Individual response of humans to ionising radiation: governing factors and importance for radiological protection.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

Usefulness of 11C-methionine-PET for predicting the efficacy of carbon ion radiation therapy for head and neck mucosal malignant melanoma.

The aim of this study was to determine whether l-methyl-[11C]-methionine (MET) positron emission tomography (PET) allows the prediction of outcomes in patients with head and neck mucosal malignant melanoma treated with carbon ion radiation therapy (CIRT). This was a retrospective cohort study involving 85 patients who underwent a MET-PET or MET-PET/computed tomography (CT) examination before and after CIRT. MET uptake in the tumour was evaluated semi-quantitatively using the tumour-to-normal tissue ratio (TNR). Local recurrence, metastasis, and outcome predictions were studied in terms of TNR before CIRT (TNRpre), TNR after CIRT (TNRpost), and the TNR change ratio. Kaplan-Meier curves revealed significant differences between patients with higher TNRpre values and those with lower TNRpre values in regard to local recurrence, metastasis, and outcome (log-rank test P<0.0001 for all three). There were also significant differences in metastasis rates and outcomes between patients with higher and lower TNRpost values (log-rank test P=0.0105 and P=0.027, respectively). The Cox proportional hazards model revealed TNRpre to be a factor significantly influencing the risk of local recurrence (hazard ratio (HR) 29.0, P<0.001), risk of metastasis (HR 2.67, P=0.024), and the outcome (HR 6.3, P<0.001). MET-PET or MET-PET/CT is useful for predicting the outcomes of patients with head and neck mucosal malignant melanoma treated with CIRT.

Influence of nuclear interactions in body tissues on tumor dose in carbon-ion radiotherapy.

PURPOSE: In carbon-ion radiotherapy treatment planning, the planar integrated dose (PID) measured in water is applied to the patient dose calculation with density scaling using the stopping power ratio. Since body tissues are chemically different from water, this dose calculation can be subject to errors, particularly due to differences in inelastic nuclear interactions. In recent studies, the authors proposed and validated a PID correction method for these errors. In the present study, the authors used this correction method to assess the influence of these nuclear interactions in body tissues on tumor dose in various clinical cases. METHODS: Using 10-20 cases each of prostate, head and neck (HN), bone and soft tissue (BS), lung, liver, pancreas, and uterine neoplasms, the authors first used treatment plans for carbon-ion radiotherapy without nuclear interaction correction to derive uncorrected dose distributions. The authors then compared these distributions with recalculated distributions using the nuclear interaction correction (corrected dose distributions). RESULTS: Median (25%/75% quartiles) differences between the target mean uncorrected doses and corrected doses were 0.2% (0.1%/0.2%), 0.0% (0.0%/0.0%), -0.3% (-0.4%/-0.2%), -0.1% (-0.2%/-0.1%), -0.1% (-0.2%/0.0%), -0.4% (-0.5%/-0.1%), and -0.3% (-0.4%/0.0%) for the prostate, HN, BS, lung, liver, pancreas, and uterine cases, respectively. The largest difference of -1.6% in target mean and -2.5% at maximum were observed in a uterine case. CONCLUSIONS: For most clinical cases, dose calculation errors due to the water nonequivalence of the tissues in nuclear interactions would be marginal compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response. In some extreme cases, however, these errors can be substantial. Accordingly, this correction method should be routinely applied to treatment planning in clinical practice.

Phase I/II trial of definitive carbon ion radiotherapy for prostate cancer: evaluation of shortening of treatment period to 3 weeks.

BACKGROUND: The purpose of this study was to evaluate the feasibility of a new shortened 3-week treatment schedule of carbon ion radiotherapy (CIRT) for prostate cancer. METHODS: Beginning in May 2010, patients with T1b-T3bN0M0, histologically proven prostate adenocarcinoma were enrolled in the phase II trial of CIRT. Patients received 51.6 GyE in 12 fractions over 3 weeks (protocol 1002). The primary end point was defined as the incidence of late adverse events that were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0. Biochemical failure was determined using the Phoenix definition (nadir +2.0 ng ml(-1)). RESULTS: Forty-six patients were enrolled, and all patients were included in the analysis. The number of low-, intermediate-, and high-risk patients was 12 (26%), 9 (20%), and 25 (54%), respectively. The median follow-up period of surviving patients was 32.3 months. Two patients had intercurrent death without recurrence, and the remaining 44 patients were alive at the time of this analysis. In the analysis of late toxicities, grade 1 (G1) rectal haemorrhage was observed in 3 (7%) patients. The incidence of G1 haematuria was observed in 6 (13%) patients, and G1 urinary frequency was observed in 17 (37%) patients. No ⩾G2 late toxicities were observed. In the analysis of acute toxicities, 2 (4%) patients showed G2 urinary frequency, and no other G2 acute toxicities were observed. CONCLUSIONS: The new shortened CIRT schedule over 3 weeks was considered as feasible. The analysis of long-term outcome is warranted.

