Simultaneous boost radiotherapy versus conventional dose radiotherapy for patients with newly diagnosed glioblastoma: a multi-institutional analysis.

We compared survival outcomes of high-dose concomitant boost radiotherapy (HDCBRT) and conventional dose radiotherapy (CRT) for newly diagnosed glioblastoma (GB). Patients treated with intensity-modulated radiation therapy for newly diagnosed GB were included. In HDCBRT, specific targets received 69, 60, and 51 Gy in 30 fractions, while 60 Gy in 30 fractions was administered with a standard radiotherapy method in CRT. Overall survival (OS) and progression-free survival (PFS) were compared using the Log-rank test, followed by multivariate Cox analysis. The inverse probability of treatment weighting (IPTW) method was also applied to each analysis. Among 102 eligible patients, 45 received HDCBRT and 57 received CRT. With a median follow-up of 16 months, the median survival times of OS and PFS were 21 and 9 months, respectively. No significant differences were observed in OS or PFS in the Kaplan-Meier analyses. In the multivariate analysis, HDCBRT correlated with improved OS (hazard ratio, 0.49; 95% confidence interval, 0.27-0.90; P = 0.021), and this result remained consistent after IPTW adjustments (P = 0.028). Conversely, dose suppression due to the proximity of normal tissues and IMRT field correlated with worse OS and PFS (P = 0.008 and 0.049, respectively). A prospective study with a stricter protocol is warranted to validate the efficacy of HDCBRT for GB.

Dosimetric and radiobiological analyses of a de-escalation strategy for elective nodal regions in human papillomavirus-associated oropharyngeal cancer.

Introduction: In this simulation study, we examined the effects of a de-escalation strategy with a reduced dose to subclinical nodal regions in patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC). Methods: We created two patterns of intensity-modulated radiotherapy for 16 patients with HPV-associated OPC. In the standard and de-escalation plans, the initial field including elective nodal regions received 46 and 30 Gy, followed by 20 and 36 Gy to the cutdown field, respectively. Comparison metrics were set for each organ at risk (OAR). We compared these metric values and the probability of adverse effects based on the normal tissue complication probability (NTCP) model between the two plans. Results: Both plans generally met the dose constraints for the targets and all OAR. Among the comparison metrics, the mean doses to the brain, pharyngeal constrictor muscle, thyroid, and skin and the dose to a 1 % volume of the skin were higher in the standard plan than in the de-escalation plan (P = 0.031, 0.007, < 0.001, < 0.001, and 0.006, respectively). NTCP analyses revealed that the probability of adverse effects in the ipsilateral parotid gland and thyroid was higher in the standard plan than in the de-escalation plan (standard vs. de-escalation plans: ipsilateral parotid gland, 6.4 % vs. 5.0 %, P = 0.016; thyroid, 3.3 % vs. 0.5 %, P < 0.001). Conclusions: A de-escalation strategy with elective nodal regions is a promising treatment to prevent a decline in the quality of life in patients with HPV-associated OPC, particularly xerostomia, dysphagia, and hypothyroidism.

Dosimetric Comparison of Helical Tomotherapy and Intensity-Modulated Proton Therapy in Hippocampus- and Scalp-Sparing Whole Brain Radiotherapy.

