Experimental study on monitoring system of clinical beam purity in multiple-ion beam operation for heavy-ion radiotherapy.

The National Institute of Radiological Sciences has investigated multiple-ion therapy using energetic beams of helium, carbon, oxygen, and neon ions, to improve treatment outcomes of refractory cancer. For this therapy, it is necessary to ensure the helium-ion beam purity to avoid irradiation by unwanted ions. Here, we develop a measurement method for monitoring beam purity. This method can measure the charge number of the ions in a high-purity beam using an ionization chamber and Faraday cup. In addition, it can be used to detect the contamination of the clinical helium-ion beam. We perform beam experiments to evaluate our beam-purity monitoring method and predict that our method is capable of detecting contamination below 1%.

Ion-production efficiency of a singly charged ion source developed toward a 11C irradiation facility for cancer therapy.

The ion-production efficiency of a newly developed singly charged ion source (SCIS) has been investigated to discuss the possibility of it being used in an isotope separation on-line system that provides 11C ions for heavy-ion cancer therapy with simultaneous verification of the irradiation field using positron emission tomography. The SCIS uses a low-energy hollow electron beam to produce singly charged carbon ions efficiently. To deliver sufficient 11C ions to the treatment room from a limited amount of 11C molecules, which are produced from a boron compound target and proton-beam irradiation via the 11B(p,n)11C reaction, the SCIS must have high ion-production efficiency. To realize this high efficiency, the SCIS was designed using a three-dimensional particle-in-cell code in previous work. With the fabricated SCIS, we performed experiments to measure the efficiency of producing CO2 + ions from nonradioactive 12CO2 molecules and C+ ions from nonradioactive 12CH4 molecules. We found that the SCIS achieved efficiencies of εC+ =4×10-3 (0.4%) for C+ production and εCO2 + =0.107 (10.7%) for CO2 + production.

Singly charged ion source designed using three-dimensional particle-in-cell method.

A singly charged ion source (SCIS) has been designed using a newly developed three-dimensional particle-in-cell (PIC) code. The SCIS is to be used in an isotope separation on-line (ISOL) system that provides 11C ions for heavy-ion cancer therapy with simultaneous verification of the dose distribution using positron emission tomography. The SCIS uses low-energy electron beams to produce singly charged carbon ions efficiently and maintain a high vacuum in the ISOL system. Because the SCIS has to realize a production efficiency of 1% if its carbon ions are to be used in the ISOL system, a suitable design for the SCIS was investigated by using the developed PIC code to study the beam trajectories of the electrons and extracted ions. The simulation results show that hollow electron beams are produced in the designed SCIS resulting in a high effective electron current. The results also predict that the designed SCIS would realize ion-production efficiencies (IPEs) of ε SCIS ≃ 6.7% for C O 2 + production from CO2 gas and ε SCIS ≃ 0.1% for C+ production from CH4 gas. Moreover, to examine the validity of the developed code and confirm that the SCIS was able to be designed appropriately, the space-charge-limited current of the electron gun and the total IPE obtained by adding the IPEs of each ion were compared between the experiment and the simulation.

Functional characterization of recombinant snake venom rhodocytin: rhodocytin mutant blocks CLEC-2/podoplanin-dependent platelet aggregation and lung metastasis.

Essentials We generated recombinant rhodocytin that could aggregate platelets via CLEC-2. Recombinant wild-type rhodocytin formed heterooctamer with four α- and ß-subunits. Asp 4 in α-subunit of rhodocytin was required for binding to CLEC-2. Inhibitory mutant of rhodocytin blocked podoplanin-dependent hematogenous metastasis. SUMMARY: Background Rhodocytin, a disulfide-linked heterodimeric C-type lectin from Calloselasma rhodostoma consisting of α-subunits and ß-subunits, induces platelet aggregation through C-type lectin-like receptor 2 (CLEC-2). CLEC-2 is a physiological binding partner of podoplanin (PDPN), which is expressed on some tumor cell types, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. Thus, modified rhodocytin may be a possible source of anti-CLEC-2 drugs for both antiplatelet and antimetastasis therapy. However, its molecular function has not been well characterized, because of the lack of recombinant rhodocytin that induces platelet aggregation. Objective To produce recombinant rhodocytin, in order to verify its function with mutagenesis, and to develop an anti-CLEC-2 drug based on the findings. Methods We used Chinese hamster ovary cells to express recombinant rhodocytin (wild-type [WT] and mutant), which was analyzed for induction/inhibition of platelet aggregation with light transmission aggregometry, the formation of multimers with blue native PAGE, and binding to CLEC-2 with flow cytometry. Finally, we investigated whether mutant rhodocytin could suppress PDPN-induced metastasis in an experimental lung metastasis mouse model. Results Functional WT] rhodocytin (αWTßWT) was obtained by coexpression of both subunits. Asp4 in α-subunits of rhodocytin was required for CLEC-2 binding. αWTßWT formed a heterooctamer similarly to native rhodocytin. Moreover, an inhibitory mutant of rhodocytin (αWTßK53A/R56A), forming a heterotetramer, bound to CLEC-2 without inducing platelet aggregation, and blocked CLEC-2-PDPN interaction-dependent platelet aggregation and experimental lung metastasis. Conclusion These findings provide molecular characterization information on rhodocytin, and suggest that mutant rhodocytin could be used as a therapeutic agent to target CLEC-2.

