Y. Demizu

DNA polymerase γ inhibition by vitamin K3 induces mitochondria-mediated cytotoxicity in human cancer cells

Among the vitamin K (VK) compounds, VK3 exhibits distinct cytotoxic activity in cancer cells and is thought to affect redox cycling; however, the underlying mechanisms remain unclear. Here we demonstrate that VK3 selectively inhibits DNA polymerase (pol) γ, the key enzyme responsible for mitochondrial DNA replication and repair. VK3 at 30 µM inhibited pol γ by more than 80%, caused impairment of mitochondrial DNA replication and repair, and induced a significant increase in reactive oxygen species (ROS), leading to apoptosis. At a lower concentration (3 µM), VK3 did not cause a significant increase in ROS, but was able to effectively inhibit cell proliferation, which could be reversed by supplementing glycolytic substrates. The cytotoxic action of VK3 was independent of p53 tumor suppressor gene status. Interestingly, VK3 only inhibited pol γ but did not affect other pol including human pol α, pol β, pol δ, and pol ɛ. VK1 and VK2 exhibited no inhibitory effect on any of the pol tested. These data together suggest that the inhibition of pol γ by VK3 is relatively specific, and that this compound seems to exert its anticancer activity by two possible mechanisms in a concentration‐dependent manner: (1) induction of ROS‐mediated cell death at high concentrations; and (2) inhibition of cell proliferation at lower concentrations likely through the suppression of mitochondrial respiratory function. These findings may explain various cytotoxic actions induced by VK3, and may pave the way for the further use of VK3. (Cancer Sci 2008; 99: 1040–1048)

Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy.

PurposeTo retrospectively analyze treatment outcomes after particle therapy using protons or carbon ions for mucosal melanoma of the head and neck (HNMM) at the Hyogo Ion Beam Medical Center, as well as to compare proton therapy (PT) and carbon ion therapy (CIT).Patients and methodsData from 62xa0HNMM patients without metastasis, treated with PT or CIT between Octoberxa02003 and Aprilxa02011 were analyzed. Median patient age was 70.5xa0years (range 33–89xa0years). Of the total patients, 33xa0(53u2009%) had received PT and 29xa0(47u2009%) had undergone CIT. Protocols for 65xa0or 70.2xa0GyE in 26xa0fractions were used for both ion types.ResultsMedian follow-up was 18.0xa0months (range 5.2–82.7xa0months). The 1-/2-year overall survival (OS) and local control (LC) rates were 93u2009%/61u2009% and 93u2009%/78u2009% for all patients, 91u2009%/44u2009% and 92u2009%/71u2009% for the PT patients and 96u2009%/62u2009% and 95u2009%/59u2009% for the CIT patients, respectively. No significant differences were observed between PT and CIT. Local recurrence was observed in 8xa0patients (PT: 5, CIT: 3) and 29xa0(PT: 18, CIT: 11) experienced distant metastases. Acute reactions were acceptable and all patients completed the planned radiotherapy. Regarding late toxicity, gradexa03 or greater events were observed in 5xa0patients (PT: 3, CIT: 2), but no significant difference was observed between PT and CIT.ConclusionOur single-institution retrospective analysis demonstrated that particle therapy for HNMM achieved good LC, but OS was unsatisfactory. There were no significant differences between PT and CIT in terms of either efficacy or toxicity.ZusammenfassungZielRetrospektive Analyse der Behandlungsergebnisse nach Partikeltherapie mit Protonen- oder Kohlenstoffionen beim Schleimhautmelanom der Kopf-Hals-Region (SMKH) am Hyogo Ion Beam Medical Center im Hinblick auf den Vergleich von Protonen- (PT) und Kohlenstoffionentherapie (CIT).Patienten und MethodikAnalysiert wurden 62xa0Patienten mit SMKH und ohne Metastasen, die zwischen Oktober 2003 und April 2011 mit PT oder CIT behandelt worden waren. Das mediane Alter der Patienten betrug 70,5xa0Jahre (Spannweite 33–89xa0Jahre). Insgesamt 33xa0Patienten (53u2009%) wurden mit PT behandelt, 29 (47u2009%) mit CIT. Bei beiden Ionenarten wurden die Protokolle für 65 oder 70,2xa0GyE in 26xa0Fraktionen angewendet.ErgebnisseDie mediane Nachbeobachtungszeit betrug 18xa0Monate (Spannweite 5,2–82,7xa0Monate). Die 1- und 2-Jahres-Raten für Gesamtüberleben und lokale Kontrolle betrugen für alle Patienten zusammen 93u2009%/61u2009% bzw. 93u2009%/78u2009% sowie 91u2009%/44u2009% bzw. 92u2009%/71u2009% bei den PT-Patienten und 96u2009%/62u2009% bzw. 95u2009%/59u2009% bei den CIT-Patienten. Zwischen PT und CIT wurden keine signifikanten Unterschiede beobachtet. Bei 8xa0Patienten (PT: 5, CIT: 3) traten lokale Rezidive auf und bei 29xa0Patienten (PT: 18, CIT: 11) wurden Fernmetastasen entdeckt. Die akuten Reaktionen waren akzeptabel und alle Patienten schlossen die Strahlentherapie planmäßig ab. Was die Langzeittoxizität angeht, wurden Ereignisse vom Schweregradxa03 oder höher bei 5xa0Patienten beobachtet (PT: 3, CIT: 2), wobei kein signifikanter Unterschied zwischen PT und CIT festzustellen war.SchlussfolgerungUnsere monozentrische retrospektive Analyse belegt gute Erfolge der SMKH-Partikeltherapie bezüglich der lokalen Beherrschung, jedoch unbefriedigende Ergebnisse im Hinblick auf das Gesamtüberleben. Weder bei der Wirksamkeit noch bei der Toxizität bestanden signifikante Unterschiede zwischen PT und CIT.

