Risk factors for survival and local recurrence after particle radiotherapy for single small hepatocellular carcinoma.

BACKGROUND: Particle radiotherapy is a novel treatment for malignant tumours. The present study aimed to evaluate risk factors for overall survival and local control after particle radiotherapy of single small hepatocellular carcinoma (HCC), and to identify suitable candidates for this treatment. METHODS: All patients with a single HCC smaller than 5 cm in diameter treated by particle radiotherapy between 2001 and 2008 were identified retrospectively from a prospectively collected database. Clinical outcomes and prognostic factors were analysed. RESULTS: A total of 150 patients were included. Five-year overall survival and local control rates were 50.9 and 92.3 per cent respectively. Multivariable analysis revealed that several factors, including age and Child-Pugh classification, significantly influenced overall survival. Proximity to the digestive tract and Child-Pugh classification were independent risk factors for local recurrence. Other tumour factors including size, gross classification, previous treatment, macroscopic vascular invasion, and tumour location in relation to the diaphragm and large vessels did not influence local control rate. CONCLUSION: Particle radiotherapy seems safe and effective, and may be a novel treatment for small HCC. Recurrences are more frequent when the tumour is located close to the gut.

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation.

Disruption of intestinal homeostasis can lead to inflammatory bowel diseases endowed susceptibility genes and environmental factors affecting intestinal accumulation and activation of colitogenic phagocytes. Plasmacytoid dendritic cells (pDCs) are immune cells that had been proposed to control innate and adaptive immunity through the massive secretion of type I interferon (IFN-I). However, the contribution of pDCs to the progression of intestinal inflammation remains unclear. Here we show a critical role of pDCs in the initiation of acute colonic inflammation using T-cell-independent acute colitis model with a selective ablation of pDCs. Although pDCs accumulated in the inflamed colon upon mucosal injury, deficiency of pDCs attenuated the development of acute colitis independent of IFN-I signaling, accompanied by the diminished colonic production of proinflammatory cytokines. Furthermore, deficiency of pDCs impaired the mobilization of colitogenic phagocytes into the inflamed colon possibly mediated by the abrogated mucosal production of C-C chemokine receptor 2 ligand. Thus, our findings highlight a critical role of pDCs in the induction of the colonic inflammation that regulates the colonic accumulation of inflammatory phagocytes leading to the initiation and exacerbation of acute colitis, and they may serve a key role in controlling gut mucosal immune homeostasis.

Scatter factors in proton therapy with a broad beam.

In the absence of a predictor of beam output in proton therapy using a broad beam, the beam output is obtained for individual treatments by calibrating the beam monitors. The calibration is carried out under conditions similar to the treatment conditions but with a phantom instead of the patient. However, the dose in the phantom a priori differs from that in the patient. In order to deliver the accurate dose, a correction factor has been introduced to correct the difference. This correction factor is referred to as a scatter factor in an analogy with photon therapy, and is defined as the ratio of the dose at the prescription point in the patient to the dose at the calibration point in the phantom. Under the calibration conditions at Hyogo Ion Beam Medical Center (HIBMC), the range compensator and the collimator, which are usually required in proton therapy with a broad beam, are not used. Therefore the scatter factor includes the effects of the devices as well as the difference between the dose in the patient and that in the phantom. We have developed an estimator using a dose calculation based on the pencil beam algorithm and implemented it in a treatment planning system (TPS) for clinical use. This estimator estimates the scatter factor by calculating the ratio of the doses under the same conditions in the TPS. In order to evaluate the performance of the estimator, demonstrations were carried out for cases with measurable outcomes using a gantry nozzle at HIBMC. We observed 2-3% differences between the measurements and the estimations. These differences were considered to result from the limitations of the dose calculation algorithm in modelling the beam and the patient.

Diminished melatonin secretion in the elderly caused by insufficient environmental illumination.