Identification of patterns of factors preceding severe or life-threatening asthma exacerbations in a nationwide study.

BACKGROUND: Reducing near-fatal asthma exacerbations is a critical problem in asthma management. OBJECTIVES: To determine patterns of factors preceding asthma exacerbations in a real-world setting. METHODS: In a nationwide prospective study of 190 patients who had experienced near-fatal asthma exacerbation, cluster analysis was performed using asthma symptoms over the 2-week period before admission. RESULTS: Three distinct clusters of symptoms were defined employing the self-reporting of a visual analogue scale. Cluster A (42.1%): rapid worsening within 7.4 hours from moderate attack to admission, young to middle-aged patients with low Body mass index and tendency to depression who had stopped anti-asthma medications, smoked, and hypersensitive to environmental triggers and furred pets. Cluster B (40.0%): fairly rapid worsening within 48 hours, mostly middle-aged and older, relatively good inhaled corticosteroid (ICS) or ICS/long-acting beta-agonist (LABA) compliance, and low perception of dyspnea. Cluster C (17.9%): slow worsening over 10 days before admission, high perception of dyspnea, smokers, and chronic daily mild-moderate symptoms. There were no differences in overuse of short-acting beta-agonists, baseline asthma severity, or outcomes after admission for patients in these 3 clusters. CONCLUSION: To reduce severe or life-threatening asthma exacerbation, personalized asthma management plans should be considered for each cluster. Improvement of ICS and ICS/LABA compliance and cessation of smoking are important in cluster A. To compensate for low perception of dyspnea, asthma monitoring of peak expiratory flow rate and/or exhaled nitric oxide would be useful for patients in cluster B. Avoidance of environmental triggers, increase usual therapy, or new anti-type 2 response-targeted therapies should be considered for cluster C.

A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood. OBJECTIVE: To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach. METHODS: This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell-related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period. RESULTS: The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1-5.6) in cluster 1 and 2.3 (95% CI, 1.0-5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥310 IU/mL, blood eosinophil counts ≥280 cells/µL, a higher ratio of TBX21/GATA3, FEV1 /FVC ratio <0.67 and smoking ≥10 pack-years with an area under the curve of 0.94 (95% CI, 0.90-0.98) in the receiver operating characteristic analysis. CONCLUSIONS AND CLINICAL RELEVANCE: The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype.

The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice.

Essentials Regeneration role of C-type lectin receptor-2 (CLEC-2) after 70% hepatectomy (HPx) was investigated. Wild-type or CLEC-2 deleted from platelets of chimeric mice (flKO) underwent HPx. The liver/body weight ratio was significantly lower in the flKO than in the wild-type. CLEC-2 plays an essential role in liver regeneration after HPx. SUMMARY: Background and aim The aim of the present study was to investigate the role of C-type lectin receptor (CLEC)-2 in liver regeneration following partial liver resection in mice. Materials and methods Irradiated chimeric mice transplanted with fetal liver cells from wild-type (WT) mice, CLEC-2-deleted (KO) mice or mice with CLEC-2 deleted specifically from platelets (flKO) were generated. Mice underwent 70% partial hepatectomy (PH). Immunohistochemical staining was performed to investigate the expression of the endogenous ligand for CLEC-2, podoplanin. The accumulation of platelets in the liver was also quantified. The hepatic expression of the IL-6/gp130 and STAT3, Akt and ERK1/2 was also examined. Results The liver/body weight ratio and expression of all cell proliferation markers were significantly lower in the flKO group than in the WT group. The expression of phosphorylated (p) Akt and pERK1/2 was similar in the WT and flKO groups. On the other hand, the expression of pSTAT3 and IL-6 was significantly stronger in the WT group than in the flKO group. The expression of podoplanin was detected in the hepatic sinusoids of both groups. However, the extent to which platelets accumulated in hepatic sinusoids was significantly less in the flKO group than in the WT group. Conclusion CLEC-2 was involved in hepatic regeneration after liver resection and CLEC-2-related liver regeneration was attributed to the interaction between platelets and sinusoidal endothelial cells.