Particle therapy for mucosal melanoma of the head and neck

PurposeTo retrospectively analyze treatment outcomes after particle therapy using protons or carbon ions for mucosal melanoma of the head and neck (HNMM) at the Hyogo Ion Beam Medical Center, as well as to compare proton therapy (PT) and carbon ion therapy (CIT).Patients and methodsData from 62xa0HNMM patients without metastasis, treated with PT or CIT between Octoberxa02003 and Aprilxa02011 were analyzed. Median patient age was 70.5xa0years (range 33–89xa0years). Of the total patients, 33xa0(53u2009%) had received PT and 29xa0(47u2009%) had undergone CIT. Protocols for 65xa0or 70.2xa0GyE in 26xa0fractions were used for both ion types.ResultsMedian follow-up was 18.0xa0months (range 5.2–82.7xa0months). The 1-/2-year overall survival (OS) and local control (LC) rates were 93u2009%/61u2009% and 93u2009%/78u2009% for all patients, 91u2009%/44u2009% and 92u2009%/71u2009% for the PT patients and 96u2009%/62u2009% and 95u2009%/59u2009% for the CIT patients, respectively. No significant differences were observed between PT and CIT. Local recurrence was observed in 8xa0patients (PT: 5, CIT: 3) and 29xa0(PT: 18, CIT: 11) experienced distant metastases. Acute reactions were acceptable and all patients completed the planned radiotherapy. Regarding late toxicity, gradexa03 or greater events were observed in 5xa0patients (PT: 3, CIT: 2), but no significant difference was observed between PT and CIT.ConclusionOur single-institution retrospective analysis demonstrated that particle therapy for HNMM achieved good LC, but OS was unsatisfactory. There were no significant differences between PT and CIT in terms of either efficacy or toxicity.ZusammenfassungZielRetrospektive Analyse der Behandlungsergebnisse nach Partikeltherapie mit Protonen- oder Kohlenstoffionen beim Schleimhautmelanom der Kopf-Hals-Region (SMKH) am Hyogo Ion Beam Medical Center im Hinblick auf den Vergleich von Protonen- (PT) und Kohlenstoffionentherapie (CIT).Patienten und MethodikAnalysiert wurden 62xa0Patienten mit SMKH und ohne Metastasen, die zwischen Oktober 2003 und April 2011 mit PT oder CIT behandelt worden waren. Das mediane Alter der Patienten betrug 70,5xa0Jahre (Spannweite 33–89xa0Jahre). Insgesamt 33xa0Patienten (53u2009%) wurden mit PT behandelt, 29 (47u2009%) mit CIT. Bei beiden Ionenarten wurden die Protokolle für 65 oder 70,2xa0GyE in 26xa0Fraktionen angewendet.ErgebnisseDie mediane Nachbeobachtungszeit betrug 18xa0Monate (Spannweite 5,2–82,7xa0Monate). Die 1- und 2-Jahres-Raten für Gesamtüberleben und lokale Kontrolle betrugen für alle Patienten zusammen 93u2009%/61u2009% bzw. 93u2009%/78u2009% sowie 91u2009%/44u2009% bzw. 92u2009%/71u2009% bei den PT-Patienten und 96u2009%/62u2009% bzw. 95u2009%/59u2009% bei den CIT-Patienten. Zwischen PT und CIT wurden keine signifikanten Unterschiede beobachtet. Bei 8xa0Patienten (PT: 5, CIT: 3) traten lokale Rezidive auf und bei 29xa0Patienten (PT: 18, CIT: 11) wurden Fernmetastasen entdeckt. Die akuten Reaktionen waren akzeptabel und alle Patienten schlossen die Strahlentherapie planmäßig ab. Was die Langzeittoxizität angeht, wurden Ereignisse vom Schweregradxa03 oder höher bei 5xa0Patienten beobachtet (PT: 3, CIT: 2), wobei kein signifikanter Unterschied zwischen PT und CIT festzustellen war.SchlussfolgerungUnsere monozentrische retrospektive Analyse belegt gute Erfolge der SMKH-Partikeltherapie bezüglich der lokalen Beherrschung, jedoch unbefriedigende Ergebnisse im Hinblick auf das Gesamtüberleben. Weder bei der Wirksamkeit noch bei der Toxizität bestanden signifikante Unterschiede zwischen PT und CIT.

