Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

Sister Mary Joseph's Nodule From Renal Cell Carcinoma: A Case Report.

Sister Mary Joseph's nodules (SMJNs) are umbilical skin metastases of various abdominopelvic malignancies, and they rarely originate from renal cell carcinomas. Radiotherapy is typically used to treat the nodules as a palliative intention. We report a rare case of SMJN that originated from clear cell renal cell carcinoma, which was treated with external beam radiation therapy (EBRT) and interstitial brachytherapy (ISBT). A 74-year-old male patient with a history of left renal cell carcinoma developed an umbilical nodule which was diagnosed as SMJN. The patient underwent EBRT (30 Gy in 10 fractions) and ISBT (12 Gy in two fractions), leading the nodule to complete resolution. This case report might support that radiotherapy, including ISBT, is effective for the treatment of SMJN from renal cell carcinoma.

Comparison of thoracic and abdominal deep inspiration breath holds in whole-breast irradiation for patients with left-sided breast cancer.

BACKGROUND: The deep inspiration breath hold (DIBH) technique is effective for heart dose reduction in patients with left-sided breast cancer. In deep breathing, some women breathe in thoracic respiration; and others, in abdominal respiration. This study evaluated differences in dose reduction in organs at risk (OAR) and reproducibilities of the target and OAR between thoracic DIBH (T-DIBH) and abdominal DIBH (A-DIBH). METHODS: Fourteen patients with left-sided breast cancer who had planned to receive whole-breast irradiation were included. Computed tomography (CT) was performed in free breathing (FB), T-DIBH, and A-DIBH, and the dosimetric indexes of the target and OAR for three treatment plans were compared. In T-DIBH and A-DIBH, two series CTs were taken in each breathing method and the displacements of the target and heart were calculated. RESULTS: The averaged mean heart doses (MHDs) were 1.5 Gy and 1.6 Gy in T-DIBH and A-DIBH, respectively, significantly lower than 2.7 Gy in FB (p < 0.001 for both breathing methods). Between T-DIBH and A-DIBH, no significant difference in MHD was found (p = 0.95); however, the percentage increase in lung volume positively moderately correlated with the reduction in MHD (R = 0.68). The three-dimensional target displacements were 2.3 mm in T-DIBH and 2.0 mm in A-DIBH (p = 0.64). The three-dimensional heart displacements were 1.7 mm in T-DIBH and 1.8 mm in A-DIBH (p = 0.85). CONCLUSION: The present study demonstrates that the MHD and reproducibility did not differ between T-DIBH and A-DIBH. However, the superior breathing method for increasing lung volume should be determined for each patient.

Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.

INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer.

Purpose Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids-common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting µ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer. Patients and Methods This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety. Results In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia. Conclusion Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.

Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients With Cancer.

Purpose This randomized, double-blind, multicenter study aimed to determine the dose of naldemedine, a peripherally-acting µ-opioid receptor antagonist, for future trials by comparing the efficacy and safety of three doses of naldemedine versus placebo in patients with cancer and opioid-induced constipation. Methods Patients ≥ 18 years old with cancer, an Eastern Cooperative Oncology Group performance status ≤ 2, who had been receiving a stable regimen of opioid analgesics for ≥ 2 weeks, had at least one constipation symptom despite laxative use, and no more than five spontaneous bowel movements (SBMs) during the past 14 days, were randomly assigned (1:1:1:1) to oral, once-daily naldemedine 0.1, 0.2, or 0.4 mg, or placebo, for 14 days. The primary end point was change in SBM frequency per week from baseline during the treatment period. Secondary end points included SBM responder rates, change from baseline in the frequency of SBM without straining, and complete SBM. Safety was also assessed. Results Of 227 patients who were randomly assigned, 225 were assessed for efficacy (naldemedine 0.1 mg, n = 55; 0.2 mg, n = 58; 0.4 mg, n = 56; placebo, n = 56) and 226 for safety. Change in SBM frequency (primary end point) was higher with all naldemedine doses versus placebo ( P < .05 for all comparisons), as were SBM responder rates and change in complete SBM frequency. Change in SBM frequency without straining was significantly improved with naldemedine 0.2 and 0.4 (but not 0.1) mg versus placebo (at least P < .05). Treatment-emergent adverse events were more common with naldemedine (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than placebo (51.8%); the most common treatment-emergent adverse event was diarrhea. Conclusion Fourteen-day treatment with naldemedine significantly improved opioid-induced constipation in patients with cancer and was generally well tolerated. Naldemedine 0.2 mg was selected for phase III studies.

