Intraoperative radiotherapy for resectable advanced lower rectal cancer-final results of a randomized controlled trial (UMIN000021353).

AIM: Pelvic autonomic nerve preservation (PANP) is useful to preserve voiding and sexual function after rectal cancer surgery. The aim of this study was to investigate the benefit of intraoperative radiotherapy (IORT) to have complete PANP without affecting oncological outcomes. METHODS: Patients undergoing potentially curative resection of the rectum were included. They were randomized to intraoperative radiotherapy of the completely preserved bilateral pelvic nerve plexuses (IORT group) or the control group without IORT, but with limited nerve preservation. The primary endpoint was pelvic sidewall recurrence. Moreover, patients' clinicopathologic parameters, postoperative complications, voiding function, and other oncologic outcomes were compared. RESULTS: From 79 patients, three were excluded from analysis, resulting in 38 patients in each group. Patients' demographic and pathological parameters were well balanced between the two groups. The trial was terminated prematurely in July 2017, because distant metastasis-free survivals were found to be significantly worse in the IORT group compared to the control group (odds ratio 2.554; 95% CI, 1.041 ~ 6.269; p = 0.041). Neither overall survival nor pelvic sidewall recurrence did differ between the two groups (overall survival: odds ratio 1.264; 95% CI, 0.523~3.051; p = 0.603/pelvic sidewall recurrence; odds ratio 1.350; 95% CI, 0.302~6.034; p = 0.694). Postoperative complications did not differ between the groups; however, the urinary function was significantly better in the IORT group in the short and long term. CONCLUSION: With the aid of IORT, complete PANP can be done without increase of pelvic sidewall recurrence; however, IORT may increase the incidence of distant metastases. Therefore, IORT cannot be recommended as a standard therapy to compensate less radical resection for advanced lower rectal cancer.

Comparison of biological activities of human antithrombins with high-mannose or complex-type nonfucosylated N-linked oligosaccharides.

The structure of the N-linked oligosaccharides attached to antithrombin (AT) has been shown to affect its anticoagulant activity and pharmacokinetics. Human AT has biantennary complex-type oligosaccharides with the unique feature of lacking a core fucose, which affects its biological activities by changing its heparin-binding affinity. In human plasma, AT circulates as a mixture of the α-form bearing four oligosaccharides and the ß-form lacking an oligosaccharide at Asn135. However, it remains unclear how the immature high-mannose-type oligosaccharides produced by mammalian cells affect biological activities of AT. Here, we succeeded in directly comparing the activities between the high-mannose and complex types. Interestingly, although there were no substantial differences in thrombin inhibitory activity, the high-mannose type showed higher heparin-binding affinity. The anticoagulant activities were increased by heparin and correlated with the heparin-binding affinity, resulting in the strongest anticoagulant activity being displayed in the ß-form with the high-mannose type. In pharmacokinetic profiling, the high-mannose type showed a much shorter plasma half-life than the complex type. The ß-form was found to have a prolonged plasma half-life compared with the α-form for the high-mannose type; conversely, the α-form showed a longer half-life than the ß-form for the complex-type. The present study highlights that AT physiological activities are strictly controlled not only by a core fucose at the reducing end but also by the high-mannose-type structures at the nonreducing end. The ß-form with the immature high-mannose type appears to function as a more potent anticoagulant than the AT typically found in human plasma, once it emerges in the blood.

Perindopril increases the swallowing reflex by inhibiting substance P degradation and tyrosine hydroxylase activation in a rat model of dysphagia.