The pineal hormone melatonin has some circadian regulatory effects and is assumed to have a close relation with sleep initiation and maintenance. Many previous reports have described age-related decreases in melatonin levels, especially in elderly insomniacs (EIs), which may act as causal or exacerbating factors in sleep disturbances in the elderly. Ten elderly residents with psychophysiological insomnia (mean age, 74.2 yr), 10 healthy residents of the same home [elderly control (EC) group; mean age, 72.7 yr], and 10 healthy young control subjects (mean age, 20.9 yr) living at home participated in this study. The elderly persons, especially the EIs, were exposed to significantly less environmental light and simultaneously suffered from significantly diminished nocturnal melatonin secretion. Supplementary exposure to 4 h (1000 to 1200 h, 1400 to 1600 h) of midday bright light in the EI group significantly increased melatonin secretion to levels similar to those in the young control group without circadian phase-shifting. There was a tendency for the magnitude of the increase in nocturnal melatonin secretion stimulated by bright light to parallel amelioration of sleep disturbances in these subjects. The present findings suggest that we need to pay attention to elderly individuals who suffer under conditions of poor environmental light resulting in disorganized circadian rhythms, including the sleep-wake cycle.

High sialic acid reactivity of sugar chain structure Lewis-X in patients with mental retardation.

It has been reported that platelet-derived growth factor B-chains homodimer (PDGF-BB) improves learning function of mice, and that sugar chain structure Lewis-X of N-glycosylated glycoprotein promotes PDGF-BB secretion from platelets. Based on these findings, we assumed that learning dysfunction in some patients with mental retardation might be due to abnormality in PDGF-BB metabolism and/or Lewis-X structure. No difference in the reactivity of PDGF-BB and Lewis-X was found between the serum of patients with mental retardation and that of normals. But sialic acid reactivity of the Lewis-X fraction in some patients was remarkably higher than that in other patients and in normals. These findings suggest that sialic acids in the Lewis-X fraction may have a relation to one of the causes of learning dysfunction in these patients.

Polysomnographic characteristics of healthy elderly subjects with somnambulism-like behaviors.

We compared the sleep characteristics of seven healthy elderly people complaining of nocturnal somnambulism-like behaviors with those of 14 age-matched healthy elderly people who had never shown such behavior. Polysomnographic data revealed the appearance of "Stage 1-REM with tonic electromyographic (EMG) activity" sometimes accompanied by abnormal behavior in the first group, but the sleep architecture and parameters showed no significant difference between the two groups except for higher REM density in the first group. "Stage 1-REM with tonic EMG," observed in the first group was considered equivalent to REM sleep without muscle atonia. It is suggested that both reduced activity of tonic phenomena (muscle atonia) and increased activity of phasic phenomena (higher REM density) of REM sleep are essential for the induction of somnambulism-like behaviors during sleep in healthy elderly subjects.

Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer's type with disturbed sleep-waking.

BACKGROUND: There is growing evidence that the dysregulation of circadian rhythms may play an important role in irregular sleep-waking in demented elderly. In this study, we investigated daily variation of the pineal hormone melatonin, which has been reported to possess hypnogenic and synchronizing effects, in patients with senile dementia of Alzheimer's type. METHODS: Serum melatonin secretion rhythms in inpatients with senile dementia of Alzheimer's type (SDAT group, n = 10, average age = 75.7 years) with disturbed sleep-waking and nondemented elderly (ND group, n = 10, age = 78.3 years) without clinical sleep disorders in the same facility were monitored under a dim light condition without excessive physical exercise. RESULTS: The SDAT group showed a significantly higher degree of irregularities in actigraphically recorded rest-activity (R-A) rhythm during the 7-day baseline period compared with the ND group. The SDAT group simultaneously showed significantly reduced amplitude, larger variation of peak times, and diminished amount of total secretion in the melatonin secretion rhythm compared with the ND group. There were significantly positive correlations between the severity of R-A rhythm disorder and the reduced amplitude as well as diminished amount of total melatonin secretion. CONCLUSIONS: The SDAT patients with disturbed sleep-waking possessed melatonin secretion rhythm disorders that may play an important role in irregular sleep-waking in demented elderly.

