Development of C6⁺ laser ion source and RFQ linac for carbon ion radiotherapy.

A prototype C(6+) injector using a laser ion source has been developed for a compact synchrotron dedicated to carbon ion radiotherapy. The injector consists of a laser ion source and a 4-vane radio-frequency quadrupole (RFQ) linac. Ion beams are extracted from plasma and directly injected into the RFQ. A solenoid guides the low-energy beams into the RFQ. The RFQ is designed to accelerate high-intensity pulsed beams. A structure of monolithic vanes and cavities is adopted to reduce its power consumption. In beam acceleration tests, a solenoidal magnetic field set between the laser ion source and the RFQ helped increase both the peak currents before and after the RFQ by a factor of 4.

Employment status among non-retired cancer survivors in Japan.

Employed cancer patients confront some challenges as they attempt to return to work after treatment. We aimed to identify correlates of return to work for cancer survivors in Japan, with an emphasis on employment status. Participants were 260 patients (aged <65 years) who had received a cancer diagnosis ≥ 1 year previously and who were employed at the time of diagnosis. Participants completed questionnaires at consultations at any Regional Cancer Center Hospitals in Yamagata, Japan between 28 November 2011 and 9 December 2011. Logistic regression analysis was used to identify correlates of return to work. Data cross-tabulation was used to evaluate relationships to workplace and income-changes by employment status. A high proportion of patients (75.8%) had returned to work. Non-regularly employed survivors were less likely to return to work (odds ratio = 5.03; 95% confidence interval, 1.18-21.35). Individuals with poor health, advanced-stage tumours, of advanced age and women were significantly less likely to return to work. Only 52.8% of non-regular employees continued to be employed, and their income decreased by as much as 61.1%. Social and financial support policies should be organised based on more intensive study of employment circumstances.

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.

Results of chemoradiotherapy for stage I esophageal cancer in medically inoperable patients compared with results in operable patients.

The purpose of the present study was to evaluate long-term results of chemoradiotherapy for clinical T1b-2N0M0 esophageal cancer and to compare outcomes for operable and inoperable patients. Patients with stage I esophageal cancer (Union for International Cancer Control [UICC] 2009), excluding patients with cT1a esophageal cancer, were studied. All patients had histologically proven squamous cell carcinoma. Operable patients received cisplatin and 5-fluorouracil with concurrent radiotherapy of 60 Gy including a 2-week break. Inoperable patients received nedaplatin and 5-fluorouracil with concurrent radiotherapy of 60-70 Gy without a pause. End-points were overall survival rate (OS), cause-specific survival rate (CSS), progression-free survival rate (PFS), and locoregional control rate (LC). Thirty-seven operable patients and 30 medically inoperable patients were enrolled. There was a significant difference in only age between the operable group and inoperable group (P = 0.04). The median observation period was 67.9 months. In all patients, 5-year OS, CSS, PFS, and LC were 77.9%, 91.5%, 66.9%, and 80.8%, respectively. Comparison of the operable group and inoperable group showed that there was a significant difference in OS (5-year, 85.5% vs. 68.7%, P = 0.04), but there was no difference in CSS, PFS, or LC. Grade 3 or more late toxicity according to Common Terminology Criteria for Adverse Events v 3.0 was found in seven patients. Even in medically inoperable patients with stage I esophageal cancer, LC of more than 80% can be achieved with chemoradiotherapy. However, OS in medically inoperable patients is significantly worse than that in operable patients.

Impact of superselective transarterial infusion therapy of high-dose cisplatin on maxillary cancer with orbital invasion.

