Hirofumi Asakura

Selective Eosinophil Adhesion to Fibroblast Via IFN-γ-Induced Galectin-9

Among galectin family members, galectin-9 was first described as a potent eosinophil chemoattractant derived from Ag-stimulated T cells. In the present study a role of galectin-9 in the interaction between eosinophils and fibroblasts was investigated using a human lung fibroblast cell line, HFL-1. RT-PCR, real-time PCR, and Western blot analyses revealed that both galectin-9 mRNA and protein in HFL-1 cells were up-regulated by IFN-γ stimulation. On the one hand, IL-4, known as a Th2 cytokine, did not affect the galectin-9 expression in HFL-1 cells. We further confirmed that IFN-γ up-regulated the expression of galectin-9 in primary human dermal fibroblasts. Flow cytometric analysis revealed that IFN-γ up-regulated surface galectin-9 expression on HFL-1 cells. Stimulation of HFL-1 cells with IFN-γ up-regulated adhesion of eosinophils, but not neutrophils, to HFL-1 cells. This adherence of eosinophils to HFL-1 cells was inhibited by both lactose and anti-galectin-9 Ab. These findings demonstrate that IFN-γ-induced galectin-9 expression in fibroblasts mediates eosinophil adhesion to the cells, suggesting a crucial role of galectin-9 in IFN-γ-stimulated fibroblasts as a physiological modulator at the inflammatory sites.

Usefulness of FDG-PET imaging for the radiotherapy treatment planning of pyothorax-associated lymphoma

Pyothorax-associated lymphoma (PAL) is a non-Hodgkin’s lymphoma developing in the pleural cavity after a long-standing history of chronic pyothorax (CP). F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is a useful modality for determination of disease extent of various malignant tumors, including malignant lymphoma, but there have been no reports describing the usefulness of FDG-PET imaging in PAL. Here we report a case of PAL that relapsed after chemotherapy and was successfully treated by radiotherapy. FDG-PET imaging revealed that the tumor was localized to a soft-tissue attenuation mass behind the CP cavity in the right thorax, but did not infiltrate the CP cavity. A total dose of 40 Gy was administered to the area that included the PET-positive lesion, instead of including the entire CP cavity in the radiation field. Although computed tomography (CT) showed a residual mass, no FDG uptake was indicated by FDG-PET imaging performed just after the end of radiotherapy, and additional irradiation was not performed. No sign of relapse was found by FDG-PET imaging 3 months later. FDG-PET imaging was useful for both the planning of radiotherapy and assessing the treatment response of PAL.

Unknown primary carcinoma, diagnosed as inflammatory breast cancer,and successfully treated with trastuzumab and vinorelbine.

Occult breast cancer presenting with axillary lymph node metastases is uncommon, and inflammatory breast cancer (IBC), as a subtype, is quite rare. Here we describe a case of IBC, which arose as an unknown primary carcinoma; the patient presented with axillary lymph node metastasis, and was successfully treated with trastuzumab and vinorelbine. Specifically, a 55-year-old woman presented with right axillary lymphadenopathy. Although she underwent various examinations, the primary site of the disease was not revealed. Axillary lymph node dissection was performed, and the lesion was diagnosed as a poorly differentiated adenocarcinoma. The patient chose to be treated by alternative medicine. About 6 months later, she was referred to our hospital, due to marked bilateral neck and axillary lymph node swelling. She presented withdiffuse right breast enlargement, redness, and peau d’orange. Computed tomography (CT) of the breast showed skin thickening and swelling of the right breast.F-18 Fluorodeoxyglucose positron emission tomography (FDG-PET) showed FDG uptake in the right breast. The patient was clinically diagnosed with IBC. Because overexpression of the human epidermal growth factor receptor 2 (HER2) was found in the specimen from her right axillary lymph node, she was treated with trastuzumab and vinorelbine. Two months after the start of chemotherapy, CT revealed a complete response in the lymph nodes, and the skin thickening and parenchymal edema of the right breast had improved. FDG-PET was also performed at this time, and revealed no FDG uptake in either the right breast or the lymph nodes.