Identification of serum miRNAs as novel non-invasive biomarkers for detection of high risk for early gastric cancer.

BACKGROUND: Many micro-RNAs (miRNAs) are differentially expressed in Helicobacter pylori-infected gastric mucosa and in gastric cancer tissue and previous reports have suggested the possibility of serum miRNAs as complementary tumour markers. The aim of the study was to investigate serum miRNAs and pepsinogen levels in individuals at high risk for gastric cancer both before and after H. pylori eradication. METHODS: Patients with recent history of endoscopic resection for early gastric cancer and the sex- and age-matched controls were enrolled. Serum was collected from subjects before or after eradication and total RNA was extracted to analyse serum levels of 24 miRNAs. Serum pepsinogen (PG) I and II levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: Using miR-16 as an endogenous control, the relative levels of miR-106 and let-7d before and after H. pylori eradication and miR-21 after eradication were significantly higher in the high-risk group than in the controls. H. pylori eradication significantly decreased miR-106b levels and increased let-7d only in the control group. After eradication, the combination MiR-106b with miR-21 was superior to serum pepsinogen and the most valuable biomarker for the differentiating high-risk group from controls. CONCLUSION: Serum miR-106b and miR-21 may provide a novel and stable marker of increased risk for early gastric cancer after H. pylori eradication.

Total spondylectomy following carbon ion radiotherapy to treat chordoma of the mobile spine.

The main form of treatment of a chordoma of the mobile spine is total en bloc spondylectomy (TES), but the clinical results are not satisfactory. Stand-alone carbon ion radiotherapy (CIRT) for bone and soft-tissue sarcomas has recently been reported to have a high rate of local control with a low rate of local recurrence. We report two patients who underwent TES after CIRT for treating a chordoma in the lumbar spine with good medium-term outcomes. At operation, there remained histological evidence of viable tumour cells in both cases. After the combination use of TES following CIRT, neither patient showed signs of recurrence at the follow-up examination. These two cases suggest that CIRT should be combined with total spondylectomy in the treatment of chordoma of the mobile spine.

Dietary supplementation with 5-aminolevulinic acid modulates growth performance and inflammatory responses in broiler chickens.

The objective of this study was to investigate the effect of dietary supplementation with 5-aminolevulinic acid (5-ALA) on the immune system, inflammatory response, and growth performance of broiler chickens. The levels of cluster of differentiation 3 (CD3) mRNA in the spleens of chickens gradually increased with dietary 5-ALA concentration, while the expression levels of interleukin (IL)-2 decreased. Mitogen-induced proliferation of splenic mononuclear cells and blood mononuclear cell phagocytosis in chickens fed 0.001 and 0.01% 5-ALA-supplemented diets were significantly greater than in chickens fed a basal diet (control). Plasma thiobarbituric acid reactive substance (TBARS) concentration gradually increased along with 5-ALA supplement concentration. These results provide the first evidence that the use of dietary 0.001 and 0.01% 5-ALA supplementation induces the T-cell immune system via mild oxidative stress in chickens. Three hours after Escherichia coli lipopolysaccharide-induced immune stimulation, the levels of mRNA encoding pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor-like ligand 1A (TL1A), in chickens fed a 0.001% 5-ALA-supplemented diet were significantly lower than those in chickens exposed to other treatments. The plasma caeruloplasmin concentration in chickens fed a 0.001% 5-ALA-supplemented diet was significantly lower than in controls or in chickens fed diets supplemented with other concentrations of 5-ALA 24 h after injection of LPS. In addition, BW at 21 and 50 d of age was significantly higher in chickens fed a 0.001% 5-ALA-supplemented diet than in control chickens. The findings suggest that supplementation of diets with 0.001% 5-ALA could prevent the catabolic changes induced by immunological stimulation. These results show that 5-ALA might be useful as an immunomodulator to stimulate T-cells via mild oxidative stress in growing broiler chickens, thereby improving the growth performance.