Particle therapy using carbon ions or protons as a definitive therapy for patients with primary sacral chordoma

OBJECTIVEnThis study retrospectively evaluated the efficacy and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas.nnnMETHODSnWe evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan. The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4u2009GyE in 32 fractions. CIT was used for 16 patients, and PT was used for 7 patients.nnnRESULTSnThe median follow-up period was 38 months. At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94%, 83% and 68%, respectively. The log-rank test revealed that male sex was significantly related to better PFS (p=0.029). No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS. In nine patients, ≥ Grade 3 acute dermatitis was observed, and ≥ Grade 3 late toxicities were observed in nine patients. The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol.nnnCONCLUSIONnParticle therapy for patients with sacral chordoma showed favourable LC and OS. Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era. Thus, this therapeutic modality should be considered useful and safe.nnnADVANCES IN KNOWLEDGEnThis is the first study including both CIT and PT for sacral chordomas.

Alterations of Cellular Redox State During NNK-Induced Malignant Transformation and Resistance to Radiation

Cancer cells often exhibit increased reactive oxygen species generation and altered redox regulation. The current study was conducted to investigate the biochemical and molecular events associated with redox alterations during chemical-induced malignant transformation and to evaluate their potential roles in radiation sensitivity. Immortalized nonmalignant human bronchial epithelial cells were exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and a clone of cells exhibiting malignant behaviors was isolated and characterized. This clone initially exhibited an increase in cellular superoxide that eventually decreased after a long-term culture in vitro, associated with altered expression of antioxidant molecules, including an increase in thioredoxin-1 and manganese superoxide dismutase, and a decrease in glutathione peroxidase-1. These cells also showed a significant decrease in sensitivity to ionizing radiation, as demonstrated by less cell death in acute apoptosis analyses and long-term cell proliferation assays. Using biochemical redox modulation and siRNA approach, we showed that the increase in thioredoxin-1 played a significant role in conferring resistance to IR. Although there was a substantial increase in cellular glutathione, inhibition of glutathione synthesis did not increase IR sensitivity. Our study showed complex redox alterations during NNK-induced malignant transformation, and identified Trx-1 as a radiosensitivity modulator.

Hypofractionated stereotactic radiotherapy for brain metastases from lung cancer : Evaluation of indications and predictors of local control.