C-type lectin-like receptor 2 promotes hematogenous tumor metastasis and prothrombotic state in tumor-bearing mice.

Essentials The role of C-type lectin-like receptor-2 (CLEC-2) in cancer progression is unclear. CLEC-2-depleted mouse model is generated by using a rat anti-mouse CLEC-2 monoclonal antibody. CLEC-2 depletion inhibits hematogenous tumor metastasis of podoplanin-expressing B16F10 cells. CLEC-2 depletion prolongs cancer survival by suppressing thrombosis and inflammation. SUMMARY: Background C-type lectin-like receptor 2 (CLEC-2) is a platelet activation receptor of sialoglycoprotein podoplanin, which is expressed on the surface of certain types of tumor cells. CLEC-2-podoplanin interactions facilitate hematogenous tumor metastasis. However, direct evidence of the role of CLEC-2 in hematogenous metastasis and cancer progression is lacking. Objective and methods We generated immunological CLEC-2-depleted mice by using anti-mouse CLEC-2 monoclonal antibody 2A2B10 and investigated whether CLEC-2 promoted hematogenous tumor metastasis and tumor growth and exacerbated the prognosis of mice bearing podoplanin-expressing B16F10 melanoma cells. Results Our results showed that hematogenous metastasis was significantly inhibited in CLEC-2-depleted mice. B16F10 cells co-cultured with wild-type platelets, but not with CLEC-2-deficient platelets, showed increased proliferation. However, B16F10 cell proliferation was not inhibited in CLEC-2-depleted mice. Histological analysis showed that thrombus formation in tumor vessels was significantly inhibited and functional vessel density was significantly increased in CLEC-2-depleted mice. These data suggest that CLEC-2 deficiency may inhibit thrombus formation in tumor vessels and increase the density of functional vessels, thus improving oxygen and nutrient supply to tumors, indirectly promoting tumor proliferation. Furthermore, the overall survival of CLEC-2-depleted mice was significantly prolonged, which may be due to the suppression of thrombus formation in the lungs and subsequent inhibition of systemic inflammation and cachexia. Conclusions These data provide a rationale for the targeted inhibition of CLEC-2 as a new strategy for preventing hematogenous tumor metastasis and for inhibiting cancer-related thromboembolism.

Severe or life-threatening asthma exacerbation: patient heterogeneity identified by cluster analysis.

BACKGROUND: Severe or life-threatening asthma exacerbation is one of the worst outcomes of asthma because of the risk of death. To date, few studies have explored the potential heterogeneity of this condition. OBJECTIVES: To examine the clinical characteristics and heterogeneity of patients with severe or life-threatening asthma exacerbation. METHODS: This was a multicentre, prospective study of patients with severe or life-threatening asthma exacerbation and pulse oxygen saturation < 90% who were admitted to 17 institutions across Japan. Cluster analysis was performed using variables from patient- and physician-orientated structured questionnaires. RESULTS: Analysis of data from 175 patients with severe or life-threatening asthma exacerbation revealed five distinct clusters. Cluster 1 (n = 27) was younger-onset asthma with severe symptoms at baseline, including limitation of activities, a higher frequency of treatment with oral corticosteroids and short-acting beta-agonists, and a higher frequency of asthma hospitalizations in the past year. Cluster 2 (n = 35) was predominantly composed of elderly females, with the highest frequency of comorbid, chronic hyperplastic rhinosinusitis/nasal polyposis, and a long disease duration. Cluster 3 (n = 40) was allergic asthma without inhaled corticosteroid use at baseline. Patients in this cluster had a higher frequency of atopy, including allergic rhinitis and furred pet hypersensitivity, and a better prognosis during hospitalization compared with the other clusters. Cluster 4 (n = 34) was characterized by elderly males with concomitant chronic obstructive pulmonary disease (COPD). Although cluster 5 (n = 39) had very mild symptoms at baseline according to the patient questionnaires, 41% had previously been hospitalized for asthma. CONCLUSIONS & CLINICAL RELEVANCE: This study demonstrated that significant heterogeneity exists among patients with severe or life-threatening asthma exacerbation. Differences were observed in the severity of asthma symptoms and use of inhaled corticosteroids at baseline, and the presence of comorbid COPD. These findings may contribute to a deeper understanding and better management of this patient population.