Carbon ion radiotherapy for sacral chordoma.

The National Institute of Radiological Sciences in Chiba, Japan has offered carbon ion radiotherapy (CIRT) since 1994 using carbon ion beams generated by the heavy ion medical accelerator in Chiba (HIMAC). The total number of cases treated with the HIMAC exceeded 5000 in July 2009. Here, we present a retrospective analysis of CIRT for sacral chordoma. The study included 95 patients with medically unresectable sacral chordomas treated between 1996 and 2007. The median age of the patients was 66 years. Of all the patients, 84 had not been treated previously and 11 had a locally recurrent tumour following previous resection. The carbon ion dose ranged from 52.8 to 73.6 GyE (median 70.4 GyE) in a total of 16 fixed fractions over 4 weeks. The median clinical target volume was 370 cm(3). The overall survival rate at 5 years for all 95 patients was 86%, and follow-up survival time was 42 months (range, 13-112 months). The 5-year local control rate was 88% and median time to local failure was 35 months (range, 13-60 months). Of the 95 patients, 91% remained ambulatory with or without a supportive device. Two patients experienced severe skin or soft tissue complications requiring skin grafts. 15 patients experienced severe sciatic nerve complications requiring continuing medication. CIRT appears effective and safe in the management of patients with sacral chordoma and offers a promising alternative to surgery.

Carbon-ion radiotherapy: clinical aspects and related dosimetry.

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

Anti-parietal cell antibody and serum pepsinogen assessment in screening for gastric carcinoma.

BACKGROUND: Anti-parietal cell antibody is found in patients with Helicobacter pylori-positive gastritis and is related to atrophic gastritis and gastric carcinoma. AIM: To identify the characteristics of patients at high-risk for gastric carcinoma in terms of anti-parietal cell antibody and serum pepsinogen. PATIENTS AND METHODS: Subjects were 92 H. pylori-positive patients (54 men, 38 women; mean age, 57.9 years; range, 15-88 years). The serum concentrations of pepsinogen I and II were determined by radioimmunoassay, and the presence of anti-parietal cell antibody was assessed by enzyme-linked immunosorbent assay. Degrees of inflammation and atrophy in the corpus of the stomach were evaluated histologically. RESULTS: Patients were classified into four groups according to anti-parietal cell antibody status and pepsinogen I/II ratio. Anti-parietal cell antibody-negative/pepsinogen I/II-low patients had the highest risk for gastric carcinoma (prevalence of gastric carcinoma: 7/13=53.8%, odds ratio=7.6, 95% confidence interval, 1.2-48.0). Anti-parietal cell antibody titre was high when inflammation in the corpus was severe (p=0.06) and significantly low when atrophy in the corpus was severe (p=0.01). CONCLUSION: Our results showed that patients with a negative anti-parietal cell antibody titre and low pepsinogen I/II ratio are at high-risk for gastric carcinoma.

Effect of famotidine on recurrent bleeding after successful endoscopic treatment of bleeding peptic ulcer.

AIM: We investigated the effect of acid suppression therapy on recurrent bleeding after successful endoscopic treatment of bleeding peptic ulcer. METHODS: A total of 400 patients with bleeding peptic ulcer received either intravenous infusion of famotidine (40 mg/day) (n = 207, 163 males, 44 females, mean age 61.5 years) or drip infusion of omeprazole (40 mg/day; n = 193, 134 males, 59 females, mean age 59.8 years) after successful endoscopic treatment. The fasting duration, hospital stay, volume of transfused blood, incidence of rebleeding and mortality were compared between the two groups. RESULTS: The incidence of rebleeding did not differ significantly between the famotidine group (9%) and the omeprazole group (8%). The mean hospital stay was significantly shorter in the omeprazole group (18.4 days) than in the famotidine group (21.5 days, P = 0.009). However, there was no statistically significant difference in fasting duration, volume of transfused blood or mortality. CONCLUSION: Our findings indicate that intravenous infusion of famotidine after successful endoscopic treatment is equivalent to drip infusion of omeprazole for prevention of recurrent bleeding.

Effect of long-term half-dose famotidine therapy on corpus gastritis in peptic ulcer disease.

