidy of tumor cells was not significantly different between the two groups before treatment, both the labeling index with BrdU and the proliferation index with flow cytometry significantly increased 24 hours after treatment in responding tumors but not in nonresponding tumors. These results show that intra-arterial infusion with CDDP and BLM improves the prognosis of recurrent cervical cancer and that labeling and proliferation indices may be useful for determining the response of cervical cancer to intra-arterial chemotherapy.

Significance of cytoreductive surgery including bowel resection for patients with advanced ovarian cancer.

The aim of this study was to determine the significance of bowel resection in advanced ovarian cancer. A total of 64 women with stage IIIc or IV epithelial ovarian cancer, who consecutively received primary treatment between 1991 and 1995, were entered in this prospective study. The outcome of the patients undergoing bowel resection was evaluated. Thirty-nine patients underwent cytoreductive surgery at initial surgery. Of them, 16 patients could undergo optimal operation without bowel resection. Twenty-three patients received bowel resection at initial surgery. Of these 23 patients, 16 underwent optimal operation and 7 did not. Among 25 patients judged as inoperable cases at initial surgery, 21 responded to chemotherapy and underwent second surgery. Of 21 patients receiving second surgery, 15 underwent optimal operation (7 without bowel resection and 8 with bowel resection). The 3-year survival rate for 24 patients undergoing optimal operation with bowel resection (46.8%) was not significantly different from that for 23 patients without bowel resection (59.1%). Postoperative complications were seen in 8 patients (21.6%) of the patients receiving bowel resection and 3 (13.0%) of those without bowel resection. Cytoreductive surgery including bowel resection is effective for an improvement of the survival in patients with advanced ovarian cancer, if an optimal operation can be performed.