Transduction of Oct6 or Oct9 gene concomitant with Myc family gene induced osteoblast-like phenotypic conversion in normal human fibroblasts.

INTRODUCTION: Osteoblasts play essential roles in bone formation and regeneration, while they have low proliferation potential. Recently we established a procedure to directly convert human fibroblasts into osteoblasts (dOBs). Transduction of Runx2 (R), Osterix (X), Oct3/4 (O) and L-myc (L) genes followed by culturing under osteogenic conditions induced normal human fibroblasts to express osteoblast-specific genes and produce calcified bone matrix both in vitro and in vivo Intriguingly, a combination of only two factors, Oct3/4 and L-myc, significantly induced osteoblast-like phenotype in fibroblasts, but the mechanisms underlying the direct conversion remains to be unveiled. MATERIALS AND METHODS: We examined which Oct family genes and Myc family genes are capable of inducing osteoblast-like phenotypic conversion. RESULTS: As result Oct3/4, Oct6 and Oct9, among other Oct family members, had the capability, while N-myc was the most effective Myc family gene. The Oct9 plus N-myc was the best combination to induce direct conversion of human fibroblasts into osteoblast-like cells. DISCUSSION: The present findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases.

Surgical treatment for pyogenic vertebral osteomyelitis using iodine-supported spinal instruments: initial case series of 14 patients.

Reports have detailed the increasing use of spinal instrumentation in the treatment of pyogenic vertebral osteomyelitis, with the aims of achieving a lower pseudoarthrosis rate and restoring spinal alignment. However, controversy remains over the use of instrumentation in the presence of active infection because of concerns about increased bacterial adherence and biofilm formation on the metallic implant surface. Fourteen consecutive patients were followed who were diagnosed as having pyogenic vertebral osteomyelitis and underwent surgery with spinal instrumentation with iodine-containing surfaces that could be directly supported to existing titanium implants. Bone-cage interfaces and implant-related complications after surgery were evaluated. The white blood cell (WBC) count and C-reactive protein (CRP) level were analyzed during the follow-up period. To confirm the influence of iodine release from the implant, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were also examined. The infection subsided in all 14 patients. Both WBC counts and CRP levels returned to normal ranges by the final follow-up. One patient showed a lucent area around the screw and two patients showed lucencies inside the cage. However, no cage dislocations, cage migrations, or screw pull-outs were noted, and all patients' FT3, FT4, and TSH levels were within normal ranges during the follow-up period. We demonstrated the efficacy of iodine-supported titanium implants in the management of pyogenic vertebral osteomyelitis. No cytotoxicity or adverse effects were noted in this series.

Effect of secondary particles on image quality of dynamic flat panels in carbon ion scanning beam treatment.

OBJECTIVE: Real-time markerless tumour tracking using radiographic fluoroscopic imaging is one of the better solutions to improving respiratory-gated radiotherapy. However, particle beams cause secondary particles from patients, which could affect radiographs. Here, we evaluated the quality of radiographs during carbon ion pencil beam scanning (CPBS) irradiation for respiratory gating. METHODS: A water phantom and chest phantom were used. The phantoms were irradiated with CPBS at 290 MeV n(-1) from orthogonal directions. Dose rates were 3.4 × 10(8), 1.14 × 10(8) and 3.79 × 10(7) particles per second. A dynamic flat panel detector (DFPD) was installed on the upstream (DFPD1) or downstream (DFPD2) side of the vertical irradiation port. DFPD images were acquired during CPBS at 15.00, 7.50 and 3.75 frames per second (fps). Charge on the DFPD was cleaned using fast readout technique every 30 fps. DFPD images were acquired during CPBS with radiographic exposure, and results with and without fast readout technique were compared. RESULTS: Secondary particles were visualized as spots or streak-like shapes. Capture of secondary particles from the horizontal beam direction was lower with fast readout technique than without it. With regard to beam irradiation direction dependency, CPBS from the horizontal direction resulted in a greater magnitude of secondary particles reaching DFPD2 than reaching DFPD1. When CPBS was delivered from the vertical direction, however, the magnitude of secondary particles on both DFPDs was very similar. CONCLUSION: Fast readout technique minimized the effect of secondary particles on DFPD images during CPBS. ADVANCES IN KNOWLEDGE: This technique may be useful for markerless tumour tracking for respiratory gating.