BACKGROUND AND PURPOSE: We have been performing the superselective transarterial infusion of high-dose cisplatin for advanced maxillary cancer since 1998 and the local control rate, disease free survival rate, and organ preservation have improved markedly compared with our former therapy. This study evaluates the effectiveness of superselective transarterial infusion therapy by using high-dose cisplatin on maxillary cancer with orbital invasion. MATERIALS AND METHODS: We treated 23 patients with maxillary cancer by using superselective transarterial infusion therapy with high-dose cisplatin and concomitant radiation therapy for 10 years. Of all patients, 15 showed orbital invasion, with 11 of these tumors fed by both internal maxillary and ophthalmic arteries. In all patients, we performed superselective transarterial infusion therapy via the internal maxillary artery and/or the other feeding branches from the external carotid artery. After the operation, we determined whether a pCR had occurred by checking for the presence of viable cells. In addition, we calculated the overall survival rate, preservation rate of the eyeball, and disease-free survival rate. RESULTS: For all 23 patients, pCR and overall survival rates were 95.7% and 78.4%, respectively. To date, 2 of these patients died of lung metastasis without local recurrence. For the 15 patients with orbital invasion, the respective pCR and disease-free survival rates were 93.3% and 87.5%. Eyeballs were preserved in all patients, and local recurrence occurred in only 1 patient, at the inferior wall of the maxillary sinus (not in the orbit). CONCLUSIONS: Superselective transarterial infusion therapy with high-dose cisplatin remarkably improved the local control rate and disease-free survival rate of maxillary cancer. Even in patients with orbital invasion, a high local control rate was achieved, with preservation of the eyeball, through infusion only into branches of the external carotid artery.

MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death.

Recently developed heavy ion irradiation therapy using a carbon beam (CB) against systemic malignancy has numerous advantages. However, the clinical results of CB therapy against glioblastoma still have room for improvement. Therefore, we tried to clarify the molecular mechanism of CB-induced glioma cell death. T98G and U251 human glioblastoma cell lines were irradiated by CB, and caspase-dependent apoptosis was induced in both cell lines in a dose-dependent manner. Knockdown of Bax (BCL-2-associated X protein) and Bak (BCL-2-associated killer) and overexpression of Bcl-2 or Bcl-xl (B-cell lymphoma-extra large) showed the involvement of Bcl-2 family proteins upstream of caspase activation, including caspase-8, in CB-induced glioma cell death. We also detected the activation of extracellular signal-regulated kinase (ERK) and the knockdown of ERK regulator mitogen-activated protein kinase kinase (MEK)1/2 or overexpression of a dominant-negative (DN) ERK inhibited CB-induced glioma cell death upstream of the mitochondria. In addition, application of MEK-specific inhibitors for defined periods showed that the recovery of activation of ERK between 2 and 36 h after irradiation is essential for CB-induced glioma cell death. Furthermore, MEK inhibitors or overexpression of a DN ERK failed to significantly inhibit X-ray-induced T98G and U251 cell death. These results suggested that the MEK-ERK cascade has a crucial role in CB-induced glioma cell death, which is known to have a limited contribution to X-ray-induced glioma cell death.

Deoxyspergualin in relapsing and refractory Wegener's granulomatosis.

OBJECTIVES: Conventional therapy of Wegener's granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease. METHODS: A prospective, international, multicentre, single-limb, open-label study. Entry required active Wegener's granulomatosis with a Birmingham vasculitis activity score (BVAS) > or =4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5 mg/kg per day, was self-administered by subcutaneous injection in six cycles of 21 days with a 7-day washout between cycles. Cycles were stopped early for white blood count less than 4000 cells/mm(3). The primary endpoint was complete remission (BVAS 0 for at least 2 months) or partial remission (BVAS <50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for 6 months. RESULTS: 42/44 patients (95%) achieved at least partial remission and 20/44 (45%) achieved complete remission. BVAS fell from 12 (4-25), median (range) at baseline to 2 (0-14) at the end of the study (p<0.001). Prednisolone doses were reduced from 20 to 8 mg/day (p<0.001). Relapses occurred in 18 (43%) patients after a median of 170 (44-316) days after achieving remission. Severe or life-threatening (> or = grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. CONCLUSIONS: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener's granulomatosis. Adverse events were common but rarely led to treatment discontinuation.

Sural nerve grafting for long defects of the femoral nerve after resection of a retroperitoneal tumour.

Most injuries to the femoral nerve are iatrogenic in origin and occur during resection of large retroperitoneal tumours. When the defect is considerable a nerve graft is mandatory to avoid tension across the suture line. We describe two cases of iatrogenic femoral nerve injury which recovered well after reconstruction with long sural nerve grafts. The probable reasons for success were that we performed the grafting soon after the injury, the patients were not too old, the nerve repairs were reinforced with fibrin glue and electrical stimulation of the quadriceps was administered to prevent muscle atrophy. Good functional results may be obtained if these conditions are satisfied even if the length of a nerve graft is more than 10 cm.