Patients with hypertension have a high risk of ischemic stroke and subsequent stroke-associated pneumonia. Stroke-associated pneumonia is most likely to develop in patients with dysphagia. The present study was designed to compare the ameliorative effects of different treatments in rat model of dysphagia. Spontaneously hypertensive rats were treated with bilateral common carotid artery occlusion (BCAO) to induce chronic cerebral hypoperfusion causing disorders of the swallowing reflex. Angiotensin-converting enzyme (ACE) inhibitors (perindopril, imidapril and enalapril), an angiotensin II type 1-receptor blocker (losartan), a vasodilator (hydralazine) and an indirect dopamine agonist (amantadine) were dissolved in drinking water and administered to the rats for six weeks. The blood pressure, the swallowing reflex under anesthesia, the substance P content in the striatum and the tyrosine hydroxylase (TH) expression in the substantial nigra were measured. Compared to the vehicle control, the decrease in the swallowing reflex induced by BCAO was attenuated significantly by enalapril, imidapril and perindopril, but only slightly by losartan. Hydralazine had no effect on the swallowing reflex. Amantadine significantly attenuated the decreased swallowing reflex but increased the blood pressure. Cerebral hypoperfusion for six weeks decreased the TH expression and substance P level. Perindopril improved both the TH expressions and substance P level, but imidapril, enalapril and amantadine only improved the substance P level. The present findings indicate that perindopril could be useful for preventing dysphagia in the chronic stage of stroke by attenuating the decrease in TH expression and the decrease in the substance P level.

Impact of intraluminal brachytherapy on survival outcome for radiation therapy for unresectable biliary tract cancer: a propensity-score matched-pair analysis.

PURPOSE: To determine whether adding intraluminal brachytherapy (ILBT) to definitive radiation therapy (RT) for unresectable biliary tract cancer has a positive impact on survival outcome. METHODS AND MATERIALS: The original cohort comprised 209 patients, including 153 who underwent external beam RT (EBRT) alone and 56 who received both ILBT and EBRT. By matching propensity scores, 56 pairs (112 patients) consisting of 1 patient with and 1 patient without ILBT were selected. They were well balanced in terms of sex, age, performance status, clinical stage, jaundice, and addition of chemotherapy. The impact of ILBT on overall survival (OS), disease-specific survival (DSS), and local control (LC) was investigated. RESULTS: The 2-year OS rates were 31% for the ILBT+ group and 40% for theILBT- group (P=.862). The 2-year DSS rates were 42% for the ILBT+ group and 41% for the ILBT- group (P=.288). The 2-year LC rates were 65% for the ILBT+ group and 35% for the ILBT- group (P=.094). Three of the 4 sensitivity analyses showed a significantly better LC for the ILBT+ group (P=.010, .025, .049), and another showed a marginally better LC (P=.068), and none of the sensitivity analyses showed any statistically significant differences in OS or DSS. CONCLUSIONS: In the treatment for unresectable biliary tract cancer, the addition of ILBT to RT has no impact on OS or DSS but is associated with better LC. Therefore, the role of ILBT should be addressed by other measures than survival benefit, for example, by less toxicity, prolonged biliary tract patency decreasing the need for further palliative interventions, or patient quality of life.

Patterns of radiotherapy practice for biliary tract cancer in Japan: results of the Japanese radiation oncology study group (JROSG) survey.

BACKGROUND: The patterns of radiotherapy (RT) practice for biliary tract cancer (BTC) in Japan are not clearly established. METHODS: A questionnaire-based national survey of RT used for BTC treatment between 2000 and 2011 was conducted by the Japanese Radiation Oncology Study Group. Detailed information was collected for 555 patients from 31 radiation oncology institutions. RESULTS: The median age of the patients was 69 years old (range, 33-90) and 81% had a good performance status (0-1). Regarding RT treatment, 78% of the patients were treated with external beam RT (EBRT) alone, 17% received intraluminal brachytherapy, and 5% were treated with intraoperative RT. There was no significant difference in the choice of treatment modality among the BTC subsites. Many patients with EBRT were treated with a total dose of 50 or 50.4 Gy (~40%) and only 13% received a total dose ≥60 Gy, even though most institutions (90%) were using CT-based treatment planning. The treatment field consisted of the primary tumor (bed) only in 75% of the patients. Chemotherapy was used for 260 patients (47%) and was most often administered during RT (64%, 167/260), followed by after RT (63%, 163/260). Gemcitabine was the most frequently used drug for chemotherapy. CONCLUSIONS: This study established the general patterns of RT practice for BTC in Japan. Further surveys and comparisons with results from other countries are needed for development and optimization of RT for patients with BTC in Japan.

Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats.

