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Purpose: In real-time image-gated spot-scanning proton therapy (RGPT), the dose distribution is distorted by gold fiducial markers placed in the prostate. Distortion can be suppressed by using small markers and more than 2 fields, but additional fields may increase the dose to organs at risk. Therefore, we conducted a prospective study to evaluate the safety and short-term clinical outcome of RGPT for prostate cancer. Methods and Materials: Based on the previously reported frequency of early adverse events (AE) and the noninferiority margin of 10%, the required number of cases was calculated to be 43 using the one-sample binomial test by the Southwest Oncology Group statistical tools with the one-sided significance level of 2.5% and the power 80%. Patients with localized prostate cancer were enrolled and 3 to 4 pure gold fiducial markers of 1.5-mm diameter were inserted in the prostate. The prescribed dose was 70 Gy(relative biologic effectiveness) in 30 fractions, and treatment was performed with 3 fields from the left, right, and the back, or 4 fields from either side of slightly anterior and posterior oblique fields. The primary endpoint was the frequency of early AE (≥grade 2) and the secondary endpoint was the biochemical relapse-free survival rate and the frequency of late AE. Results: Forty-five cases were enrolled between 2015 and 2017, and all patients completed the treatment protocol. The median follow-up period was 63.0 months. The frequency of early AE (≥grade 2) was observed in 4 cases (8.9%), therefore the noninferiority was verified. The overall 5-year biochemical relapse-free survival rate was 88.9%. As late AE, grade 2 rectal bleeding was observed in 8 cases (17.8%). Conclusions: The RGPT for prostate cancer with 1.5-mm markers and 3- or 4- fields was as safe as conventional proton therapy in early AE, and its efficacy was comparable with previous studies.

BackgroundThe Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.MethodsWe retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.ResultsThe median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, and 2.5-3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).ConclusionsWe confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients

Most oncogenic human papilloma virus (HPV) genotypes stratify into two species, alpha-7 HPV and alpha-9 HPV. There are several studies that evaluate the relationship between HPV species and treatment outcomes and reports that HPV species is prognostic. The HPV genotyping was conducted using biopsy specimens which had been stored in these studies. We conducted the study using the HPV test performed by cytology specimens which is less invasive and more useful in clinical settings. This study enrolled 46 patients who received HPV genotyping before the definitive radiotherapy. The results of the HPV genotyping were classified into HPV alpha-7, HPV alpha-9 and negatives. Of the 46 patients, 10 were positive for HPV alpha-7, 21 positive for HPV alpha-9 and 15 were negative. The median follow-up period was 38 months (range 4-142). The HPV alpha-7, HPV alpha-9 and negative groups showed the 3-year overall survival (OS; 59.3%, 80.4% and 72.2% [P = 0.25]); local control (LC; 67.5%, 81% and 80% [P = 0.78]); pelvic control (PC) (50%, 81% and 72.7% [P = 0.032]); pelvic lymph node (PLN) control (78.7%, 95% and 92.3% [P = 0.012]); distant metastasis free (DMF) survival (50%, 75.4% and 42.8% [P = 0.098]); and progression free survival (PFS) rate of patients (30%, 66.7% and 38.9% [P = 0.085]), respectively. Patients with HPV alpha-7 showed statistically significant poorer PC than the HPV alpha-9 group, in multivariate analysis. This result is consistent with previous studies for HPV positive patients. The HPV negativity rate was higher in this study than in other studies and further work on this may be needed for clinical use.