Extended storage of granulocyte concentrates mobilized by G-CSF with/without dexamethasone and collected by bag separation method.

The aim of this study was to examine the extended storage of granulocyte concentrates mobilized by granulocyte-colony-stimulating factor (G-CSF) with/without dexamethasone (DEX) and collected by a bag separation method. Ten healthy adult volunteers donated blood three times: twice after granulocyte mobilization by (1) injecting G-CSF at 3 microg kg(-1) subcutaneously (s.c.) and (2) injecting G-CSF at 3 microg kg(-1) s.c. + DEX at 8 mg per oral and once (3) for a baseline control without any forms of mobilization. Granulocytes were collected by a bag separation method. The functions (phagocytosis and oxidative killing levels), viability and levels of interleukin (IL)-1beta, IL-8, IL-6 and tumour necrosis factor-alpha of granulocytes were measured. The average numbers of granulocytes collected from 200-mL samples of whole blood from the G-CSF and G-CSF + DEX groups were 35.1 x 10(8) and 49.4 x 10(8), respectively. Phagocytosis level, oxidative killing level and the viability of the granulocytes mobilized by G-CSF with/without DEX were well maintained for up to 72 h of storage after collection. The levels of the cytokines increased in a time-dependent manner. The in vitro phagocytosis level, oxidative killing level and the viability of granulocytes mobilized by G-CSF with/without DEX and collected by bag separation method can be maintained for as long as 72 h after collection.

Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia.

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.

Abductor pollicis longus transfer to restore index abduction in severe cases of cubital tunnel syndrome.

Transfer of the abductor pollicis longus tendon to restore index abduction was performed simultaneously with ulnar nerve decompression in severe cases of cubital tunnel syndrome. Eighteen elbows in 18 patients were evaluated with an average follow-up period of 46 (range 12-120) months. The status of the ulnar nerve palsy was evaluated by the Yasutake's scoring method. The mean score improved from 48 points pre-operatively to 78 points at final follow-up (maximum score 100 points). Pinch strength improved from 39% of the opposite side pre-operatively to 81% finally and it reached a plateau one year postoperatively. Despite this improvement in pinch strength, atrophy of the interosseous muscle did not disappear in nine of 12 patients with a follow-up of more than two years. All patients were satisfied with the results of increased strength and stability in pinching ability. No complications occurred.

In vivo effects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis.

15-Deoxyspergualin (DSG) is an alternative treatment modality for Wegener's granulomatosis (WG) patients refractory to conventional treatment. Nevertheless, it is unclear how DSG modulates disease activity in these patients. This study was conducted to investigate which parameters of adaptive and acquired immunity were influenced during two subsequent cycles of DSG treatment. Emphasis was put upon T cell and monocyte activation, neutrophil function and surface expression of proteinase-3 (PR-3). Anti-CD3/anti-CD28 and interleukin (IL)-15/IL-7-mediated T cell proliferation were assessed by fluorescence activated cell sorter (FACS) analysis using carboxyfluorescein succinimidyl ester (CSFE) labelling. Interferon (IFN)-gamma and IL-10 production were determined in the supernatants of these cultures by enzyme-linked immunosorbent assay. Monocyte activation was assessed in lipopolysaccharide (LPS)-stimulated whole blood, using tumour necrosis factor (TNF)-alpha as read-out. Neutrophil function was determined by measuring oxidative burst, chemotaxis and phagocytosis. T cell activation markers and PR3 expression were measured by FACS. All parameters were determined directly before and after each DSG cycle. Anti-CD3/anti-CD28-mediated T cell proliferation was reduced directly after DSG treatment. Directly before a subsequent cycle of DSG was started, T cell proliferation was increased. Similar findings were observed for IFN-gamma and IL-10 production by T cells. DSG did not influence IL-15/IL-7-mediated T cell proliferation. LPS-mediated TNF-alpha production was also impaired directly after DSG treatment. No influence on T cell activation markers, neutrophil function and surface PR-3 expression was observed in peripheral blood of these patients. Our data demonstrate that DSG influences T cell and monocyte activation in a reversible fashion. Although DSG causes neutropenia in these patients, it does not influence neutrophil function.

Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction.