We have previously demonstrated that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated the cognitive deficits in Alzheimer's disease model animals, independently of its anti-hypertensive effect. In this study, we again investigated the effects of perindopril on cognitive function in a vascular dementia model animal, comparing it with other ACE inhibitors. We also determined ACE activity in the brain and extracellular acetylcholine (ACh) concentration in the perirhinal cortex in order to elucidate the mechanism(s) responsible for the effects of these ACE inhibitors on cognitive function. Perindopril was suggested to be more centrally active than imidapril and enalapril, in consideration of the relative distribution of their active metabolites in the brain. This property was at least partially attributed to the lipophilicity of the compound. While the 3 day treatment with perindopril, imidapril or enalapril lowered blood pressure to the same level in spontaneous hypertensive rats, only perindopril reversed the decline in the recognition index in chronic cerebral hypo-perfusion rats, regarded as an animal model of vascular dementia, during an object recognition task. Using the same dosing regimen, perindopril inhibited the brain ACE activities of rats more than imidapril or enalapril. Moreover, a single treatment with perindopril enhanced the extracellular level of ACh in the perirhinal cortex of normal rats. Therefore, we confirmed that only centrally active ACE inhibitors, such as perindopril, can inhibit the ACE in the brain, augmenting cholinergic neurotransmission and thereby ameliorating cognitive impairment in the animal model of vascular dementia.

Intraoperative radiotherapy for unresectable pancreatic cancer: a multi-institutional retrospective analysis of 144 patients.

PURPOSE: To retrospectively analyze the results of intraoperative radiotherapy (IORT) + external beam radiotherapy (EBRT) for unresectable pancreatic cancer. METHODS AND MATERIALS: The records of 144 patients treated with IORT, with or without, EBRT were reviewed. One hundred and thirteen patients (78.5%) were treated with IORT + EBRT and 114 patients (79.2%) were treated in conjunction with chemotherapy. The median doses of IORT and EBRT were 25 Gy and 45 Gy, respectively. The median follow-up of all 144 patients was 9.6 months (range, 0.5-69.7 months). RESULTS: At the time of this analysis, 131 of 144 patients (91.0%) had disease recurrences. Local progression was observed in 60 patients (41.7%), and the 2-year local control (LC) rate in all patients was 44.6%. Patients treated with IORT, with or without, EBRT had significantly more favorable LC (2-year LC, 50.9%) than those treated with IORT without EBRT (p = 0.0004). The 2-year overall survival (OS) rate and the median survival time in all 144 patients were 14.7% and 10.5 months, respectively. Patients treated with chemotherapy had a significantly favorable OS than those treated without chemotherapy (p < 0.0001). On univariate analysis, chemotherapy use alone had a significant impact on OS and on multivariate analysis; chemotherapy use was a significant prognostic factor. Late gastrointestinal morbidity of National Cancer Institute-Common Terminology Criteria Grade 3 was observed in 2 patients (1.4%). CONCLUSION: IORT + EBRT yields a relatively favorable LC rate for unresectable pancreatic cancer with low frequency of severe late toxicity, and IORT combined with chemotherapy conferred a survival benefit compared with IORT without chemotherapy.

Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease.

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimer's disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Abeta(25-35)-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3mg/kg/day) nor enalapril (1, 3 or 10mg/kg/day) had any effect on cognitive performance. Perindopril (1mg/kg/day), imidapril (3mg/kg/day), or enalapril (10mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimer's disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimer's disease as well as hypertension.

Quality assurance of pelvic autonomic nerve-preserving surgery for advanced lower rectal cancer--preliminary results of a randomized controlled trial.

BACKGROUND: Pelvic autonomic nerve-preserving (PANP) lateral node dissection (LLND) has been introduced in rectal cancer surgery in Japan, but quality assurance of this approach has not been tested by randomized controlled trials. METHODS: Patients with advanced lower rectal cancer were randomized either to complete PANP + LLND surgery combined with intraoperative radiotherapy (preserved group; n = 28) or to pelvic autonomic nerve resection + LLND surgery (resected group; n = 27). Operation-related parameters were compared statistically. RESULTS: Patient and tumor characteristics were well comparable. The incidence of anastomotic breakdown, intrapelvic abscess, and small bowel obstruction was not different between the two groups. In the preserved group, no patients had ureteral stenosis, pelvic bone fractures, or peripheral neuropathy due to intraoperative radiotherapy. Sphincter-preserving operation was possible with similar ratio in both groups. Adjuvant chemotherapy was given with similar ratio in both groups. The average operation time was 513 minutes in the preserved group and 409 minutes in the resected group, with a significant difference between the two groups. The average amount of hemorrhage was not different significantly between the preserved group (996 ml) and the resected group (970 ml). Circumferential resection margin status and operative curability were similar between the two groups. The average number of harvested and metastatic nodes in the mesentery and pelvic sidewall was not different significantly between the two groups. CONCLUSIONS: This study revealed, for the first time, that the surgical quality of PANP + LLND is the same as pelvic autonomic nerve resection + LLND.

Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients.

PURPOSE: To retrospectively analyze the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (EBRT) for resected pancreatic cancer. METHODS AND MATERIALS: The records of 210 patients treated with gross complete resection (R0: 147 patients; R1: 63 patients) and IORT with or without EBRT were reviewed. One hundred forty-seven patients (70.0%) were treated without EBRT and 114 patients (54.3%) were treated in conjunction with chemotherapy. The median doses of IORT and EBRT were 25 Gy (range, 20-30 Gy) and 45 Gy (range, 20-60Gy), respectively. The median follow-up of the surviving 62 patients was 26.3 months (range, 2.7-90.5 months). RESULTS: At the time of this analysis, 150 of 210 patients (71.4%) had disease recurrences. Local failure was observed in 31 patients (14.8%), and the 2-year local control rate in all patients was 83.7%. The median survival time and the 2-year actuarial overall survival (OS) in all 210 patients were 19.1 months and 42.1%, respectively. Patients treated with IORT and chemotherapy had a significantly more favorable OS than those treated with IORT alone (p = 0.0011). On univariate analysis, chemotherapy use, degree of resection, carbohydrate antigen 19-9, and pathological N stage had a significant impact on OS and on multivariate analysis; these four factors were significant prognostic factors. Late gastrointestinal morbidity of NCI-CTC Grade 4 was observed in 7 patients (3.3%). CONCLUSION: IORT yields an excellent local control rate for resected pancreatic cancer with few frequencies of severe late toxicity, and IORT combined with chemotherapy confers a survival benefit compared with that of IORT alone.

Radiosurgery for cerebral arteriovenous malformation during pregnancy: A case report focusing on fetal exposure to radiation.

INTRODUCTION: We present the case of a pregnant woman who underwent linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) and we discuss the fetal exposure to radiation. CLINICAL PRESENTATION: A 20-year-old woman at 18 weeks of gestation presented with right cerebral hemorrhage and underwent urgent evacuation of the hematoma. She recovered well after surgery, but cerebral angiography after the surgery revealed a small deeply seated arteriovenous malformation (AVM) in the right frontal lobe extending to the right basal ganglia. METHODS AND RESULTS: We examined the diffuse AVM and treated it with LINAC-based SRS at 24 weeks of gestation. Before SRS, the fetus was exposed to a radiation dose of 8.26 mGy, which was estimated by conducting an experiment using an adult RANDO phantom, and a radiophotoluminescent (RPL) glass rod dosimeter (GRD) system. The patient underwent Caesarean delivery at 36 weeks of gestation and gave birth to a healthy baby. CONCLUSION: The exposure of fetus to radiation during SRS was exceedingly low. SRS can be used as an alternative treatment to microsurgery for resolving small deeply seated AVMs even in pregnant patients.

The dihydropyridine calcium channel blocker benidipine prevents lysophosphatidylcholine-induced endothelial dysfunction in rat aorta.