Most oncogenic human papilloma virus (HPV) genotypes stratify into two species, alpha-7 HPV and alpha-9 HPV. There are several studies that evaluate the relationship between HPV species and treatment outcomes and reports that HPV species is prognostic. The HPV genotyping was conducted using biopsy specimens which had been stored in these studies. We conducted the study using the HPV test performed by cytology specimens which is less invasive and more useful in clinical settings. This study enrolled 46 patients who received HPV genotyping before the definitive radiotherapy. The results of the HPV genotyping were classified into HPV alpha-7, HPV alpha-9 and negatives. Of the 46 patients, 10 were positive for HPV alpha-7, 21 positive for HPV alpha-9 and 15 were negative. The median follow-up period was 38 months (range 4-142). The HPV alpha-7, HPV alpha-9 and negative groups showed the 3-year overall survival (OS; 59.3%, 80.4% and 72.2% [P = 0.25]); local control (LC; 67.5%, 81% and 80% [P = 0.78]); pelvic control (PC) (50%, 81% and 72.7% [P = 0.032]); pelvic lymph node (PLN) control (78.7%, 95% and 92.3% [P = 0.012]); distant metastasis free (DMF) survival (50%, 75.4% and 42.8% [P = 0.098]); and progression free survival (PFS) rate of patients (30%, 66.7% and 38.9% [P = 0.085]), respectively. Patients with HPV alpha-7 showed statistically significant poorer PC than the HPV alpha-9 group, in multivariate analysis. This result is consistent with previous studies for HPV positive patients. The HPV negativity rate was higher in this study than in other studies and further work on this may be needed for clinical use.

In urethra-sparing radiation therapy, prostatic urinary tract visualization is important in decreasing the urinary side effect. A methodology has been developed to visualize the prostatic urinary tract using post-urination magnetic resonance imaging (PU-MRI) without a urethral catheter. This study investigated whether the combination of PU-MRI and super-resolution (SR) deep learning models improves the visibility of the prostatic urinary tract. We enrolled 30 patients who had previously undergone real-time-image-gated spot scanning proton therapy by insertion of fiducial markers. PU-MRI was performed using a non-contrast high-resolution two-dimensional T2-weighted turbo spin-echo imaging sequence. Four different SR deep learning models were used: the enhanced deep SR network (EDSR), widely activated SR network (WDSR), SR generative adversarial network (SRGAN), and residual dense network (RDN). The complex wavelet structural similarity index measure (CW-SSIM) was used to quantitatively assess the performance of the proposed SR images compared to PU-MRI. Two radiation oncologists used a 1-to-5 scale to subjectively evaluate the visibility of the prostatic urinary tract. Cohen's weighted kappa (k) was used as a measure of agreement of inter-operator reliability. The mean CW-SSIM in EDSR, WDSR, SRGAN, and RDN was 99.86%, 99.89%, 99.30%, and 99.67%, respectively. The mean prostatic urinary tract visibility scores of the radiation oncologists were 3.70 and 3.53 for PU-MRI (k = 0.93), 3.67 and 2.70 for EDSR (k = 0.89), 3.70 and 2.73 for WDSR (k = 0.88), 3.67 and 2.73 for SRGAN (k = 0.88), and 4.37 and 3.73 for RDN (k = 0.93), respectively. The results suggest that SR images using RDN are similar to the original images, and the SR deep learning models subjectively improve the visibility of the prostatic urinary tract.

BackgroundThe Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.MethodsWe retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.ResultsThe median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, and 2.5-3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).ConclusionsWe confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patie

Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.

Most oncogenic human papilloma virus (HPV) genotypes stratify into two species, alpha-7 HPV and alpha-9 HPV. There are several studies that evaluate the relationship between HPV species and treatment outcomes and reports that HPV species is prognostic. The HPV genotyping was conducted using biopsy specimens which had been stored in these studies. We conducted the study using the HPV test performed by cytology specimens which is less invasive and more useful in clinical settings. This study enrolled 46 patients who received HPV genotyping before the definitive radiotherapy. The results of the HPV genotyping were classified into HPV alpha-7, HPV alpha-9 and negatives. Of the 46 patients, 10 were positive for HPV alpha-7, 21 positive for HPV alpha-9 and 15 were negative. The median follow-up period was 38 months (range 4-142). The HPV alpha-7, HPV alpha-9 and negative groups showed the 3-year overall survival (OS; 59.3%, 80.4% and 72.2% [P = 0.25]); local control (LC; 67.5%, 81% and 80% [P = 0.78]); pelvic control (PC) (50%, 81% and 72.7% [P = 0.032]); pelvic lymph node (PLN) control (78.7%, 95% and 92.3% [P = 0.012]); distant metastasis free (DMF) survival (50%, 75.4% and 42.8% [P = 0.098]); and progression free survival (PFS) rate of patients (30%, 66.7% and 38.9% [P = 0.085]), respectively. Patients with HPV alpha-7 showed statistically significant poorer PC than the HPV alpha-9 group, in multivariate analysis. This result is consistent with previous studies for HPV positive patients. The HPV negativity rate was higher in this study than in other studies and further work on this may be needed for clinical use.