Allogeneic stem cell transplantation (SCT) can cure several nonmalignant diseases in children. However, patients frequently have significant morbidity before transplantation and there is a high transplant-related mortality. Nonmyeloablative SCT might achieve the same goals but with less toxicity. Six pediatric patients with nonmalignant diseases underwent nonmyeloablative SCT from different stem cell sources. All patients were conditioned with fludarabine/melphalan with additional anti-thymocyte globulin for haploidentical grafts and prophylaxis for graft-versus-host disease (GVHD) consisting of tacrolimus and methotrexate with additional prednisolone for haploidentical grafts. Hematopoietic stem cells were neither T-cell depleted nor purged. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. Five of the six are alive and in complete disease resolution at a median of 19 months (range, 7-53 months) after SCT. One patient died of bacteremia before engraftment. Three patients achieved complete donor chimerism. Two patients remained stable mixed chimerism. Short-term toxicities were minimal. Acute and chronic GVHD were not seen. In summary, the fludarabine-based nonmyeloablative regimen followed by SCT provides a good approach for children with nonmalignant diseases. Even patients with severe organ dysfunctions had adequate engraftment with acceptable toxicities.

Therapeutic transfusions of granulocytes collected by simple bag method for children with cancer and neutropenic infections: results of a single-centre pilot study.

BACKGROUND AND OBJECTIVES: Granulocyte transfusion therapy (GTX) can be effective for life-threatening infections unresponsive to conventional antimicrobial therapies in severely neutropenic children with cancer. We developed a new granulocyte collection method, named the 'bag method', in which apheresis, hydroxyethyl starch (HES) or dexamethasone are not used. We undertook a pilot study to determine the feasibility and the safety of GTX collected by the bag method for children with cancer and life-threatening infections. MATERIALS AND METHODS: A total of 25 GTX were administered to 13 patients (median age 3 years, range: 0.3-17; median weight 10.6 kg, range: 4.5-49.8) with neutropenia-related infections. Thirteen blood-relative donors received granulocyte colony-stimulating factor (G-CSF) (5-10 microg/kg), subcutaneously, 14 h before collection. Major end-points were granulocyte yields, post-transfusion absolute neutrophil counts (ANC) in patients, donor and patient safety, and clinical outcome on day 30. RESULTS: The median yield of ANC per 400 ml of processed whole blood was 6.2 x 10(9) (range: 2.5-15.0 x 10(9)). Patients received a mean of 6.4 +/- 0.8 x 10(8) granulocytes per kg of body weight per transfusion. The 1-h and 24-h post-transfusion ANC rose to 607 +/- 124/microl and 704 +/- 300/microl, respectively, from the baseline of 21/microl before the first GTX. Adverse reactions were observed in five of 13 donors (bone pain, headache, vasovagal reaction; all < or = grade 2) and in two of 25 transfusions of 13 patients (transient hypoxia; grade 3). Ten patients had favourable responses, and infection resolved in nine patients. CONCLUSIONS: The bag method without apheresis relieves the physical load of donors and enables patients with a low body weight to provide an adequate dose of granulocytes.

Severe scoliosis associated with Costello syndrome: a case report.

Costello syndrome is characterised by dwarfism, unique cutaneous lesions, a distinct facial gestalt, and mental retardation. There have been no detailed reports of severe spinal deformities requiring surgical treatment as a complication of Costello syndrome. We report a case of a 10-year-old girl with progressive scoliosis associated with Costello syndrome. She underwent anterior release and posterior surgical correction and fusion from T5 to L2 using a third generation hook and rod system plus spinous process wiring. Congenital portal vein deficiency and coagulopathy were other major complications. At 15-month follow-up, the patient had good balance and no evidence of instrumentation failure.

Clinical and pathological features of children with Henoch-Schoenlein purpura nephritis: risk factors associated with poor prognosis.

OBJECTIVE: To clarify the risk factors related to prognosis in patients with Henoch-Schoenlein purpura nephritis (HSPN), we investigated the cases with HSPN on long-term observation. METHODS: We enrolled 114 patients who had been diagnosed with HSPN from 1974-1997. These patients were divided into 2 groups based upon features at last follow-up. One group, designated "favorable", consisted of 69 patients with normal urine and 25 patients with minor urinary abnormalities, and the second group, designated "unfavorable", consisted of 15 patients with active renal disease and 5 patients with renal failure. The clinical features, laboratory data and pathological findings were investigated in 2 groups. RESULTS: Nephrotic syndrome, decreased factor XIII activity, hypertension and renal failure at onset were more frequent in "unfavorable" than in "favorable". The rate of glomeruli with crescents, macrophage infiltrations, tubulointerstitial changes and acute exacerbation in "unfavorable" were higher than those in "favorable". There were 5 cases with renal insufficiency, and renal survival rate was 95.6% for over 15 years. CONCLUSIONS: These results suggest that the above mentioned risk factors play an important role in prognosis of the patients with active renal disease and renal failure.