Different manifestations of circadian rhythms in senile dementia of Alzheimer's type and multi-infarct dementia.

Using an actigraph and a long-term body temperature (BT) monitoring system, we simultaneously monitored rest-activity (R-A) and BT rhythms in patients with senile dementia of Alzheimer's type (SDAT; n = 20) or multi-infarct dementia (MID; n = 21) for 5-7 consecutive days. The SDAT group exhibited a well-organized BT rhythm with significantly higher amplitude compared with the MID group. The SDAT group also showed significant positive correlation between the total daily activity as well as percentage of nighttime activity and the degree of dementia, while no such tendency was observed in the MID group. The different properties of the biological rhythm disorders among the SDAT and MID groups possibly underlie their sleep and behavioral disorders.

High-dose-rate intraluminal brachytherapy (HDRIBT) for esophageal cancer.

High-dose-rate intraluminal brachytherapy (HDRIBT) for patients with esophageal cancer has been performed with and without external radiotherapy (ERT) in our department since May 1980. From May 1980 through December 1986, 92 patients with esophageal squamous cell carcinoma were treated with HDRIBT following ERT. These patients were divided into a limited disease (LD) group and an extensive disease (ED) group. Complete response and partial response rates after treatment were 48% and 38% in the LD group, and 9% and 65% in the ED group, respectively. The median survival time and 2-year survival rate was 13 months and 39% in the LD group, and 8.5 months and 7% in the ED group, respectively. The 5-year survival was 17% in the LD group. HDRIBT without ERT was used to treat six patients with small, superficial esophageal squamous cell carcinoma from August 1987 through July 1988. No patients were candidates for surgery because of coexisting medical problems. Each patient received 6 Gy per treatment, twice weekly with a total of 24 Gy; five of the six patients were treated on an outpatient basis. The tumor had disappeared completely in all six patients at the time of first follow-up endoscopic study less than 1 month after treatment, and no local recurrence had occurred after 11 to 22 months in five of the six patients. Five of the six patients were alive after 11 to 22 months, and one died with mediastinal metastasis at 15 months.

Radiotherapy for carcinoma of the esophagus in patients aged eighty or older.

Between 1980 and 1988, 206 patients with esophageal cancer were treated initially with radiotherapy. The patients were classified into three groups according to age. Ninety-four patients aged 43-69 years comprised Group A, 83 patients aged 70-79 years comprised Group B, and 29 patients aged 80-86 years comprised Group C. There were no statistically significant differences in background factors between Groups A, B, and C, except for the sex ratio. The male:female ratio was 7.5:1 in Group A, 3.9:1 in Group B, and 1.9:1 in Group C, with the difference between Groups A and C being statistically significant (p less than 0.05). High-dose-rate intracavitary irradiation (HDRII) with or without external irradiation (EI) was performed in 64%, 69%, and 83% of the patients from Groups A, B, and C, respectively. Patients in Groups A, B, and C achieved CR in 23%, 24%, and 34% of cases following radiotherapy. Two- and 5-year survival rates were 16.7% and 6.7% in Group A, 17.2% and 6.0% in Group B, and 27.1% and 20.3% in Group C. No significant differences were found in the patterns of failure and in the radiation-induced injuries between the three groups. Our data suggested that radiotherapy was the treatment of first choice for patients 80 years old and older.

Multi-institutional randomized trial of external radiotherapy with and without intraluminal brachytherapy for esophageal cancer in Japan. Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group.

