Kenshiro Shiraishi

Exceptionally high incidence of symptomatic grade 2-5 radiation pneumonitis after stereotactic radiation therapy for lung tumors.

BackgroundTo determine the usefulness of dose volume histogram (DVH) factors for predicting the occurrence of radiation pneumonitis (RP) after application of stereotactic radiation therapy (SRT) for lung tumors, DVH factors were measured before irradiation.MethodsFrom May 2004 to April 2006, 25 patients were treated with SRT at the University of Tokyo Hospital. Eighteen patients had primary lung cancer and seven had metastatic lung cancer. SRT was given in 6–7 fields with an isocenter dose of 48 Gy in four fractions over 5–8 days by linear accelerator.ResultsSeven of the 25 patients suffered from RP of symptomatic grade 2–5 according to the NCI-CTC version 3.0. The overall incidence rate of RP grade2 or more was 29% at 18 months after completing SRT and three patients died from RP. RP occurred at significantly increased frequencies in patients with higher conformity index (CI) (p = 0.0394). Mean lung dose (MLD) showed a significant correlation with V5–V20 (irradiated lung volume) (p < 0.001) but showed no correlation with CI. RP did not statistically correlate with MLD. MLD had the strongest correlation with V5.ConclusionEven in SRT, when large volumes of lung parenchyma are irradiated to such high doses as the minimum dose within planning target volume, the incidence of lung toxicity can become high.

Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1α

Purpose: We studied whether i.v. administration of a chemokine after local tumor site irradiation could prevent remaining, as well as distant, nonirradiated tumor cell growth by leukocyte recruitment. Experimental Design: Tumors were implanted s.c. in the right or both flanks. After local irradiation at the right flank, ECI301, a human macrophage inflammatory protein-1α variant was injected i.v. Tumor volumes were measured every 3 days after treatment. Results: In Colon26 adenocarcinoma-bearing BALB/c mice, repeated daily administration (over 3-5 consecutive days) of 2 μg per mouse ECI301 after local irradiation of 6 Gy prolonged survival without significant toxicity, and in about half of the treated mice, the tumor was completely eradicated. Three weekly administrations of ECI301 after local irradiation also led to significant, although less effective, antitumor radiation efficacy. ECI301 also inhibited growth of other syngenic tumor grafts, including MethA fibrosarcoma (BALB/c) and Lewis lung carcinoma (C57BL/6). Importantly, tumor growth at the nonirradiated site was inhibited, indicating that ECI301 potentiated the abscopal effect of radiation. This abscopal effect observed in BALB/c and C57BL/6 mice was tumor-type independent. Leukocyte depletion studies suggest that CD8+ and CD4+ lymphocytes and NK1.1 cells were involved. Conclusions: Marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of the abscopal effect, was potentiated by i.v. administration of ECI301. The results of this study may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer.

A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen.

We conducted a phase I clinical trial of a cancer vaccine using a 20‐mer NY‐ESO‐1f peptide (NY‐ESO‐1 91–110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 μg of NY‐ESO‐1f peptide mixed with 0.2 KE Picibanil OK‐432 and 1.25 ml Montanide ISA‐51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY‐ESO‐1f peptide vaccine was well tolerated. Vaccine‐related adverse events observed were fever (Grade 1), injection‐site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY‐ESO‐1f peptide resulted in an increase or induction of NY‐ESO‐1 antibody responses in nine of ten patients. The sera reacted with recombinant NY‐ESO‐1 whole protein as well as the NY‐ESO‐1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine‐induced CD4 and CD8 T cells responded to NY‐ESO‐1 91–108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20‐mer NY‐ESO‐1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY‐ESO‐1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients.

Taste dysfunction in patients receiving radiotherapy.

Taste loss is a major cause of morbidity in patients undergoing head and neck irradiation.

Quality assurance of volumetric modulated arc therapy using Elekta Synergy

Purpose. Recently, Elekta has supplied volumetric modulated arc therapy (VMAT) in which multi-leaf collimator (MLC) shape, jaw position, collimator angle, and gantry speed vary continuously during gantry rotation. A quality assurance procedure for VMAT delivery is described. Methods and materials. A single-arc VMAT plan with 73 control points (CPs) and 5-degree gantry angle spacing for a prostate cancer patient has been created by ERGO + + treatment planning system (TPS), where MLC shapes are given by anatomic relationship between a target and organs at risk and the monitor unit for each CP is optimized based on given dose prescriptions. Actual leaf and jaw positions, gantry angles and dose rates during prostate VMAT delivery were recorded in every 0.25 seconds, and the errors between planned and actual values were evaluated. The dose re-calculation using these recorded data has been performed and compared with the original TPS plan using the gamma index. Results. Typical peak errors of gantry angles, leaf positions, and jaw positions were 3 degrees, 0.6 mm, and 1 mm, respectively. The dose distribution obtained by the TPS plan and the recalculated one agreed well under 2%-2 mm gamma index criteria. Conclusions. Quality assurance for prostate VMAT delivery has been performed with a satisfied result.

Radiotherapy for lymph node metastases in patients with hepatocellular carcinoma: Retrospective study

Aim:  This study was conducted to evaluate the effect of external radiation therapy on lymph node metastases from hepatocellular carcinoma (HCC).