BackgroundThe Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.MethodsWe retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.ResultsThe median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0-1.0, 1.5-2.0, and 2.5-3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).ConclusionsWe confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patie

Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.

Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.

In urethra-sparing radiation therapy, prostatic urinary tract visualization is important in decreasing the urinary side effect. A methodology has been developed to visualize the prostatic urinary tract using post-urination magnetic resonance imaging (PU-MRI) without a urethral catheter. This study investigated whether the combination of PU-MRI and super-resolution (SR) deep learning models improves the visibility of the prostatic urinary tract. We enrolled 30 patients who had previously undergone real-time-image-gated spot scanning proton therapy by insertion of fiducial markers. PU-MRI was performed using a non-contrast high-resolution two-dimensional T2-weighted turbo spin-echo imaging sequence. Four different SR deep learning models were used: the enhanced deep SR network (EDSR), widely activated SR network (WDSR), SR generative adversarial network (SRGAN), and residual dense network (RDN). The complex wavelet structural similarity index measure (CW-SSIM) was used to quantitatively assess the performance of the proposed SR images compared to PU-MRI. Two radiation oncologists used a 1-to-5 scale to subjectively evaluate the visibility of the prostatic urinary tract. Cohen's weighted kappa (k) was used as a measure of agreement of inter-operator reliability. The mean CW-SSIM in EDSR, WDSR, SRGAN, and RDN was 99.86%, 99.89%, 99.30%, and 99.67%, respectively. The mean prostatic urinary tract visibility scores of the radiation oncologists were 3.70 and 3.53 for PU-MRI (k = 0.93), 3.67 and 2.70 for EDSR (k = 0.89), 3.70 and 2.73 for WDSR (k = 0.88), 3.67 and 2.73 for SRGAN (k = 0.88), and 4.37 and 3.73 for RDN (k = 0.93), respectively. The results suggest that SR images using RDN are similar to the original images, and the SR deep learning models subjectively improve the visibility of the prostatic urinary tract.

Introduction Sequential boost intensity-modulated radiotherapy (SQB-IMRT) uses two different planning CTs (pCTs) and treatment plans. SQB-IMRT is a form of adaptive radiotherapy that allows for responses to changes in the shape of the tumour and organs at risk (OAR). On the other hand, dose accumulation with the two plans can be difficult to evaluate. The purpose of this study was to analyse patterns of loco-regional failure using deformable image registration (DIR) in hypopharyngeal cancer patients treated with SQB-IMRT. Methods Between 2013 and 2019, 102 patients with hypopharyngeal cancer were treated with definitive SQB-IMRT at our institution. Dose accumulation with the 1st and 2nd plans was performed, and the dose to the loco-regional recurrent tumour volume was calculated using the DIR workflow. Failure was classified as follows: (i) in-field (>= 95% of the recurrent tumour volume received 95% of the prescribed dose); (ii) marginal (20-95%); or (iii) out-of-field (<20%). Results After a median follow-up period of 25 months, loco-regional failure occurred in 34 patients. Dose-volume histogram analysis showed that all loco-regional failures occurred in the field within 95% of the prescribed dose, with no marginal or out-of-field recurrences observed. Conclusion The dosimetric analysis using DIR showed that all loco-regional failures were within the high-dose region. More aggressive treatment may be required for gross tumours.

Objectives : We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ventral horn. ……

Objectives : We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ventral horn. ……

It has been recognized that heavily overparameterized deep neural networks (DNNs) exhibit surprisingly good generalization performance in various machine-learning tasks. Although benefits of depth have been investigated from different perspectives such as the approximation theory and the statistical learning theory, existing theories do not adequately explain the empirical success of overparameterized DNNs. In this work, we report a remarkable interplay between depth and locality of a target function. We introduce $k$-local and $k$-global functions, and find that depth is beneficial for learning local functions but detrimental to learning global functions. This interplay is not properly captured by the neural tangent kernel, which describes an infinitely wide neural network within the lazy learning regime., Comment: 15 pages. This paper is a revised version of arXiv:2005.12488

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of thesepatientshad a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% formucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of thesepatientshad a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% formucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of thesepatientshad a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% formucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of thesepatientshad a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% formucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.