BACKGROUND: Lysophosphatidylcholine (LPC), an atherogenic component of oxidized low-density lipoprotein, has been shown to induce the attenuation of endothelium-dependent vascular relaxation. Although benidipine, a dihydropyridine-calcium channel blocker, is known to have endothelial protective effects, the effects of benidipine on LPC-induced endothelial dysfunction remain unknown. We examined the effects of benidipine on the impairment of endothelium-dependent relaxation induced by LPC. METHODS: Benidipine was administered orally to rats and aortas were then isolated. Aortic rings were treated with LPC and endothelial functions were then evaluated. Additionally, the effects of benidipine on intracellular calcium concentration ([Ca2+]i) and membrane fluidity altered by LPC in primary cultured rat aortic endothelial cells were examined. [Ca2+]i was measured using the fluorescent calcium indicator fura-2. Membrane fluidity was monitored by measuring fluorescence recovery after photobleaching. RESULTS: Treatment with LPC impaired endothelial function. Benidipine prevents the impairment of relaxation induced by LPC. Acetylcholine elicited an increase in [Ca2+]i in fura-2 loaded endothelial cells. The increase in [Ca2+]i was suppressed after exposure to LPC. Plasma membrane fluidity increased following incubation with LPC. Benidipine inhibited the LPC-induced increase in membrane fluidity and impairment of increase in [Ca2+]i. CONCLUSION: These results suggest that benidipine inhibited LPC-induced endothelial dysfunction by maintaining increase in [Ca2+]i. Benidipine possesses membrane stabilization properties in LPC-treated endothelial cells. It is speculated that the preservation of membrane fluidity by benidipine may play a role in the retainment of calcium mobilization. The present findings may provide new insights into the endothelial protective effects of benidipine.

Impact of intra-operative radiotherapy on evacuatory function following ultra-low anterior resection. A preliminary result of prospective randomized trial.

BACKGROUND/AIMS: Preoperative radiotherapy and/or chemotherapy have been reported as effective treatment for locally advanced low rectal carcinoma. However, recent follow-up studies represented severe postoperative evacuatory disorder, which annoys patients' quality of life. METHODOLOGY: The present study was a part of a randomized trial protocol comparing between intraoperative radiotherapy with pelvic autonomic nerve preservation and control group without radiation. Of these, 24 patients having sphincter preservation were followed in terms of their bowel function with questionnaire and anorectal manometry. RESULTS: In terms of background, patients' age, gender, depth of the tumor invasion and lymph node metastasis showed no significant difference between the groups. After stoma closure, frequency of bowel movement was increased and incontinence scores worsened in both groups. However, no significant difference was noted between the groups, postoperatively. Regarding anorectal manometry, postoperative anal sphincter tones were stable compared even to pre-operative findings and no difference was noted between the groups postoperatively. Anal canal length and sensory factor were stable and no difference between the groups. Volumetric factors such as rectal capacity and maximum tolerable volume were also stable even after ultra-low anterior resection. CONCLUSIONS: Intraoperative radiotherapy did not affect adversely on evacuatory function following ultra-low anterior resection in the early postoperative period. Long-term follow-up is warranted.

Intraoperative radiotherapy for oncological and function-preserving surgery in patients with advanced lower rectal cancer.

BACKGROUND: Pelvic autonomic nerve preservation (PANP) with lateral lymph node dissection (LLND) has been introduced in rectal cancer surgery in Japan; however, its indication has not been standardized yet. MATERIALS AND METHODS: Forty-four patients with advanced lower rectal cancer were randomized to either the standard treatment group (control group) or the intraoperative radiotherapy (IORT) group. All patients underwent potentially curative resection of the rectum with total mesorectal excision. The control group underwent bilateral LLND and limited PANP. The IORT group underwent bilateral LLND, complete PANP, and IORT. Patients allocated to the IORT group received IORT to the bilateral preserved pelvic nerve plexuses. Patients' clinicopathologic parameters, postoperative complications, voiding function, and prognosis were compared between the two groups. RESULTS: Among 44 patients enrolled, three patients were excluded from the analysis, resulting in 19 patients in the IORT group and 22 patients in the control group. Patients' demographic and pathological parameters and postoperative complications were well balanced between the two groups. Oncological outcomes including overall and disease-free survival were also similar. Local recurrence was observed in one patient in each group. Among the 34 patients not complicated with intrapelvic abscess, the mean duration of urinary catheter indwelling was 8 days in the IORT group and 13 days in the control group (p = 0.055). In the long term, medication for urination was necessitated in four patients in the control group, whereas in none in the IORT group (p = 0.059). DISCUSSIONS: Oncological outcomes in the IORT group are equal to those in the control group, and voiding functions in the IORT group are superior to those in the control group. These results suggest that IORT may be useful to expand the indication of complete PANP with LLND for advanced lower rectal cancer.