Clinical pilot studies on pre-operative hyperthermic tumour ablation for advanced breast carcinoma using an 8 MHz radiofrequency heating device.

The multimodality treatment approach for advanced breast cancer provides survival advantages with decreased locoregional and distant recurrences, but these intensive anti-tumour treatments cause severe myelosuppression. Thus, in this study, the usefulness of pre-operative anti-tumour treatment without myelosuppression was investigated. Nine patients with advanced breast carcinoma underwent pre-operative hyperthermic tumour ablation (HTA) using an 8 MHz radiofrequency (RF) heating device (Thermotron RF-8) combined with a grounded needle electrode. The patients had a mean age of 58.3+/-13.9 years and included four patients with stage IIIA, two with stage IIIB and three with stage IV cancer. The target temperature was over 50 degrees C. They tolerated pre-operative HTA therapy well with no early or late complications. The initial mean tumour size was 122.1+/-71.5 cm3 and the post-HTA tumour size was 82.2+/-63.4 cm3; the reduction rate was significant (p = 0.000 293). After the pre-operative HTA, all patients underwent surgery with Level III nodal extirpation. Post-operatively, no locoregional recurrence was observed. Microscopic examination of the primary focus showed complete coagulation necrosis expanding for a diameter of 3.5-5.0 cm. Taken together, the pre-operative HTA was a safe, well-tolerated and effective treatment, achieving tumour reduction as well as complete coagulation necrosis that resulted in a large volume of destruction in breast cancer tissue.

Radiation therapy for loco-regionally recurrent esophageal cancer after surgery.

PURPOSE: To evaluate the treatment outcome of radiation therapy for 33 loco-regionally recurrent esophageal cancer patients. METHODS: Between 1988 and 1997, 33 patients with loco-regional recurrence of esophageal cancer after curative surgery received radiation therapy at an average total dose of 61 Gy. The site of recurrence was the supraclavicular region in 14 patients, the mediastinal region in 13 patients, and both the supraclavicular and mediastinal regions in six patients. If patients had ether distant metastasis or malignant pleural effusion, they were excluded from analysis. Patients who received prophylactic postoperative irradiation were also excluded from analysis. RESULTS: The median survival period was 7 months. The survival rates at 1, 2, and 3 years were 33, 15, and 12%, respectively. In univariate analysis, patients with a short time interval between surgery and recurrence (P=0.0098) and patients with recurrence in both the supraclavicular and mediastinal regions (P=0.036) had a worse prognosis. In multivariate analysis, the time interval between surgery and recurrence (P<0.001) and age (worse prognosis in younger patients, P=0.019) were the significant prognostic factors. Complete or partial responses were observed in nine (27%) and 21 (64%) of the patients, respectively. Changes in clinical symptoms, such as dysphagia, chest pain and back pain, could be evaluated in 11 patients, and improvement in symptoms was obtained in eight (73%) patients. CONCLUSIONS: The prognosis of patients who received radiation therapy for postoperative loco-regional recurrence of esophageal cancer is poor. However, there is symptomatic relief in a significant proportion of such patients, and long-term survival is possible in some patients.

FK506 suppressed the inflammatory change of EAM in SJL/J mice.

Experimental autoimmune myositis (EAM) is a good model of human inflammatory myopathy. We induced EAM in SJL/J mice by injection with myosin and treated inflammatory changes with FK506. The mice developed inflammatory changes after the fifth myosin injection. After treatment with FK506, inflammation was suppressed and central nuclei of the muscle fibers increased. These findings indicate that FK506 is effective in the treatment of EAM. The data suggests that FK506 inhibits interaction with calcineurin. Intercellular adhesion molecule-1 (ICAM-1) positive cells were present in the inflammatory and non-inflammatory areas of EAM. The FK506-treated group stained more weakly for ICAM-1 than the untreated EAM group.