BACKGROUND: Recent studies showed that acid-suppressive therapy aggravates corpus gastritis in patients with Helicobacter pylori infection. AIM: The aim of this study was to evaluate the effect of famotidine, a histamine receptor antagonist on corpus gastritis in patients with peptic ulcer disease. METHODS: We enrolled 287 patients, 173 with duodenal ulcer and 114 with gastric ulcer and 100 patients with H. pylori-positive gastritis as control subjects. Patients with peptic ulcer were classified according to whether or not they received famotidine-maintenance therapy (20 mg/day) after primary treatment. At the time of endoscopy, biopsy specimens were obtained from the antrum and the corpus. The degrees of neutrophil and lymphocyte infiltration, atrophy and intestinal metaplasia were scored according to the updated Sydney System. RESULTS: The degrees of neutrophil infiltration and atrophy in the corpus were significantly less in patients with gastric ulcer or duodenal ulcer than in patients with H. pylori-positive gastritis (P < 0.01). Differences in the degrees of neutrophil infiltration and atrophy in the corpus between the non-maintenance group and the maintenance group were not significant. CONCLUSION: Long-term therapy with famotidine does not appear to lead to an increase in the incidence of corpus gastritis or corpus atrophy in patients with peptic ulcer disease.

Clinical features of gastric cancer discovered after successful eradication of Helicobacter pylori: results from a 9-year prospective follow-up study in Japan.

BACKGROUND: Eradication of Helicobacter pylori is expected to prevent the development of gastric cancer. However, gastric cancer is sometimes discovered after successful eradication of H. pylori. AIM: To conduct a prospective study to determine the clinical features of patients who underwent successful eradication and were later diagnosed with gastric cancer. METHODS: A total of 1787 patients (1299 males and 488 females; mean age, 58.2 years; range: 15-84) who underwent successful eradication therapy between April 1994 and March 2001 were our study subjects. RESULTS: Gastric cancer occurred at a rate of 1.1% (20 of 1787) during the follow-up period. Gastric cancer comprises six of 105 (5.7%) with early gastric cancer after endoscopic resection, 12 of 575 (2.1%) with gastric ulcer and two of 453 (0.4%) with atrophic gastritis. Gastric cancer did not develop in any patient with duodenal ulcer. All patients with gastric cancer had baseline severe atrophic gastritis in the corpus. CONCLUSION: Careful endoscopic examination is necessary even after successful eradication of H. pylori in patients with early gastric cancer or gastric ulcer with severe mucosal atrophy in the corpus.

The long-term effect of Helicobacter pylori eradication therapy on symptoms in dyspeptic patients with fundic atrophic gastritis.

AIM: To investigate whether curing Helicobacter pylori infection improves symptoms over the long-term in Japanese patients with nonulcer dyspepsia and fundic atrophic gastritis. METHODS: Ninety H. pylori-positive dyspeptic patients with fundic atrophic gastritis were enrolled in this study. We performed a randomized double-blind placebo-controlled trial comparing triple therapy (n=45) with that of placebo alone (n=45). Inflammation and mucosal atrophy were scored according to the Updated Sydney System. Symptoms were scored on a scale of 0 to 3 for six items. Fasting samples of gastric juice were taken before endoscopy, and gastric pH was determined. Serum gastrin and pepsinogen levels were measured, and body mass index was determined. These patients were followed up for 3 years, and all measures were evaluated both before and after therapy. RESULTS: Significant improvement in dyspeptic symptoms and gastritis scores, significant decrease in gastric pH, and significant increase in body mass index were found after 3 years eradication in nonulcer dyspepsia patients treated successfully for H. pylori infection. There were no significant changes in the placebo group. CONCLUSION: Our study shows that eradicating of H. pylori results in significant long-term reduction in symptoms of nonulcer dyspepsia with fundic atrophic gastritis.

Initial medical management of patients severely irradiated in the Tokai-mura criticality accident.