Reirradiation of spinal metastases with intensity-modulated radiation therapy: an analysis of 23 patients

This study aimed to evaluate the efficacy and safety of reirradiation with intensity-modulated radiation therapy (IMRT) for spinal metastases. We retrospectively analyzed 23 patients with spinal metastases who underwent IMRT reirradiation between December 2006 and July 2013. We evaluated the spinal radiation doses during the first and second radiation therapy courses, the interval between the courses, and the clinical outcomes after reirradiation, including skeletal-related events, local control rates (LCRs), overall survival (OS), and toxicities. The median time from the first irradiation to reirradiation was 13 months (range, 2–75 months). The median reirradiation dose delivered to 90% of the planning target volume was 24.5 Gy in 5 fractions (range, 14.7–50 Gy in 3–25 fractions). Nineteen patients experienced pain at reirradiation, and 15 of these attained pain relief. Two of the three patients with paresis in the upper or lower extremities upon initiation of reirradiation demonstrated improvement. Local progression was identified in four patients. The median time to local progression was 37 months. The 1- and 2-year LCRs after reirradiation were 88% and 75%, respectively. The 1- and 2-year OS rates after reirradiation were 45% and 20%, respectively, with a median OS of 12 months. No late toxicities occurred. In conclusion, spinal metastasis reirradiation using IMRT appears safe; pain relief and paresis improvement and/or prevention can be expected, along with a reduced risk of radiation-induced toxicity, especially in the spinal cord.

Re-irradiation for locoregionally recurrent tumors of the thorax: a single-institution, retrospective study.

BackgroundRe-irradiation (re-RT) of the thorax is challenging due to the impact of prior therapies on normal tissues, and there are few reports of definitive re-RT. The treatment toxicities and efficacy of re-RT are not well known. The aim of the present study was to assess the safety and efficacy of definitive re-RT of the thorax.MethodsPatients who were treated with thoracic re-RT between March 2007 and December 2014 were retrospectively analyzed. Primary and re-irradiation plans were required to have an overlap of dose distributions for the 80xa0% isodose level. All doses were recalculated to an equivalent dose of 2xa0Gy per fraction (EQD2). When possible, analysis of dose accumulation was carried out using the medical image merge (MIM) (®) software program (version 6.5, MIM Software Inc., Cleveland, OH). Administration dosages for organs at risk were defined.ResultsFourteen (67xa0%) and seven (33xa0%) patients with non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC), respectively, were identified. The patients’ median age was 72 (range 53–85) years. Fifteen patients (71xa0%) had “proximal” tumors, defined as tumors at the distal 2xa0cm of the trachea, carina, and main bronchi. The median interval from initial RT to re-RT was 26.8 (range 11.4–92.3) months. Re-RT was delivered by X-ray beam and proton beam therapy in 20 (95xa0%) patients and 1 (5xa0%) patient, respectively. The median radiation dose of re-RT was 60 (range 54–87.5) Gy10 and 50 (range 50.0–87.5) Gy10 for patients with NSCLC and SCLC, respectively. Grade 3 acute radiation pneumonitis occurred in only one patient. There were no other serious complications. The median follow-up time was 22.1 (range 2.3–56.4) months. The median local progression-free survival time (LPFS) and overall survival time (OS) were 12.9 (95xa0% confidence interval (CI): 8.9–27.9) months and 31.4 (95xa0% CI: 16.9–45.9) months, respectively. Patients receivingu2009≥u200960xa0Gy10 at re-RT had longer LPFS (pu2009=u20090.04).ConclusionsGood safety with longer OS than in previous reports was demonstrated. Re-RT seems to be a promising treatment option. Further study to define the risk-benefit ratios is necessary.

Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer.

The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non‐small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m2, day 1) and oral S‐1 (80, 100 or 120 mg based on body surface area, days 1–14), repeated as four cycles every 4 weeks. Dose‐limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1–90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow‐up time was 43 months, and the median progression‐free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585)

Fracture after radiation therapy for femoral metastasis: incidence, timing and clinical features

ABSTRACT We analyzed 428 femoral metastases initially treated with radiotherapy between 2002 and 2011 to clarify the clinical details of post-irradiation fractures of femoral metastasis. Patients included 161 men and 167 women, with a mean age of 62 years. Fracture incidence, fracture site, fracture risk based on X-ray images before radiotherapy, and interval from completion of radiotherapy to fracture occurrence were assessed. In addition, 24 pathological specimens obtained during 27 surgeries for these fractures were examined. Fractures occurred in 7.7% of 428 femoral metastases (total 33: 28 actual fractures and five virtual fractures with progressive pain and bone destruction). The fracture rate was 7.8% in the proximal femur and 1.5% in the shaft (P = 0.001). Fractures occurred a median of 4.4 months after radiotherapy, with 39.4% occurring within 3 months and 63.6% within 6 months. Among femurs with high fracture risk according to Harrington’s criteria or Mirels’ score, the fracture rate was 13.9% and 11.8%, respectively. Viable tumor cells were detected in all five patients with painful virtual fracture, in 85.7% of femurs with actual fractures that occurred within 3 months, and in only 25.0% of actual fractures occurring after 3 months. Post-irradiation fractures of femoral metastasis most frequently occurred within 3 months after radiotherapy, and were more common in the peritrochanteric area than in the shaft. Radiological evidence of impending fracture did not correlate with a high fracture rate. Actual fractures occurring after more than 3 months were likely caused by post-irradiation fragility of the femur, without viable tumor cells.