AimTo evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for brain metastases (BMs) from lung cancer, and to explore prognostic factors associated with local control (LC) and indication.Patients and methodsWe evaluated patients who were treated with linac-based HSRT for BMs from lung cancer. Lesions treated with stereotactic radiosurgery (SRS) in the same patients during the same periods were analysed and compared with HSRT in terms of LC or toxicity. There were 53xa0patients with 214xa0lesions selected for this analysis (HSRT: 76xa0lesions, SRS: 138xa0lesions). For HSRT, the median prescribed dose was 35xa0Gy in 5xa0fractions.ResultsThe 1‑year LC rate was 83.6xa0% in HSRT; on multivariate analysis, a planning target volume (PTV) of <4xa0cm3, biologically effective dose (BED10) of ≥51xa0Gy, and adenocarcinoma were significantly associated with better LC. Moreover, in PTVs ≥xa04xa0cm3, there was a significant difference in LC between BED10 <xa051xa0Gy and ≥xa051xa0Gy (pxa0= 0.024). On the other hand, in PTVs <xa04xa0cm3, both HSRT and SRS had good LC with no significant difference (pxa0= 0.195). Radiation necrosis emerged in 5xa0of 76xa0lesions (6.6xa0%) treated with HSRT and 21xa0of 138 (15.2xa0%) lesions treated with SRS (pxa0= 0.064).ConclusionLinac-based HSRT was safe and effective for BMs from lung cancer, and hence might be particularly useful in or near an eloquent area. PTV, BED10, and pathological type were significant prognostic factors. Furthermore, in BMs ≥xa04xa0cm3, a dose of BED ≥xa051xa0Gy should be considered.ZusammenfassungZielBeurteilung von Wirksamkeit und Toxizität einer hypofraktionierten stereotaktischen Strahlentherapie (HSRT) zur Behandlung von Hirnmetastasen (HM) eines Lungenkarzinoms und Erforschung von mit der lokalen Kontrolle (LK) und der Indikation assoziierten Prognosefaktoren.Patienten und MethodenAnalysiert wurden Daten von Patienten (nxa0= 53), die sich einer Linearbeschleuniger-basierten HSRT unterzogen (mit HSRT behandelte Läsionen nxa0=xa076; Median der verordneten Dosis: 35 Gy in 5 Fraktionen). Analysiert wurden ferner bei den gleichen Patienten im gleichen Zeitraum mit stereotaktischer Strahlenchirurgie (SRS) behandelte Läsionen (nxa0= 138). Die Ergebnisse wurden in Bezug auf LK oder Toxizität verglichen.ErgebnisseNach einem Jahr betrug die LK nach HSRT 83,6xa0%; bei der multivariaten Analyse zeigte sich, dass ein „planning target volume“ (PTV) <xa04xa0cm3, eine biologisch effektive Dosis (BED10) ≥xa051xa0Gy und ein Adenokarzinom signifikant mit einer besseren LK assoziiert waren. Darüber hinaus wurde bei einem PTV ≥xa04xa0cm3 ein signifikanter Unterschied in der LK zwischen BED10 <xa051xa0Gy und ≥xa051xa0Gy beobachtet (pxa0= 0,024). Andererseits wurde bei einem PTV <xa04xa0cm3 sowohl mit der HSRT als auch mit der SRS eine gute LK erreicht, der Unterschied war nicht signifikant (pxa0= 0,195). Bei 5xa0der 76 (6,6xa0%) mit HRST behandelten Läsionen und bei 21 der 138 (15,2xa0%) mit SRS behandelten Läsionen traten Strahlennekrosen auf (pxa0= 0,064).SchlussfolgerungDie Linearbeschleuniger-basierte HSRT war eine sichere und effektive Behandlung von HM eines Lungenkarzinoms. Sie kann also besonders hilfreich sein bei Metastasen in einem eloquenten Hirnareal oder in der Nähe eines eloquenten Areals. Signifikante Prognosefaktoren waren PTV, BEDxa010 und der histopathologische Typ. Bei HM mit einer Ausdehnung ≥xa04xa0cm3 sollte eine BED ≥xa051xa0Gy erwogen werden.

Medical Application of Nonwoven Fabrics - Intra-abdominal Spacers for Particle Therapy

The authors aimed to introduce a medical application for nonwoven fabric as spacers in particle therapy. Particle therapy, exhibiting more focused effects on target tissues, has emerged as a promising treatment modality. However, close proximity of tumor tissue and adjacent organs makes delivery of curative doses to the tumor difficult because severe radiation morbidities might occur. A method using surgically placed GORE-TEX sheets as a spacer has been reported. Although this method provides for separation of adjacent organs, the material is not resorbed. To overcome these anatomical and therapeutic difficulties, and to deliver effective radiation doses to treat upper abdominal tumors, we have developed a nonwoven fabric spacer composed of bioabsorbable suture material. The absorbable polyglycolic acid (PGA) spacer had water-equivalent, biocompatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to block particle beams and to separate normal tissues from the radiation field. These findings suggest that the nonwoven-fabric PGA spacer might become a useful device in particle therapy.