PURPOSE: With the aim of improving the results of treatment of esophageal cancer, we designed this multi-institutional, randomized trial to establish the optimal irradiation method in radical radiation therapy for esophageal cancer by clinically evaluating external irradiation alone and in combination with intraluminal brachytherapy. METHODS AND MATERIALS: The study population consisted of patients with squamous cell carcinoma who were expected to be successfully treated with radical radiation therapy. The patients who could be given intraluminal brachytherapy at the end of external irradiation of 60 Gy were stratified into 2 groups. Patients assigned to receive external irradiation alone received boost irradiation of 10 Gy/week on a schedule similar to the previous one, and with the same or smaller irradiation field. Intraluminal brachytherapy was performed, as a rule, with the reference dose point set at a depth of 5 mm of the esophageal submucosa, and a total of 10 Gy was irradiated at a daily dose of 5 Gy, on a once-weekly schedule with low-dose-rate or high-dose-rate brachytherapy equipment. RESULTS: A total of 103 patients were registered, 94 of whom were analyzable, with 8 ineligible, and 1 for whom complete information was unavailable. The overall cumulative survival rate was 20.3% at 5 years. The cause-specific survival rate was 31.8% at 5 years. The cause-specific survival rate at 5 years was 27% in the external irradiation alone group and 38% in intraluminal brachytherapy combined group. There was no significant difference between the 2 groups (p = 0.385). However, in the patients with 5 cm or less tumor length, the cause-specific survival rate was 64% at 5 years in the intraluminal brachytherapy combined group, which showed a significant improvement over 31.5% in the external irradiation alone group (p = 0.025). In the patients with Stage T1 and T2 disease, cause-specific survival rates tended to be better in the intraluminal brachytherapy combined group than in the external irradiation alone group (p = 0.088). In the patients with more than 5 cm tumor length or Stage T3-4 disease, there were no significant differences between the two groups by treatment methods (p = 0.290). The incidence of early and late complications did not differ according to whether intraluminal brachytherapy was used. CONCLUSION: For the purpose of establishing the usefulness of intraluminal brachytherapy, further prospective randomized studies are necessary to evaluate the efficacy in tumors with short length and those with shallow invasion, or to assess the usefulness of intraluminal brachytherapy, as additional irradiation in large advanced tumors have been shown to have disappeared by diagnostic imaging after chemoradiotherapy with 60 Gy/6w external irradiation.

Clinical outcomes of orbital irradiation combined with or without systemic high-dose or pulsed corticosteroids for Graves' ophthalmopathy.

PURPOSE: To evaluate the outcomes of orbital irradiation with or without high-dose or pulsed corticosteroids in patients with Graves' ophthalmopathy (GO). METHODS AND MATERIALS: One hundred and twenty-one patients with moderate to severe GO who received orbital irradiation from 1987 to 1997 were retrospectively analyzed. A total dose of 20 Gy in 10 fractions was delivered to the bilateral retrobulbar volume. Eighty-six patients were treated in combination with high-dose or pulsed corticosteroids and irradiation. Univariate and multivariate analyses were performed to assess the prognostic variables. RESULTS: The median follow-up period was 26 months. The overall clinical response was evaluated as excellent in 17 patients (14%), good in 65 (54%), fair in 31 (25%), no response in 7 (6%), and worse in 1 (1%). The best responses were noted for soft-tissue signs, extraocular muscle involvement, and sight loss, while a limited response was noted for proptosis. Multivariate analysis revealed that the use of high-dose corticosteroid or pulsed corticosteroids, female gender, and a shorter duration of ophthalmopathy before radiotherapy were significantly correlated with favorable outcomes. No long-term complications related to radiotherapy were observed. CONCLUSION: Orbital irradiation combined with high-dose or pulsed corticosteroids is an effective treatment for moderate to severe GO, especially in cases with major manifestations of soft-tissue signs, extraocular muscle impairment, or sight loss.

Dosimetric predictors of radiation esophagitis in patients treated for non-small-cell lung cancer with carboplatin/paclitaxel/radiotherapy.