Objective: Cognitive decline and alopecia after radiotherapy are challenging problems. We aimed to compare whole brain radiotherapy (WBRT) plans reducing radiation dose to the hippocampus and scalp between helical tomotherapy (HT) and intensity-modulated proton therapy (IMPT). Methods: We conducted a planning study of WBRT for 10 patients. The clinical target volume was defined as the whole brain excluding the hippocampus avoidance (HA) region. The prescribed dose was 30 Gy in 10 fractions to cover 95% of the target. Constraint goals were defined for the target and organs at risk (OAR). Results: Both techniques met the dose constraints for the target and OAR. However, the coverage of the target (dose covering 95% [D95%] and 98% [D98%] of the volume) were better in IMPT than HT (HT vs IMPT: D95%, 29.9 Gy vs 30.0 Gy, P < .001; D98%, 26.7 Gy vs 28.1 Gy, P = .002). The homogeneity and conformity of the target were also better in IMPT than HT (HT vs IMPT: homogeneity index, 1.50 vs 1.28, P < .001; conformity index, 1.30 vs 1.14, P < .001). IMPT reduced the D100% of the hippocampus by 59% (HT vs IMPT: 9.3 Gy vs 3.8 Gy, P < .001) and reduced the Dmean of the hippocampus by 37% (HT vs IMPT: 11.1 Gy vs 7.0 Gy, P < .001) compared with HT. The scalp IMPT reduced the percentage of the volume receiving at least 20 Gy (V20Gy) and V10Gy compared with HT (HT vs IMPT: V20Gy, 56.7% vs 6.6%, P < .001; V10Gy, 90.5% vs 37.1%, P < .001). Conclusion: Both techniques provided acceptable target dose coverage. Especially, IMPT achieved excellent hippocampus- and scalp-sparing. HA-WBRT using IMPT is a promising treatment to prevent cognitive decline and alopecia.

Dosimetric Comparison of Helical Tomotherapy, Volumetric-Modulated Arc Therapy, and Intensity-Modulated Proton Therapy for Angiosarcoma of the Scalp.

OBJECTIVE: We compared radiotherapy plans among helical tomotherapy (HT), volumetric-modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT) for angiosarcoma of the scalp (AS). METHODS: We conducted a planning study for 19 patients with AS. The clinical target volume (CTV) 1 and CTV2 were defined as the gross tumor volume with a specific margin and total scalp, respectively. For HT and VMAT, the planning target volume (PTV) 1 and PTV2 were defined as CTV1 and CTV2 with 0.5-cm margins, respectively. For IMPT, robust optimization was used instead of a CTV-PTV margin (i.e. CTV robust). The targets of the HT and VMAT plans were the PTV, whereas the IMPT plans targeted the CTV robust. In total, 70 Gy and 56 Gy were prescribed as the D95% (i.e. dose to 95% volume) of PTV1 (or CTV1 robust) and PTV2 (or CTV2 robust), respectively, using the simultaneous integrated boost (SIB) technique. Other constraint goals were also defined for the target and organs at risk (OAR). RESULTS: All dose constraint parameters for the target and OAR met the goals within the acceptable ranges for the 3 techniques. The coverage of the targets replaced by D95% and D98% were almost equivalent among the 3 techniques. The homogeneity index of PTV1 or CTV1 robust was equivalent among the 3 techniques, whereas that of PTV2 or CTV2 robust was significantly higher in the IMPT plans than in the other plans. IMPT reduced the Dmean of the brain and hippocampus by 49% to 95%, and the Dmax of the spinal cord, brainstem, and optic pathway by 70% to 92% compared with the other techniques. CONCLUSION: The 3 techniques with SIB methods provided sufficient coverage and satisfactory homogeneity for the targets, but IMPT achieved the best OAR sparing.

Early salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: Its impact and optimal candidate.

AIM: We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level < 0.50) and BCR after SRT was tested in each subgroup according to our own risk stratification. RESULTS: The median follow-up time was 51 months. By multivariate analysis, pT3b, Gleason score ≥ 8, negative surgical margins, PSA doubling time < 6 months, and non-early SRT were associated with BCR after SRT. Patients were stratified by four risk factors other than non-early SRT: (1) low risk (0 risk factor), (2) intermediate risk (1 risk factor), and (3) high risk (≥2 risk factors). The BCR-free survival was higher in the early SRT group than the nonearly SRT group in the high-risk subgroup (P = 0.020), whereas that was similar between two groups in the low-risk and intermediate-risk subgroups (P = .79 and .18, respectively). Multivariate analysis revealed that early SRT was beneficial for the high-risk subgroup (P = .032), whereas early SRT was not associated with improved outcomes in the low-risk and intermediate-risk subgroups (P = .92 and 1.0, respectively). CONCLUSIONS: This study suggested that early SRT seemed to contribute to better biochemical control for patients with more adverse features, whereas no benefit was observed in men with no adverse features.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy.