Detection of γH2AX foci in mouse normal brain and brain tumor after boron neutron capture therapy.

AIM: In this study, we investigated γH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT. BACKGROUND: Boron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. (10)B captures neutrons and produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation. MATERIALS AND METHODS: We analyzed the number of γH2AX foci by immunohistochemistry 30 min or 24 h after neutron irradiation. RESULTS: In both normal brain and brain tumor, γH2AX foci induced by (10)B(n,α)(7)Li reaction remained 24 h after neutron beam irradiation. In contrast, γH2AX foci produced by γ-ray irradiation at contaminated dose in BNCT disappeared 24 h after irradiation in these tissues. CONCLUSION: DSBs produced by (10)B(n,α)(7)Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24 h. These DSBs would be more difficult to repair than those by γ-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by (10)B(n,α)(7)Li reaction.

DNA damage induced by boron neutron capture therapy is partially repaired by DNA ligase IV.

Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron ((10)B)-containing compound that specifically accumulates in tumor. (10)B captures neutrons and the resultant fission reaction produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end-joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of (10)B-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D 50) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that (10)B uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53-/- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent (10)B concentration. These results indicate that BNCT-induced DNA damage is partially repaired using DNA ligase IV.

Independent Validation of the Japanese Version of the EORTC QLQ-C15-PAL for Patients With Advanced Cancer.

CONTEXT: Although the psychometric properties of the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative Care (EORTC QLQ-C15-PAL) have been examined previously, that study had several limitations, for example, small sample size. OBJECTIVES: To examine the validity and reliability, including test-retest reliability, of the Japanese version of EORTC QLQ-C15-PAL for cancer patients with metastasis or recurrence. METHODS: A cross-sectional anonymous questionnaire was administered to cancer patients who were being treated on an oncology inpatient ward, in an oncology outpatient clinic, and in seven inpatient palliative units in Japan, from August 2007 to March 2008. RESULTS: Data from a total of 312 cancer patients were analyzed. The proportion of missing values was less than 4% for all items. The factor structure was reproduced identically with the original EORTC QLQ-C15-PAL, English version. The correlation of subscales showed a reasonable matrix. Cronbach's alpha coefficients were 0.76 to 0.86, and intraclass correlation coefficients, which indicate test-retest reliability, ranged from 0.52 to 0.77. All subscales, especially physical functioning, fatigue, and pain, were significantly correlated with self-reported Eastern Cooperative Oncology Group performance status. CONCLUSION: The Japanese version of EORTC QLQ-C15-PAL has sufficient validity, acceptable reliability, and feasibility for patients with advanced cancer.

Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a 10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide.

Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a (10)BSH-containing WOW emulsion.

A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a (10)BSH-containing water-in-oil-in-water emulsion ((10)BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that (10)BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC.

Safety and effectiveness of stereotactic body radiotherapy for a clinically diagnosed primary stage I lung cancer without pathological confirmation.

BACKGROUND: Pathological diagnosis fails in some pulmonary tumors, although they may be highly suspected to be primary lung cancer. We studied the outcome of stereotactic body radiotherapy for a clinically diagnosed primary stage I lung cancer without pathological confirmation. METHODS: The current study included 37 patients (39 lesions) treated with stereotactic body radiotherapy who were clinically diagnosed with primary stage I lung cancer between August 1998 and April 2009 at our hospital. Pulmonary tumors were highly suspected to be malignant from physical and imaging examinations. Biopsies were performed for 62 % of patients, although malignancy was not pathologically confirmed. In the other 38 % of patients, a biopsy was not feasible. Median age of the patients was 77 years. Median tumor diameter was 20 mm. A total median dose of 48 Gy was prescribed to the isocenter in four fractions. Median follow-up period was 39 months. RESULTS: The 3-year overall survival, local control, and regional-distant control were 74.2, 94.0, and 68.6 %, respectively. In patients with tumors ≤20 mm, overall survival and regional-distant control were significantly higher than in patients with tumors >20 mm (p ≤ 0.001), whereas no significant difference was observed regarding local control. No grade 3-5 adverse events possibly, probably, or definitely related to the treatment were observed. CONCLUSIONS: Stereotactic body radiotherapy is safe and effective for a clinically diagnosed primary stage I lung cancer when pathological diagnosis is difficult even with repeat biopsies, or a biopsy is not feasible for reasons of the patient's health condition or wishes.