PURPOSE: To establish dosimetric predictors of radiation esophagitis (RE) in patients treated with a combination of carboplatin, paclitaxel, and radiotherapy. METHODS AND MATERIALS: Three-dimensional radiotherapy plans of 26 patients with non-small-cell lung cancer who received 50-60 Gy of radiotherapy concurrently with weekly administration of carboplatin (AUC 2) and paclitaxel (40-45 mg/m(2)) were reviewed in conjunction with RE. The factors analyzed included the following: percentages of organ volumes receiving >40 Gy (V40), >45 Gy (V45), >50 Gy (V50), and >55 Gy (V55); the length of esophagus (total circumference) treated with >40 Gy (LETT40), >45 Gy (LETT45), >50 Gy (LETT50), and >55 Gy (LETT55); the maximum dose in the esophagus (Dmax); and the mean dose in the esophagus (Dmean). Data were obtained on the basis of superposition algorithm. RESULTS: All factors except Dmax showed statistical correlation with RE. Good correlations were shown between RE and LETT45 (rho = 0.714) and V45 (rho = 0.686). CONCLUSIONS: LETT45 and V45 appear to be useful dosimetric predictors of RE. It is also suggested that Dmax does not predict RE.

Radiotherapy of esophageal carcinoma: role of high-dose-rate intracavitary irradiation.

A total of 119 patients with squamous cell carcinoma of the esophagus who were seen during a 10-year period were analyzed retrospectively in terms of survival rate and local control rate in relation to treatment method and disease stage. All patients were treated with radiotherapy alone: 43 patients were treated with external irradiation plus high-dose-rate intracavitary irradiation (Group 1), 46 with external irradiation only, to 50 Gy or more (Group 2), and 30 with external irradiation to less than 50 Gy (Group 3). All patients of Group 3 died within 8 months (mean 3.5 months) after the initiation of radiotherapy. In Group 1, the 2-year survival rate was 27.9% for the patients in all disease stages and 44.0% for those in Stage 1 and Stage 2 in contrast to Group 2, with a 2-year survival rate of 4.3% for the patients in all stages and 9.1% for those in Stage 1 and 2. The local control rate was 62.8% in Group 1, significantly higher than 19.6% in Group 2. It is concluded that high-dose-rate intracavitary irradiation following external irradiation is an effective treatment modality for esophageal carcinoma, especially in a limited stage.

External beam radiotherapy alone or combined with high-dose-rate intracavitary irradiation in the treatment of cancer of the esophagus: autopsy findings in 35 cases.

Autopsy findings of 35 patients, treated with radiotherapy for an esophageal carcinoma, were reviewed. A residual tumor was seen at autopsy in 7 of 16 patients treated with high-dose-rate intracavitary irradiation following external irradiation, in 13 of 14 patients treated with external irradiation of 50 Gy or more, and in all 5 patients treated with external irradiation of less than 50 Gy. Incidence on lymph node metastasis, at autopsy, did not differ between the combined radiotherapy group and the external irradiation groups. However, it correlated with disease stage. It was observed in 11 of 17 patients with Stage 1 and Stage 2 disease, compared to 17 of 18 patients with Stage 3 and Stage 4 disease. Distant organ metastasis, at autopsy, also did not differ between the combined radiotherapy group and the external irradiation groups, and was also correlated with disease stage. It was found in 8 of 17 patients of the patients with Stage 1 and Stage 2 disease, compared to all 18 patients with Stage 3 and Stage 4 disease. Mean (average) survival was different between the patients treated by high-dose-rate intracavitary irradiation following external irradiation and those treated by external irradiation alone; 11.3 months in the 16 patients treated with combined therapy, as compared to 6.9 months in the 14 patients who received external irradiation of 50 Gy or more, and 3.6 months in the 5 patients who received external irradiation of less than 50 Gy.

Esophageal ulceration following high-dose-rate intraluminal brachytherapy for esophageal cancer.

Prophylaxis of esophageal ulceration was studied in 78 esophageal carcinoma patients after high-dose-rate intraluminal brachytherapy. Before the standard treatment regimen of radiotherapy was established, 15/17 patients developed ulcers. This decreased to 19/38 with the standard treatment regimen, and to 9/23 when antiulcer therapy was added (p < 0.01).

High-dose-rate intraluminal brachytherapy for esophageal cancer: 10 years experience in Hyogo College of Medicine.