Implementation of a target volume design function for intrafractional range variation in a particle beam treatment planning system.

OBJECTIVE: Treatment planning for charged particle therapy in the thoracic and abdominal regions should take account of range uncertainty due to intrafractional motion. Here, we developed a design tool (4Dtool) for the target volume [field-specific target volume (FTV)], which accounts for this uncertainty using four-dimensional CT (4DCT). METHODS: Target and normal tissue contours were input manually into a treatment planning system (TPS). These data were transferred to the 4Dtool via the picture archiving and communication system (PACS). Contours at the reference phase were propagated to other phases by deformable image registration. FTV was calculated using 4DCT on the 4Dtool. The TPS displays FTV contours using digital imaging and communications in medicine files imported from the PACS. These treatment parameters on the CT image at the reference phase were then used for dose calculation on the TPS. The tool was tested in single clinical case randomly selected from patients treated at our centre for lung cancer. RESULTS: In this clinical case, calculation of dose distribution with the 4Dtool resulted in the successful delivery of carbon-ion beam at the reference phase of 95% of the prescribed dose to the clinical target volume (CTV). Application to the other phases also provided sufficient dose to the CTV. CONCLUSION: The 4Dtool software allows the design of the target volume with consideration to intrafractional range variation and is now in routine clinical use at our institution. ADVANCES IN KNOWLEDGE: Our alternative technique represents a practical approach to four-dimensional treatment planning within the current state of charged particle therapy.

Implementation of a triple Gaussian beam model with subdivision and redefinition against density heterogeneities in treatment planning for scanned carbon-ion radiotherapy.

Challenging issues in treatment planning for scanned carbon-ion (C-ion) therapy are (i) accurate calculation of dose distribution, including the contribution of large angle-scattered fragments, (ii) reduction in the memory space required to store the dose kernel of individual pencil beams and (iii) shortening of computation time for dose optimization and calculation. To calculate the dose contribution from fragments, we modeled the transverse dose profile of the scanned C-ion beam with the superposition of three Gaussian distributions. The development of pencil beams belonging to the first Gaussian component was calculated analytically based on the Fermi-Eyges theory, while those belonging to the second and third components were transported empirically using the measured beam widths in a water phantom. To reduce the memory space for the kernels, we stored doses only in the regions of interest considered in the dose optimization. For the final dose calculation within the patient's whole body, we applied a pencil beam redefinition algorithm. With these techniques, the triple Gaussian beam model can be applied not only to final dose calculation but also to dose optimization in treatment planning for scanned C-ion therapy. To verify the model, we made treatment plans for a homogeneous water phantom and a heterogeneous head phantom. The planned doses agreed with the measurements within ±2% of the target dose in both phantoms, except for the doses at the periphery of the target with a high dose gradient. To estimate the memory space and computation time reduction with these techniques, we made a treatment plan for a bone sarcoma case with a target volume of 1.94 l. The memory space for the kernel and the computation time for final dose calculation were reduced to 1/22 and 1/100 of those without the techniques, respectively. Computation with the triple Gaussian beam model using the proposed techniques is rapid, accurate and applicable to dose optimization and calculation in treatment planning for scanned C-ion therapy.

The long-term outcome following the use of frozen autograft treated with liquid nitrogen in the management of bone and soft-tissue sarcomas.

In 1999, we developed a technique for biological reconstruction after excision of a bone tumour, which involved using autografts of the bone containing the tumour treated with liquid nitrogen. We have previously reported the use of this technique in 28 patients at a mean follow up of 27 months (10 to 54). In this study, we included 72 patients who underwent reconstruction using this technique. A total of 33 patients died and three were lost to follow-up, at a mean of 23 months (2 to 56) post-operatively, leaving 36 patients available for a assessment at a mean of 101 months 16 to 163) post-operatively. The methods of reconstruction included an osteo-articular graft in 16, an intercalary in 13 and, a composite graft with prosthesis in seven. Post-operative function was excellent in 26 patients (72.2%), good in seven (19.4%), and fair in three (8.3%) according to the functional evaluation system of Enneking. No recurrent tumour occurred within the grafts. The autografts survived in 29 patients (80.6%), and the rates of survival at five and ten years were 86.1% and 80.6 %, respectively. Seven of 16 osteo-articular grafts (44%) failed because of fracture or infection, but all the composite and intercalary grafts survived. The long-term outcomes of frozen autografting, particularly using composite and intercalary grafts, are satisfactory and thus represent a good method of treatment for patients with a sarcoma of bone or soft tissue.