Oral pilocarpine (5 mg t.i.d.) used for xerostomia causes adverse effects in Japanese

OBJECTIVE To evaluate Japanese tolerability to pilocarpine of 5 mg t.i.d. METHODS From January 2006 to July 2006, 39 patients with xerostomia received 5 mg t.i.d. pilocarpine for at least for 12 weeks unless they had experienced unacceptable adverse effects. All patients received radiotherapy that included the parotid glands in the radiation field >50 Gy. The body weights of the patients ranged from 42 to 73 kg (median 60 kg). RESULTS Thirty-six of the 39 patients were evaluable. The tolerated rate was only 47%. Of the 25 patients whose body weights were less than 65 kg, the tolerated rate was 36%, whereas the rate of the 11 patients whose body weights were 65 kg or above was 72% (p=0.050). The most common adverse effect was sweating with an incidence of 64%. Response rate, which was defined as the total number of patients with an increase of at least 25 mm from the baseline in the VAS score divided by the number of maintaining patients among those who started pilocarpine after more than 4 months from the start of radiotherapy, was 40% at 12 weeks (n=15). CONCLUSION For Japanese, 5mg t.i.d. pilocarpine caused a high incidence of unacceptable adverse effects. A lower dose of pilocarpine needs to be considered.

Stereotactic body radiotherapy for metastatic lung cancer as oligo-recurrence: an analysis of 42 cases.

Purpose. To investigate the outcome and toxicity of stereotactic body radiotherapy (SBRT) in patients with oligo-recurrence cancer in the lung (ORCL). Methods and Materials. A retrospective review of 42 patients with ORCL who underwent SBRT in our two hospitals was conducted. We evaluated the outcome and adverse effects after SBRT for ORCL. Results. All patients finished their SBRT course without interruptions of toxicity reasons. The median follow-up period was 20 months (range, 1–90 months). The 2-year local control rate and overall survival were 87% (95% CI, 75–99%) and 65% (95% CI, 48–82%). As for prognostic factor, the OS of patients with a short disease-free interval (DFI) <31.9 months, between the initial therapy and SBRT for ORCL, was significantly worse than the OS of long DFI ≧31.9 months (P < 0.05). The most commonly observed late effect was radiation pneumonitis. One patient had grade 4 gastrointestinal toxicity (perforation of gastric tube). No other ≧ grade 3 acute and late adverse events occurred. There were no treatment-related deaths during this study. Conclusions. In patients with ORCL, radical treatment with SBRT is safe and provides a chance for long-term survival by offering favorable local control.

Correlation among 16 biological factors [p53, p21waf1, MIB-1 (Ki-67), p16INK4A, cyclin D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β, MMP-7, COX-2, EGFR, HER2/neu, ER, and HIF-1α] and clinical outcomes following curative chemoradiation therapy in 10 patients with esophageal squamous cell carcinoma

The expression levels of 16 proteins were analyzed to identify prognostic correlations in esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiation therapy (CCRT). The immunohistochemical expression levels of p53, p21waf1, molecular immunology borstel-1 (MIB-1, Ki-67), p16INK4A, cyclin D1, E-cadherin, Bcl-2, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, transforming growth factor (TGF)-β, matrix metalloproteinase (MMP)-7, cyclooxygenase (COX)-2, epidermal growth factor receptor (EGFR), human EGFR type 2 (HER2/neu), estrogen receptor (ER) and hypoxia-inducible factor (HIF)-1α were studied in 10 cases of ESCC treated with CCRT. The patients underwent CCRT between 2000 and 2010. The mean patient age was 68.1 years (range, 46-80 years). The numbers of patients in stages I, II, III and IV of the disease were 2, 2, 3 and 3, respectively. Of the tumors, 8 were positive for p53, 6 for p21waf1, 7 for MIB-1 (Ki-67), 7 for p16INK4A, 7 for cyclin D1, 8 for E-cadherin, 3 for Bcl-2, 0 for TNF-α, 5 for NF-κB, 7 for TGF-β, 9 for MMP-7, 7 for COX-2, 5 for EGFR, 1 for HER2/neu, 1 for ER and 7 for HIF-1α. The 2-year overall survival rate of patients expressing high levels of MIB-1 was 71% (±17%) compared with 0% (P=0.019) for those expressing low levels. For NF-κB, the rate was 0% for patients with high levels compared with 100% (P<0.018) for those with low levels. The 2-year local control rates of HER2/neu were 0% in patients expressing high levels and 88% (±12%) in patients expressing low levels (P=0.027). The 2-year disease-free survival rates of HER2/neu and ER were 0% for patients expressing high levels compared with 56% (±17%) for those with low levels (P=0.027). There were no significant correlations between the expression levels of the other proteins and clinical outcomes. In the present study, high levels of MIB-1 and low levels of NF-κB, HER2 and ER were shown to be good prognostic factors following definitive CCRT for ESCC.

Macrophage Inflammatory Protein Derivative ECI301 Enhances the Alarmin-Associated Abscopal Benefits of Tumor Radiotherapy

Radiotherapy can produce antitumor benefits beyond the local site of irradiation, an immune-based phenomenon known as the abscopal effect, but the mechanisms underlying these benefits are poorly understood. Preclinical studies of ECI301, a mutant derivative of macrophage inhibitory protein-1α, have shown that its administration can improve the antitumor effects of radiotherapy in a manner associated with a tumor-independent abscopal effect. In this article, we report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by intratumoral injection [corrected] of the alarmins HSP70 or HMGB1, but not HSP60, and i.v. administration [corrected] of ECI301 + HSP70 were sufficient to inhibit tumor growth. Although i.v. administration [corrected] of ECI301 + HMGB1 did not inhibit tumor growth, we found that administration of a neutralizing HMGB1 antibody neutralized the cooperative effects of ECI301 on tumor irradiation. Moreover, mice genetically deficient in TLR4, an immune pattern receptor that binds alarmins, including HMGB1 and HSP70, did not exhibit antitumor responses to irradiation with ECI301 administration. Although ECI301 was cleared rapidly from peripheral blood, it was found to bind avidly to HSP70 and HMGB1 in vitro. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4(+) and CD8(+) T cells against tumor cells that may evade irradiation. Cancer Res; 74(18); 5070-8. ©2014 AACR.