To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC).
Eligibility ...criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients.
Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6%-68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed.
Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
•Accelerator-BNCT produced tumor response in 71% of head and neck patients.•BNCT showed no serious adverse events such as grade 4 or 5, except hyperamylasemia.•The results support a pivotal role of ...accelerator BNCT in cancer treatment.
Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer.
In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS).
Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4–76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%).
These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To review treatment outcomes for stereotactic body radiotherapy (SBRT) in medically operable patients with Stage I non-small-cell lung cancer (NSCLC), using a Japanese multi-institutional database.
...Between 1995 and 2004, a total of 87 patients with Stage I NSCLC (median age, 74 years; T1N0M0, n=65; T2N0M0, n=22) who were medically operable but refused surgery were treated using SBRT alone in 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. Total dose was 45-72.5 Gy at the isocenter, administered in 3-10 fractions. Median calculated biological effective dose was 116 Gy (range, 100-141 Gy). Data were collected and analyzed retrospectively.
During follow-up (median, 55 months), cumulative local control rates for T1 and T2 tumors at 5 years after SBRT were 92% and 73%, respectively. Pulmonary complications above Grade 2 arose in 1 patient (1.1%). Five-year overall survival rates for Stage IA and IB subgroups were 72% and 62%, respectively. One patient who developed local recurrences safely underwent salvage surgery.
Stereotactic body radiotherapy is safe and promising as a radical treatment for operable Stage I NSCLC. The survival rate for SBRT is potentially comparable to that for surgery.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Background
The aim of this study was to investigate the prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a predictive marker prior to treatment ofcervical cancer with ...radiation therapy (RT) alone or concurrent chemoradiation therapy (CCRT).
Methods
Fifty-six patients with squamous cell carcinoma (SCC) of the uterine cervix who underwent RT or CCRT from 2005−2013 at the Hirosaki University Hospital were retrospectively identified using electronic databases. Patients were divided into a high NLR group (≥2.5) and a low NLR group (<2.5). The efficacy of RT and CCRT in the two groups was compared.
Result
Of the 56 patients, 35 were in the high NLR group and 21 were in the low NLR group. In comparison to a high NLR, a low NLR was significantly associated with a complete response (
P
< 0.001). When cancer was divided into stages I/II and III/IV, patients with a low NLR had a significantly better therapeutic outcome than those with a high NLR (
P
< 0.05). Multivariate analysis showed that only the NLR was a significant prognostic factor for progression-free survival (PFS) and overall survival (OS). Patients with a high NLR had significantly shorter PFS and OS than those with a low NLR.
Conclusion
Results showed that a low NLR before treatment could predict a good response to RT or CCRT at all stages of uterine cervical cancer. The NLR may be a promising parameter on which to base the choice of a therapeutic strategy to treat SCC of the uterine cervix.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the ...phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14–48 days) for oral mucositis, 40 days (IQR, 24–56 days) for dermatitis, 58 days (IQR, 53–80 days) for dysgeusia and 156 days (IQR, 82–163 days) for alopecia. In the FF beam group, parotitis (P = 0.007) was less frequent, while oral mucositis (P = 0.032), fatigue (P = 0.002), conjunctivitis (P = 0.001), epistaxis (P = 0.001) and abdominal discomfort (P = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT.