Effects of a difference in respiratory cycle between treatment planning and irradiation for phase-controlled rescanning and carbon pencil beam scanning.

OBJECTIVE: To evaluate the impact of variation in respiratory cycle between treatment planning and irradiation for pencil beam scanning and phase-controlled rescanning (PCR) on the resulting dose distribution, we conducted a simulation study based on four-dimensional CT (4DCT) data for lung cancer patients. METHODS: 4DCT data were acquired for seven patients with lung tumours. Treatment planning was designed to ensure the delivery of 95% of the prescribed dose to the clinical target volume in respective phases of the 4DCT by taking account of intrafractional beam range variations. Carbon ion pencil beam scanning dose distributions were calculated for various respiratory cycles that differed from the reference respiration (=4.4 s) but which stayed regular during irradiation. The number of rescannings was changed to 1, 4 or 8 times. PCR was correlated with the gating window in treatment planning to calculate the beam weighting map. RESULTS: 8×PCR improved dose conformation to the target for all irradiation respiratory cycles. Minimum dose (Dmin) and lowest dose encompassing 95% of the target (D95) values with 4×PCR were decreased from 94.1% and 98.1% to 88.4% and 93.5% with an altered irradiation respiratory cycle of 2.4 s. However, these values were improved with 8×PCR to over 94.9% for Dmin and 98.6% for D95 for respective irradiation respiratory cycles. CONCLUSION: Pencil beam scanning treatment with eight or more PCRs consistently improved dose conformation for moving lung targets even when different respiratory cycles were used for treatment planning and irradiation. ADVANCES IN KNOWLEDGE: Scanning treatment with eight or more rescannings consistently improved dose homogeneity to a moving target even though respiratory cycles varied during treatment.

Molecular cloning and characterization of Th1 and Th2 cytokines of African buffalo (Syncerus caffer).

The African buffalo (Syncerus caffer) has been implicated as the reservoir of several bovine infectious agents. However, there is insufficient information on the protective immune responses in the African buffalo, particularly in infected animals. In this study, we analysed Th1 cytokines IL-2 and IFN-γ, and Th2 cytokines IL-4 and IL-10. The cloned cDNA of IL-2, IL-4, IL-10 and IFN-γ contained an open reading frame of 468, 501, 408 and 540 nucleotides, encoding polypeptides of 155, 166, 135 and 179 amino acids, respectively. Nucleotide sequence homology of IL-2, IFN-γ and IL-4 was more than 98% between the African buffalo and cattle, which resulted in identical polypeptides. Meanwhile, IL-10 gene of African buffalo and cattle had 95% homology in nucleotide sequence, corresponding to thirteen amino acid residues substitution. Cysteine residues and potential glycosylation sites were conserved within the family Bovinae. Phylogenetic analyses including cytokines of the African buffalo placed them within a cluster comprised mainly of species belonging to the order Artiodactyla, including cattle, water buffalo, sheep, goat, pig and artiodactyl wildlife. A deeper understanding of the structure of these cytokines will shed light on their protective role in the disease-resistant African buffalo in comparison with other closely related species.

Evaluation of the efficacy and safety of the combination of gemcitabine and nedaplatin for elderly patients with advanced non-small-cell lung cancer.

OBJECTIVE: The aim of the present study was to retrospectively assess the safety and efficacy of the combination of gemcitabine and nedaplatin in elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients ≥75 years with previously untreated NSCLC who underwent chemotherapy consisting of gemcitabine (800 mg/m(2) on days 1 and 8) and nedaplatin (80 mg/m(2) on day 1) every 3 weeks were retrospectively analyzed. RESULTS: Of the 35 patients, 28 were men and 7 were women, with a mean age of 78 years (range 75-87); 10 patients had stage IIIB disease and 25 patients had stage IV disease. The overall response rate was 45.7% (95% confidence interval 28.8-63.4). The median survival time was 14 months (range 3-44). Grade 3-4 toxicities included neutropenia in 74.3%, thrombocytopenia in 48.6%, anemia in 34.3%, hepatic dysfunction in 11.4%, and infection in 2.9%. There were no treatment-related deaths. There were no differences in response rate and survival between patients aged 75-79 years and patients ≥80 years, although grade 3-4 thrombocytopenia and anemia were significantly more frequent in patients ≥80 years. CONCLUSION: Our results suggest that the combination of gemcitabine and nedaplatin is effective and well tolerated for selected elderly patients with advanced NSCLC.