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8-5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0-56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3-7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Comparison of the inoculum size effects of antibiotics on IMP-6 ß-lactamase-producing Enterobacteriaceae co-harboring plasmid-mediated quinolone resistance genes.

Almost all cases of carbapenemase-producing Enterobacteriaceae infections in Japan are caused by blaIMP-positive Enterobacteriaceae (especially blaIMP-6) and infections caused by other types of carbapenemase-producing Enterobacteriaceae are quite rare. We examined drug resistance genes co-harboring with blaIMP-6 and their inoculum size effects. We screened ß-lactamase genes, plasmid-mediated quinolone resistance (PMQR) genes, and aminoglycoside-modifying enzyme genes by PCR and performed sequencing for 14 blaIMP-6-positive Enterobacteriaceae. Further, all PMQR-positive isolates were submitted to conjugation and inoculum effect evaluation. Our data showed that 13 of the 14 isolates harbored CTX-M-2 and one co-harbored CTX-M-2 and CTX-M-1 as extended-spectrum ß-lactamases. All isolates carried one or more PMQRs; aac(6')-Ib-cr was the most prevalent (92.8%), and was followed by oqxA (64.3%), qnrS (50%), oqxAB (21.4%), and qnrB (14.3%). However, Klebsiella pneumoniae contains chromosomal OqxAB. Inoculum size effects were significant in all strains for meropenem, 13 strains for imipenem, 7 for levofloxacin, and 3 for amikacin. We observed that 11 of the experimental strains (100%), 8 strains (72.7%), and 1 strain showed inoculum size effects for meropenem, imipenem, and amikacin, respectively. However, four strains harbored qnr genes and two strains harbored qnr genes and QRDR mutations concurrently; no inoculum size effect was seen for levofloxacin. The blaIMP-6-positive Enterobacteriaceae that we studied was found to harbor at least one plasmid-mediated drug resistance gene. The inoculum size effect for carbapenems was thought to be mainly due to IMP-6-type metallo-ß-lactamase; however qnrB and qnrS also had a minimal impact on the inoculum size effect for levofloxacin.

Impact of the genetic variants of GLCCI1 on clinical features of asthmatic patients.

BACKGROUND: Several gene variants are associated with a response to an inhaled corticosteroids (ICSs) treatment in patients with bronchial asthma. A variant of the glucocorticoid-induced transcript 1 (GLCCI1) genes has previously been associated with decreased lung function improvement upon treatment with ICSs in patients with bronchial asthma. Another report has also demonstrated that this genetic biomarker did not influence the change in flow volume in 1 second. However, no studies have considered the treatment content and the GLCCI1 variants. We were able to determine the relationship between the pulmonary function and clinical features and the variant of the GLCCI1 in Japanese asthmatic patients receiving long-term ICS treatment. MATERIALS AND METHODS: In this study, 405 patients with bronchial asthma, who were receiving ICS and living in Japan, were recruited, genotyped and underwent pulmonary function tests. To identify the GLCCI1 protein expression cells, endobronchial biopsy specimens were examined. RESULTS: We found that the pulmonary function was not significantly different in the homozygotes compared to the wild types. Also, the homozygotes increased the risk of a sustained step-up of the asthma treatment when compared to the wild type and heterozygotes. GLCCI1-positive cells were localized to the bronchial epithelial cells. The amount of GLCCI1 protein that cultured epithelial cells harboring GLCCI1 variants produced was less than the GLCCI1 wild type in the presence of a corticosteroid. CONCLUSIONS: A worsening of pulmonary function caused by GLCCI1 variants could be prevented due to recently used medications based on new action mechanisms.

Mitigation of tight junction protein dysfunction in lung microvascular endothelial cells with pitavastatin.

BACKGROUND: Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. METHOD: We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. RESULTS: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. CONCLUSION: Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.