Comparison of the antiatherosclerotic effects of dihydropyridine calcium channel blocker and HMG-CoA reductase inhibitor on hypercholesterolemic rabbits.

The antiatherosclerotic effects of the dihydropyridine-type calcium channel blocker, benidipine hydrochloride (benidipine), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pravastatin sodium (pravastatin), were compared in hypercholesterolemic rabbits. Male, New Zealand white rabbits were fed a 0.5% cholesterol diet. Pravastatin (10 mg/kg) or benidipine (10 mg/kg) was orally administered once daily after start of feeding. After 8 weeks of cholesterol feeding, serum cholesterol was increased and endothelial function of thoracic aorta was impaired. Pravastatin prevented elevation of serum cholesterol and aortic tunica intima hyperplasia. Although benidipine had little effect on serum cholesterol, it significantly inhibited aortic tunica intima hyperplasia and impairment of endothelial function. Expression levels of the vascular cell adhesion molecule-1 (VCAM-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mRNA in aorta of hypercholesterolemic rabbit were higher than those of normal rabbit. Benidipine significantly prevented upregulation of VCAM-1 mRNA expression and showed a tendency to inhibit elevation of LOX-1 mRNA expression. Pravastatin significantly prevented upregulation of both VCAM-1 and LOX-1 mRNA expression. The results demonstrate that pravastatin inhibits increase of serum cholesterol and vascular dysfunction in hypercholesterolemic rabbit. Benidipine is effective in preventing vascular hyperplasia without altering serum cholesterol levels and this may be due to inhibition of expression of VCAM-1.

Multi-institutional study of radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma: 84 subjects of a population of more than 5,000.

PURPOSE: Most patients who had any recurrent sites of cancer have been considered to be in their last stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence. Furthermore, for patients who had only one recurrent region, radiation therapy could play an important role. As for uterine cervical carcinoma, the most common recurrent site other than the pelvis is the para-aortic lymph nodes. Thus we conducted the current study. PATIENTS AND METHODS: Between 1994 and 2003, more than 5,000 uterine cervical carcinoma patients were treated with curative intended treatments at 13 Japanese hospitals. Of these patients, 84 developed para-aortic lymph node recurrence as the only site of initial tumor progression. These patients were treated with external beam radiation therapy. Radiation therapy protocol was as follows: 1.7-2.0 Gy per fraction, 5 fractions per week, and the mean total dose was 50.8 Gy (25-60 Gy). RESULTS: Three- and 5-year overall survival rates of all patients were 49.5% and 31.3%, respectively. Stratified by symptom sign, 3-year overall survival rate of symptom positive was 27.6% and those of the negative was 56.1% (p = 0.018). Three-year overall survival rates of the total dose > or =51 Gy and that of < or =50 Gy were 58.0% and 42.8%, respectively (p = 0.07). As for morbidity, no patients received Grade 3 or greater late toxicity. CONCLUSIONS: The current study suggested that radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma could have a significant impact on survival.

Effects of combination of angiotensin receptor blocker and calcium channel blocker on ox-LDL levels and cardiovascular dysfunction in Dahl rats.

In an effort to assess the cardiovascular benefits of combined angiotensin receptor blockage and calcium channel antagonism, we assessed the chronic effects of the angiotensin type 1 receptor blocker candesartan, the calcium channel blocker benidipine, and the use of a combination therapy in Dahl salt-sensitive (DS) rats. DS rats receiving a high salt diet were treated with either benidipine (4 mg/kg), candesartan (1 mg/kg) or both. Rat blood pressure was measured using a tail-cuff method. Following 12 weeks, the effect on heart weight, plasma-oxidized low-density lipoprotein (ox-LDL) level, endothelium-dependent vasorelaxation, and histology of the heart and aorta was assessed. Blood pressure, heart weight and plasma ox-LDL levels increased, while endothelium-dependent vasorelaxation decreased in the DS rats. Candesartan and benidipine inhibited the increase in blood pressure and heart weight, and the decrease in endothelium-dependent vasorelaxation. The use of benidipine alone or a combination significantly inhibited the increase in ox-LDL levels, whereas candesartan alone had no significant effect on ox-LDL levels. The present findings indicate that, if the monotherapy using ARB could not achieve adequate control of blood pressure, the combination therapy with ARB and benidipine provides the additional reductions in hypertension and cardiac hypertrophy. Moreover, the combination therapy inhibits cardiovascular dysfunction and ox-LDL levels more effectively than use of ARB alone. These results contribute to the possibility of lowering ox-LDL levels as a means of enhancing cardiovascular protection.