The dependency of compound biological effectiveness factors on the type and the concentration of administered neutron capture agents in boron neutron capture therapy.

PURPOSE: To examine the effect of the type and the concentration of neutron capture agents on the values of compound biological effectiveness (CBE) in boron neutron capture therapy. METHODS AND MATERIALS: After the subcutaneous administration of a (10) B-carrier, boronophenylalanine- (10) B (BPA) or sodium mercaptododecaborate- (10) B (BSH), at 3 separate concentrations, the (10) B concentrations in tumors were measured by γ-ray spectrometry. SCC VII tumor-bearing C3H/He mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells, then treated with BPA or BSH. Immediately after reactor neutron beam irradiation, during which intratumor (10) B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. RESULTS: The CBE values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. In addition, the higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in the use of BPA than BSH. The values for neutron capture agents that deliver into solid tumors more dependently on uptake capacity of tumor cells became more changeable. CONCLUSION: Tumor characteristics, such as micro-environmental heterogeneity, stochastic genetic or epigenetic changes, or hierarchical organization of tumor cells, are thought to partially influence on the value of CBE, meaning that the CBE value itself may be one of the indices showing the degree of tumor heterogeneity.

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

BACKGROUND: The aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. METHODS: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. RESULTS: Thalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. CONCLUSION: Daily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.

Differences in the dose-volume metrics with heterogeneity correction status and its influence on local control in stereotactic body radiation therapy for lung cancer.

The purpose of this study is to evaluate the dose-volume metrics under different heterogeneity corrections and the factors associated with local recurrence (LR) after stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). Eighty-three patients who underwent SBRT for pathologically proven stage I NSCLC were reviewed retrospectively. The prescribed dose was 48 Gy in four fractions at the isocenter (IC) under heterogeneity correction with the Batho power law (BPL). The clinical plans were recalculated with Eclipse (Varian) for the same monitor units under the BPL and anisotropic analytical algorithm (AAA) and with no heterogeneity correction (NC). The dose at the IC, dose that covers 95% of the volume (D95), minimum dose (Min), and mean dose (Mean) of the planning target volume (PTV) were compared under each algorithm and between patients with local lesion control (LC) and LR. The IC doses under NC were significantly lower than those under the BPL and AAA. Under the BPL, the mean PTV D95, Min and Mean were 8.0, 9.4 and 7.4% higher than those under the AAA, and 9.6, 9.2 and 4.6% higher than those under NC, respectively. Under the AAA, all dose-volumetric parameters were significantly lower in T1a patients than in those with T1b and T2a. With a median follow-up of 35.9 months, LR occurred in 18 patients. Between the LC and LR groups, no significant differences were observed for any of the metrics. Even after stratification according to T-stage, no significant difference was observed between LC and LR.

A phase II study of lapatinib for brain metastases in patients with HER2-overexpressing breast cancer following trastuzumab based systemic therapy and cranial radiotherapy: subset analysis of Japanese patients.

BACKGROUND: It is known that one third of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) treated with trastuzumab will develop brain metastases. As the development of brain metastases is fatal, controlling its progression is clinically meaningful. However, effective therapy for MBC patients with brain metastasis after cranial radiation is limited. The international clinical study in which six Japanese patients participated indicated the antitumor activity of lapatinib against brain metastases of HER2-overexpressing breast cancer. METHODS: The efficacy, safety, and pharmacokinetics of lapatinib 750 mg given twice daily to Japanese HER2-overexpressing MBC patients with brain metastases were assessed as part of the international clinical study. RESULTS: Of six Japanese patients treated in this study, two patients had shown volumetric reduction >20 % in their central nervous system (CNS), one of whom had >50 % reduction. Three patients, including two of these patients, had shown >20 % volumetric reduction in non-CNS lesions. Frequently reported adverse events were diarrhea and rash, all of which were controllable. The AUC0-12 of lapatinib on day 28 was 1.74 times higher than that on day 1. CONCLUSION: These results suggest that lapatinib monotherapy 750 mg given twice daily can exert some efficacy and has potential as a clinically meaningful treatment option for Japanese HER2-overexpressing breast cancer patients with brain metastases after cranial radiation.

Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population.

Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (= P + Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with γ-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations.

Differences in dose-volumetric data between the analytical anisotropic algorithm and the x-ray voxel Monte Carlo algorithm in stereotactic body radiation therapy for lung cancer.

The objective of this study was to evaluate the differences in dose-volumetric data obtained using the analytical anisotropic algorithm (AAA) vs the x-ray voxel Monte Carlo (XVMC) algorithm for stereotactic body radiation therapy (SBRT) for lung cancer. Dose-volumetric data from 20 patients treated with SBRT for solitary lung cancer generated using the iPlan XVMC for the Novalis system consisting of a 6-MV linear accelerator and micro-multileaf collimators were recalculated with the AAA in Eclipse using the same monitor units and identical beam setup. The mean isocenter dose was 100.2% and 98.7% of the prescribed dose according to XVMC and AAA, respectively. Mean values of the maximal dose (D(max)), the minimal dose (D(min)), and dose received by 95% volume (D95) for the planning target volume (PTV) with XVMC were 104.3%, 75.1%, and 86.2%, respectively. When recalculated with the AAA, those values were 100.8%, 77.1%, and 85.4%, respectively. Mean dose parameter values considered for the normal lung, namely the mean lung dose, V5, and V20, were 3.7Gy, 19.4%, and 5.0% for XVMC and 3.6Gy, 18.3%, and 4.7% for the AAA, respectively. All of these dose-volumetric differences between the 2 algorithms were within 5% of the prescribed dose. The effect of PTV size and tumor location, respectively, on the differences in dose parameters for the PTV between the AAA and XVMC was evaluated. A significant effect of the PTV on the difference in D95 between the AAA and XVMC was observed (p = 0.03). Differences in the marginal doses, namely D(min) and D95, were statistically significant between peripherally and centrally located tumors (p = 0.04 and p = 0.02, respectively). Tumor location and volume might have an effect on the differences in dose-volumetric parameters. The differences between AAA and XVMC were considered to be within an acceptable range (<5 percentage points).

Usefulness of Daily Fractionated Administration of Wortmannin Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

BACKGROUND: To evaluate the usefulness of fractionated administration of wortmannin combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. METHODS: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. RESULTS: Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. CONCLUSION: Daily fractionated administration of wortmannin in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.

Hypomanic episode during recurrent gastric cancer treatment: report of a rare case and literature review.

S-1 plus cisplatin is the standard chemotherapy for recurrent gastric cancer. While depression and delirium are frequent in cancer patients, hypomania during chemotherapy is rare. We describe a rare case of hypomania during S-1 plus cisplatin treatment for recurrent gastric cancer. A 66-year-old woman, with no previous psychiatric disorder, received S-1 plus cisplatin for recurrent gastric cancer. She showed peculiar behavior. Physical examination, urine, blood and imaging findings were normal. There was no gastric cancer progression. During psychiatric consultation, she behaved inappropriately. However, she behaved normally while performing daily activities. She manifested a persistently elevated, expansive or irritable mood, clearly different from her usual non-depressed state, meeting hypomania diagnostic criteria. Her condition did not require chemotherapy discontinuation or additional medication. During the second and subsequent S-1 plus cisplatin cycles, symptoms were stable. Cancer patients often have adjustment disorders, depression and delirium, but rarely hypomania. Our patient showed no significant changes in blood biochemistry and brain and whole body imaging. While S-1 plus cisplatin-induced hypomania cannot be excluded, hypomanic symptoms did not improve during the chemotherapy rest period, nor was there deterioration during subsequent cycles, suggesting drug-induced mania to be unlikely. Possible onset mechanisms include manic defense phenomena, common with stressful life events. There are no reports of recurrent gastric cancer patients experiencing hypomania during S-1 or S-1 plus cisplatin therapy, i.e. our patient represents a rare course. Clinicians should recognize psychosis or mood disorders during gastric cancer treatment. Further accumulation of such rare cases might elucidate pathological mechanisms underlying hypomania in cancer patients.