Particle therapy for mucosal melanoma of the head and neck@@@Partikeltherapie beim Schleimhautmelanom der Kopf-Hals-Region: A single-institution retrospective comparison of proton and carbon ion therapy@@@Monozentrischer retrospektiver Vergleich von Protonen- und Kohlenstoffionentherapie

PurposeTo retrospectively analyze treatment outcomes after particle therapy using protons or carbon ions for mucosal melanoma of the head and neck (HNMM) at the Hyogo Ion Beam Medical Center, as well as to compare proton therapy (PT) and carbon ion therapy (CIT).Patients and methodsData from 62xa0HNMM patients without metastasis, treated with PT or CIT between Octoberxa02003 and Aprilxa02011 were analyzed. Median patient age was 70.5xa0years (range 33–89xa0years). Of the total patients, 33xa0(53u2009%) had received PT and 29xa0(47u2009%) had undergone CIT. Protocols for 65xa0or 70.2xa0GyE in 26xa0fractions were used for both ion types.ResultsMedian follow-up was 18.0xa0months (range 5.2–82.7xa0months). The 1-/2-year overall survival (OS) and local control (LC) rates were 93u2009%/61u2009% and 93u2009%/78u2009% for all patients, 91u2009%/44u2009% and 92u2009%/71u2009% for the PT patients and 96u2009%/62u2009% and 95u2009%/59u2009% for the CIT patients, respectively. No significant differences were observed between PT and CIT. Local recurrence was observed in 8xa0patients (PT: 5, CIT: 3) and 29xa0(PT: 18, CIT: 11) experienced distant metastases. Acute reactions were acceptable and all patients completed the planned radiotherapy. Regarding late toxicity, gradexa03 or greater events were observed in 5xa0patients (PT: 3, CIT: 2), but no significant difference was observed between PT and CIT.ConclusionOur single-institution retrospective analysis demonstrated that particle therapy for HNMM achieved good LC, but OS was unsatisfactory. There were no significant differences between PT and CIT in terms of either efficacy or toxicity.ZusammenfassungZielRetrospektive Analyse der Behandlungsergebnisse nach Partikeltherapie mit Protonen- oder Kohlenstoffionen beim Schleimhautmelanom der Kopf-Hals-Region (SMKH) am Hyogo Ion Beam Medical Center im Hinblick auf den Vergleich von Protonen- (PT) und Kohlenstoffionentherapie (CIT).Patienten und MethodikAnalysiert wurden 62xa0Patienten mit SMKH und ohne Metastasen, die zwischen Oktober 2003 und April 2011 mit PT oder CIT behandelt worden waren. Das mediane Alter der Patienten betrug 70,5xa0Jahre (Spannweite 33–89xa0Jahre). Insgesamt 33xa0Patienten (53u2009%) wurden mit PT behandelt, 29 (47u2009%) mit CIT. Bei beiden Ionenarten wurden die Protokolle für 65 oder 70,2xa0GyE in 26xa0Fraktionen angewendet.ErgebnisseDie mediane Nachbeobachtungszeit betrug 18xa0Monate (Spannweite 5,2–82,7xa0Monate). Die 1- und 2-Jahres-Raten für Gesamtüberleben und lokale Kontrolle betrugen für alle Patienten zusammen 93u2009%/61u2009% bzw. 93u2009%/78u2009% sowie 91u2009%/44u2009% bzw. 92u2009%/71u2009% bei den PT-Patienten und 96u2009%/62u2009% bzw. 95u2009%/59u2009% bei den CIT-Patienten. Zwischen PT und CIT wurden keine signifikanten Unterschiede beobachtet. Bei 8xa0Patienten (PT: 5, CIT: 3) traten lokale Rezidive auf und bei 29xa0Patienten (PT: 18, CIT: 11) wurden Fernmetastasen entdeckt. Die akuten Reaktionen waren akzeptabel und alle Patienten schlossen die Strahlentherapie planmäßig ab. Was die Langzeittoxizität angeht, wurden Ereignisse vom Schweregradxa03 oder höher bei 5xa0Patienten beobachtet (PT: 3, CIT: 2), wobei kein signifikanter Unterschied zwischen PT und CIT festzustellen war.SchlussfolgerungUnsere monozentrische retrospektive Analyse belegt gute Erfolge der SMKH-Partikeltherapie bezüglich der lokalen Beherrschung, jedoch unbefriedigende Ergebnisse im Hinblick auf das Gesamtüberleben. Weder bei der Wirksamkeit noch bei der Toxizität bestanden signifikante Unterschiede zwischen PT und CIT.