A nuclear criticality accident occurred in Japan on September 30, 1999, which resulted in severe exposure of three victims to mixed flux of neutrons and gamma-rays. Estimated average doses for the three victims were 5.4 Gy of neutrons and 8.5 Gy of gamma-rays for Patient A, 2.9 Gy of neutrons and 4.5 Gy of gamma-rays for Patient B, and 0.81 Gy of neutrons and 1.3 Gy of gamma-rays for Patient C. They then suffered the consequences of the effects of ionizing radiation resulting in acute radiation syndrome. In Patients A and B, bone marrow failure was so severe that they received haematopoietic stem cell transplantation. The graft initially took successfully in both patients, although in Patient B it was later taken over by his own haematopoietic cells. They also suffered from severe skin lesions, later exhibited gastrointestinal bleeding and eventually died of multiple organ failure 82 and 210 days after the accident, respectively. The survival of these patients beyond the period of agranulocytosis means that bone marrow failure per se caused by exposure to ionizing radiation may now be overcome. Patient C also developed bone marrow failure and was treated with granulocyte colony-stimulating factor as well as supportive care. He recovered without major complications and is now under periodical follow-up. Remarkably, during the prodromal phase, all the patients exhibited hypoxaemia, two of whom also showed interstitial oedema of the lungs. In Patient C these manifestations improved within a week. The circumstances of the accident and the initial medical treatment of the victims are described.

[A giant left atrial myxoma with severe mitral valve regurgitation: report of a case].

A 76-year-old female underwent operation with a diagnosis of a left atrial myxoma with accompanied mitral regurgitation. Although no clinical findings of mitral regurgitation were noticed preoperatively, degenerative changes to the anterior leaflet as well as chordae tendinae possibly due to mechanical damage by the movement of the giant tumor through the mitral valve complex were observed in operation. Resection of the tumor and mitral valve replacement were successfully performed. Our case suggests that it is indispensable to investigate the mitral valve during operation even in case of the left atrial tumor with no preoperative findings of mitral regurgitation.

Helicobacter pylori eradication therapy improves atrophic gastritis and intestinal metaplasia: a 5-year prospective study of patients with atrophic gastritis.

AIM: : To investigate the effect of the eradication of Helicobacter pylori on histological gastritis. METHODS: : Twenty-six patients with moderate to severe atrophy received successful eradication therapy of H.pylori. Four patients dropped out and 22 were followed up prospectively for 5 years. The grades of gastritis were estimated from gastric biopsy specimens. The grade of intestinal metaplasia was also evaluated by dye-endoscopy using methylene blue (methylthioninium chloride). The serum levels of pepsinogen, gastrin and anti-parietal cell antibody were also determined. RESULTS: : The grades of atrophy decreased in patients with successful eradication therapy in the gastric corpus (before vs. 5 years after eradication, 2.09 +/- 0.15 vs. 0.91 +/- 0.17; P < 0.01) and in the antrum (2.14 +/- 0.17 vs. 1.36 +/- 0.17; P < 0.01). The levels of intestinal metaplasia were also decreased in the corpus (0.91 +/- 0.24 vs. 0.50 +/- 0.16; P < 0.05) and in the antrum (1.41 +/- 0.20 vs. 1.00 +/- 0.16; P < 0.05), which was also demonstrated by the methylene blue (methylthioninium chloride) staining method (33.4 +/- 8.2% vs. 23.0 +/- 6.5%; P < 0.05). The improvement of corpus atrophy correlated well with the high serum level of pepsinogen I (P = 0.005), but showed no correlation with the levels of anti-parietal cell antibody. CONCLUSIONS: : These results suggest that gastric atrophy and intestinal metaplasia are reversible events in some patients.

Successful treatment for leg ulcers due to hydroxyurea in a patient with chronic myelogenous leukaemia.

A 51-year-old male who had intractable leg ulcers during treatment for chronic myelogenous leukaemia with hydroxyurea (HU) is reported. His leg ulcers were treated by application of tretinoin tocoferil (TT) ointment after surgical debridement; good results were obtained. Although stopping HU administration is vitally important, surgical debridement and TT application are effective for treating leg ulcers due to HU.

Antigen presentation by murine peritoneal cavity macrophage-derived dendritic cells.

Murine peritoneal cavity macrophage derived dendritic cells (PEC-DC) generated using early growth factors, interleukin 4 and granulocyte-macrophage colony-stimulating factor followed by maturation in interferon-gamma plus either, Toxoplasma lysate antigen (TLA) or lipopolysaccharide, bind TLA by a nonspecific mechanism and continue to express major histocompatibility complex class II antigens after 24 h of culture in vitro. Moreover, the proliferation of CD3+ spleen T cells from mice immunized with Toxoplasma gondii homogenate, induced by PEC-DC-mediated antigen presentation was statistically significant and of consistent amplitude. This accessory function of PEC-DC is antigen specific.