From May 1980 through December 1989, 148 patients with thoracic esophageal cancer were treated with high-dose-rate intraluminal brachytherapy (HDRIBT) following external radiotherapy (ERT). The standard treatment protocol was 60 Gy/6 weeks of ERT and 12 Gy/1 week of HDRIBT. The patients were divided into two groups according to disease stage. Sixty-six patients had limited disease (LD), and 82 patients had extensive disease (ED). The 2-year survival rate was 37% in LD group, and 7% in ED group. The 5-year survival rate of LD group was 18%. The 1- and 2-year actuarial local control rate was 66% and 64% in LD group, and 49% and 45% in ED group, respectively. In the total patients, ulceration, stricture, and fistula were found in 42 (28%), 15 (10%) and 6 (4%) patients, respectively; however, major complication defined as one resulting in a second hospitalization or requiring surgical intervention was 3 of the 42 patients with ulceration, 1 of the 15 patients with stricture, and all of the six patients with fistula. As to cause of death, local failure, local failure with distant metastasis, distant metastasis, intercurrent disease, and unknown reason was 14, 6, 15, 16 and 0 in LD group, and 13, 24, 30, 9 and 1 in ED group, respectively. The technique and method of combined treatment are described in detail.

High-dose-rate intraluminal brachytherapy for bile duct carcinoma after surgery.

Five patients with recurrent or residual bile duct carcinoma after surgery were treated with high-dose-rate intraluminal brachytherapy (HDRIBT) using a remote afterloader. External radiotherapy was also given in three cases. HDRIBT is considered to be an effective mode of radiotherapy for residual or recurrent bile duct tumors.

Endoscopic findings of radiation esophagitis in concurrent chemoradiotherapy for intrathoracic malignancies.

BACKGROUND AND PURPOSE: The incidence and extent of radiation esophagitis were assessed endoscopically in patients treated with concurrent chemoradiotherapy. PATIENTS AND METHODS: Eighty-two patients who received thoracic radiotherapy for lung, thymic, or esophageal cancer were investigated endoscopically from July 1991 to the end of 1997. Among them, 23 esophageal cancer patients were treated with radiation alone, and the others were treated with concurrent chemoradiotherapy. Esophageal endoscopy was performed during or just after radiotherapy. The presence of radiation esophagitis was assessed and assigned an endoscopic score (i.e. grade 0 for normal, 1 for erythema, 2 for erosion or sloughing, 3 for ulcer, hemorrhage, or stricture). The symptomatic grade was assessed using the RTOG (Radiation Therapy Oncology Group) acute radiation morbidity score. RESULTS: A correlation was seen between endoscopic and RTOG scores. However, even some patients with RTOG grade 0 to 1 had endoscopic grade 3 esophagitis. Endoscopic grade 3 was observed in 16 (27.1%) patients in the concurrent chemoradiotherapy group, whereas it did not occur in any patient in the radiation alone group (P=0.004). CONCLUSIONS: Our results suggest that (1) RTOG score correlates closely to esophageal mucosal damage, and (2) more severe esophagitis occurs in those undergoing concurrent chemoradiotherapy than those undergoing radiotherapy alone [corrected].

Therapeutic effects of mazindol on narcolepsy.

Mazindol, a new anorexiant, was administered at a daily dose of 0.5-4 mg to 10 narcoleptic subjects aged 21-63 years. All the patients suffered from sleep attacks and one or more of the REM-related symptoms. Eight patients received only mazindol, and two patients received mazindol simultaneously with clomipramine or flurazepam. Sleep attacks were reduced in nine patients, and cataplexy was also markedly reduced in four patients. Mild adverse reactions were reported in six patients: two patients complained of headache, four of nocturnal sleep disturbance, and two of reduced appetite. Most side effects disappeared spontaneously or after dose reduction, and none of the patients had to stop medication. The results suggest that mazindol is effective not only for sleep attacks but also for cataplexy. It is recommended as a treatment for mild cases of narcolepsy.