Frequency and characteristics of isolated para-aortic lymph node recurrence in patients with uterine cervical carcinoma in Japan: a multi-institutional study.

OBJECTIVE: In most cases of uterine cervical carcinoma recurrence, the first site of distant metastasis or recurrence is reported to be the para-aortic region. Some reports have demonstrated that, in cases of isolated para-aortic lymph node recurrence treated by radiation therapy, patients survived for a long period, which suggests that isolated para-aortic lymph node recurrence in uterine cervical carcinoma is a regional disease rather than systemic disease. Determining the predictive characteristics of isolated para-aortic lymph node recurrence in patients at the time of the initial treatment for primary uterine cervical carcinoma is important, so we conducted the current multi-institutional study. PATIENTS AND METHODS: Patients (n=3137) with uterine cervical carcinoma of stages Ia to IVa were treated in twelve Japanese hospitals between 1994 and 2003. The current study investigated the frequency and characteristics of patients with isolated para-aortic lymph node recurrence as well as the characteristics of clinical stage, histopathology, serum squamous cell carcinoma antigen level, the treatment method at the initial treatment, the duration between the initial treatment and the recurrence, and the serum squamous cell carcinoma antigen level at the recurrence. RESULTS: Of the 3137 patients with uterine cervical carcinoma in stages Ia-IVa, 67 (2.1%) experienced recurrence in isolated para-aortic lymph nodes. Stratified by clinical stage, none of the 613 patients with stage Ia experienced recurrence in isolated para-aortic lymph nodes. However, recurrence was experienced by 14 (1.4%) of the 966 patients with stage Ib, 7 (3.5%) of the 199 patients with stage IIa, 14 (2.3%) of the 613 patients with stage IIb, 1 (2.1%) of the 48 patients with stage IIIa, 26 (4.6%) of the 538 patients with stage IIIb, and 5 (5%) of the 100 patients with stage IVa. The mean duration time between the initial treatment and isolated para-aortic recurrence was 20 months (range, 2-49 months). The correlations between duration time and the clinico-pathological factors (clinical stage, histopathology, serum squamous cell carcinoma antigen level, and treatment method) at the initial treatment were investigated. No statistically significant factors have been revealed in the current study. CONCLUSIONS: The frequency of isolated para-aortic lymph node recurrence was 2.1% and increased with increasing clinical stage at the initial treatment (stage IVa: 5%) in the current study.

Results of radiation therapy for superficial esophageal cancer using the standard radiotherapy method recommended by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group.

BACKGROUND: Superficial esophageal cancer (SEC) is defined as esophageal cancer limited to the submucosal layers, including mucosal cancer and submucosal cancer, and is squamous cell carcinoma in most patients. In 2000, the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group for SEC published a consensus guideline of standard radiotherapy methods. In this study, the interim treatment outcomes of SEC patients, who had received radiation therapy following the standard radiotherapy methods, were investigated. PATIENTS AND METHODS: From 2000 to 2003, a total of 141 SEC patients were treated in 24 institutions in Japan. RESULTS: The 1-, 2- and 3-year survival rates were 95%, 90% and 90%, respectively, for patients with mucosal cancer and 90%, 81% and 70%, respectively, for patients with submucosal cancer. The overall survival was better in patients who had undergone chemotherapy than in patients who had received radiation therapy alone, though the difference was not statistically significant. The clinical target volume (CTV) did not influence overall survival and intracavitary irradiation did not influence the local control rate in either patients with mucosal or submucosal cancer. Radiation-induced esophageal ulcer was not observed in this series. CONCLUSION: The standard radiotherapy methods are safe and effective for treating SEC. However, the usefulness of chemotherapy and intracavitary irradiation and the optimal setting of the CTV should be clarified by future randomized trials.