Prognostic factors in patients with brain metastasis from non-small cell lung cancer treated with whole-brain radiotherapy.

AIMSnThe purpose of this study was to evaluate the prognostic factors associated with overall survival (OS) in nonsmall cell lung cancer (NSCLC) patients with brain metastasis who received whole-brain radiotherapy (WBRT).nnnMATERIALS AND METHODSnThis study included 264 consecutive NSCLC patients with brain metastasis who received WBRT. Patients with leptomeningeal metastasis and those who underwent craniotomy or stereotactic radiotherapy before WBRT were excluded. The evaluated prognostic factors for OS included gender, neurological deficit, histology, epidermal growth factor receptor (EGFR) mutation status, previous cytotoxic chemotherapy, previous EGFR-tyrosine kinase inhibitor treatment, recursive partitioning analysis (RPA) class, and diagnosis-specific graded prognostic assessment (DS-GPA) score. All factors with a P < 0.05 in univariate analysis were entered into multivariate analysis using Cox regression and a confidence interval of 99%.nnnRESULTSnTwo hundred thirty patients had died, 14 patients were alive, and 20 patients were lost to follow-up. The median follow-up time was 20.9 months. The median survival time was 5.5 months (95% confidence interval; 4.8-6.3). Univariate analysis showed that gender, neurological deficit, histology, EGFR mutation status, RPA class, and DS-GPA score were significant prognostic factors for OS. In multivariate analysis, RPA class and histology were found to be significant prognostic factors for OS, with P values of 0.0039 and 0.0014, respectively.nnnCONCLUSIONSnRPA Class I or II (Karnofsky Performance Status ≥70) and adenocarcinoma histology were associated with longer OS. These factors should be taken into account when considering indication for WBRT.

Feasibility of extended-field irradiation and intracavitary brachytherapy combined with weekly cisplatin chemosensitization for IB2–IIIB cervical cancer with positive paraaortic or high common iliac lymph nodes: a retrospective review

BackgroundThe aim of this retrospective study was to investigate the feasibility of primary treatment with extended-field irradiation and weekly cisplatin (extended-field concurrent chemoradiotherapy, EFCCRT) as initial therapy in patients with International Federation of Gynecology and Obstetrics IB1 to IIIB cervical cancer with paraaortic or high common iliac lymph node metastases.MethodsParticipants comprised patients with confirmed cervical cancer, showing paraaortic or high common iliac lymph node metastases on diagnostic imaging, treated with EFCCRT. Total external radiation doses were 50.4xa0Gy to the whole pelvis and 45.0xa0Gy to the lumbar paraaortic region. High-dose-rate intracavitary brachytherapy was performed to deliver a total dose of 18–24xa0Gy in 6-Gy fractions prescribed at point A. Weekly cisplatin (30–40xa0mg/m2) was given concurrently with radiotherapy.ResultsTwenty-four patients were treated. Median follow-up interval was 34xa0months. The dose of cisplatin was 30xa0mg/m2 in 2 cases, 35xa0mg/m2 in 8 cases, and 40xa0mg/m2 in 14 cases. Twenty-two cases (92xa0%) received more than 160xa0mg/m2 cisplatin. Ten cases (42xa0%) experienced acute grade 3/4 hematological toxicity, and 9 cases (38xa0%) experienced acute grade 3 nonhematological toxicity. No case presented late grade 3/4 toxicity. Three-year progression-free and overall survival rates were 54xa0% and 72xa0%, respectively. Eleven cases recurred during follow-up. Sites of recurrence were within the irradiation field in 4 cases, outside the field in 6 cases, and in both fields in 1 case.ConclusionEFCCRT and high-dose-rate intracavitary brachytherapy for patients with paraaortic or high common iliac lymph node metastases from cervical cancer is feasible.