Colony-stimulating factor 2 (CSF2) is a potent cytokine that stimulates myeloid cells, such as dendritic cells and macrophages. We have been analyzing the roles of microglia in retinal degeneration ...through the modulation of inflammation in the eye, and examined the roles of CSF2 in this process. Both subunits of the CSF2 receptor are expressed in microglia, but no evidence suggesting the involvement of CSF2 in inflammation in the degenerating eye has been reported. We found that Csf2 transcripts were induced in the early phase of in vitro mouse adult retina culture, used as degeneration models, suggesting that CSF2 induction is one of the earliest events occurring in the pathology of retinal degeneration. The administration of CSF2 into the retina after systemic NaIO3 treatment increased the number of microglia. To examine the roles of CSF2 in retinal inflammation, we overexpressed CSF2 in retinal explants. Induction of CSF2 activated microglia and Müller glia, and the layer structure of the retina was severely perturbed. CC motif chemokine ligand 2 (Ccl2) and C-X-C motif chemokine ligand 10 (Cxcl10), both of which are expressed in activated microglia, were strongly induced by the expression of CSF2 in the retina. The addition of CSF2 to primary retinal microglia and the microglial cell lines MG5 and BV2 showed statistically significant increase in Ccl2 and Il1b transcripts. Furthermore, CSF2 induced proliferation, migration, and phagocytosis in MG5 and/or BV2. The effects of CSF2 on microglia were mild, suggesting that CSF2 induced strong inflammation in the context of the retinal environment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Renewable resource based green biocomposites were prepared using a bacterial polyester i.e., poly(hydroxybutyrate-co-valerate) (PHBV) and natural bamboo fiber. Fabrication of the biocomposites was ...carried out by injection molding following extrusion compounding of PHBV and bamboo fiber with 30 or 40wt.% fiber. The mechanical, thermo-mechanical and morphological properties of the biocomposites were evaluated. Little variation in the thermo-mechanical and impact properties was observed when the fiber content was varied. The tensile modulus of biocomposites at 40wt.% fiber improved by 175% as compared to that of neat PHBV. The theoretical tensile modulus of the biocomposites was calculated using Christensen’s equations and compared with the experimental results. It was found to be in near approximation to the experimental data. The storage modulus was affected slightly by the variation of fiber content from 30 to 40wt.% in biocomposites. The heat deflection temperature of PHBV increased by 9°C at 40wt.% of fiber reinforcement. Morphological aspects and thermal stability were studied using scanning electron microscopy and thermo-gravimetric analysis, respectively. In addition, a comparative analysis of bamboo fiber–PHBV with wood fiber–PHBV biocomposites was performed. Statistical analysis of both biocomposites was carried out by performing a two-way ANOVA on their tensile and flexural moduli in order to evaluate the effect of fiber type and content in the PHBV matrix.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I ...non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study.
This is a retrospective study to review 257 patients with stage I NSCLC (median age, 74 years: 164 T1N0M0, 93 T2N0M0) were treated with HypoFXSRT alone at 14 institutions. Stereotactic three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple static ports. A total dose of 18 to 75 Gy at the isocenter was administered in one to 22 fractions. The median calculated biological effective dose (BED) was 111 Gy (range, 57–180 Gy) based on α/β = 10.
During follow-up (median, 38 months), pulmonary complications of above grade 2 arose in 14 patients (5.4%). Local progression occurred in 36 patients (14.0%), and the local recurrence rate was 8.4% for a BED of 100 Gy or more compared with 42.9% for less than 100 Gy (p< 0.001). The 5-year overall survival rate of medically operable patients was 70.8% among those treated with a BED of 100 Gy or more compared with 30.2% among those treated with less than 100 Gy (p< 0.05).
Although this is a retrospective study, HypoFXSRT with a BED of less than 180 Gy was almost safe for stage I NSCLC, and the local control and overall survival rates in 5 years with a BED of 100 Gy or more were superior to the reported results for conventional radiotherapy. For all treatment methods and schedules, the local control and survival rates were better with a BED of 100 Gy or more compared with less than 100 Gy. HypoFXSRT is feasible for curative treatment of patients with stage I NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but ...the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 μM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 μM DFO treatment. In cells treated with 5 μM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia.
Abstract
The dosimetric effect of set-up error in boron neutron capture therapy (BNCT) for head and neck cancer remains unclear. In this study, we analyzed the tendency of dose error by treatment ...location when simulating the set-up error of patients. We also determined the tolerance level of the set-up error in BNCT for head and neck cancer. As a method, the distal direction was shifted with an interval of 2.5 mm, from 0.0 mm to +20.0 mm and compared with the dose at the reference position. Similarly, the horizontal direction and vertical direction were shifted, with an interval of 5.0 mm, from −20.0 mm to +20.0 mm. In addition, cases with 3.0 mm and 5.0 mm simultaneous shifts in all directions were analyzed as the worst-case scenario. The dose metrics of the minimum dose of the tumor and the maximum dose of the mucosa were evaluated. From unidirectional set-up error analysis, in most cases, the set-up errors with dose errors within ±5% were Δdistal < +2.5 mm, Δhorizontal < ±5.0 mm and Δvertical < ±5.0 mm. In the simulation of 3.0 mm shifts in all directions, the errors in the minimum tumor dose and maximum mucosal dose were −3.6% ±1.4% (range, −5.4% to −0.6%) and 2% ±1.4% (range, 0.4% to 4.5%), respectively. From these results, if the set-up error was within ±3.0 mm in each direction, the dose errors of the tumor and mucosa could be suppressed within approximately ±5%, which is suggested as a tolerance level.
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