Stochastic gradient descent (SGD) undergoes complicated multiplicative noise for the mean-square loss. We use this property of SGD noise to derive a stochastic differential equation (SDE) with simpler additive noise by performing a random time change. Using this formalism, we show that the log loss barrier $\Delta\log L=\log[L(\theta^s)/L(\theta^*)]$ between a local minimum $\theta^*$ and a saddle $\theta^s$ determines the escape rate of SGD from the local minimum, contrary to the previous results borrowing from physics that the linear loss barrier $\Delta L=L(\theta^s)-L(\theta^*)$ decides the escape rate. Our escape-rate formula strongly depends on the typical magnitude $h^*$ and the number $n$ of the outlier eigenvalues of the Hessian. This result explains an empirical fact that SGD prefers flat minima with low effective dimensions, giving an insight into implicit biases of SGD., Comment: 17+8 pages

The noise in stochastic gradient descent (SGD), caused by minibatch sampling, is poorly understood despite its practical importance in deep learning. This work presents the first systematic study of the SGD noise and fluctuations close to a local minimum. We first analyze the SGD noise in linear regression in detail and then derive a general formula for approximating SGD noise in different types of minima. For application, our results (1) provide insight into the stability of training a neural network, (2) suggest that a large learning rate can help generalization by introducing an implicit regularization, (3) explain why the linear learning rate-batchsize scaling law fails at a large learning rate or at a small batchsize and (4) can provide an understanding of how discrete-time nature of SGD affects the recently discovered power-law phenomenon of SGD., Comment: ICLR 2022 spotlight

Aya Kimura,1 Hiroyuki Yamasaki,1 Haruka Ishii,2 Hisako Yoshida,2 Motoko Shimizu,3 Takashi Mori1 1Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan; 2Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan; 3Department of Anesthesiology, Sumitomo Hospital, Osaka City, Osaka, JapanCorrespondence: Aya KimuraDepartment of Anesthesiology, Osaka City University Graduate School of Medicine, 1-5-7 Asahimachi, Abeno-ku, Osaka City, Osaka, 545-8586, JapanTel +81-6-6645-2186Fax +81-6-6645-2489Email aya1226kimura@gmail.comPurpose: Serotonin (5-HT) is highly associated with pain modulation. The human 5-HT transporter (5-HTT) gene (SLC6A4) features several polymorphisms in its promoter region (5-HTTLPR) that affect the 5-HTT expression. The S allele of 5-HTTLPR induces low 5-HT tone, and it may influence the modulation of chronic pain. Meanwhile, pain occurs in 40– 50% of patients after thoracic surgery, and its mechanism remains under investigation. This study assessed the role of 5-HTTLPR polymorphisms in postthoracotomy pain severity.Patients and Methods: A total of 178 patients undergoing pneumonectomy were enrolled. The genotypes of 5-HTTLPR were divided into two groups: S/S group and S/L or L/L group. Linear mixed-effects models were used to assess the association between 5-HTTLPR genotypes and the numerical rating scale (NRS) score change over time.Results: Among the participants, data were obtained for 162 patients. The genotype distribution was as follows: S/S, 67.3%; S/L or L/L, 32.7%. No significant difference in patient characteristics was found between the genotype groups. There was no significant interaction between the 5-HTTLPR genotypes and the NRS score change over time (p = 0.842).Conclusion: Polymorphisms in 5-HTTLPR were not associated with postthoracotomy pain severity.Keywords: 5-HTTLPR, pain modulation, numerical rating scale

It has been recognized that a heavily overparameterized artificial neural network exhibits surprisingly good generalization performance in various machine-learning tasks. Recent theoretical studies have made attempts to unveil the mystery of the overparameterization. In most of those previous works, the overparameterization is achieved by increasing the width of the network, while the effect of increasing the depth has remained less well understood. In this work, we investigate the effect of increasing the depth within an overparameterized regime. To gain an insight into the advantage of depth, we introduce local and global labels as abstract but simple classification rules. It turns out that the locality of the relevant feature for a given classification rule plays a key role; our experimental results suggest that deeper is better for local labels, whereas shallower is better for global labels. We also compare the results of finite networks with those of the neural tangent kernel (NTK), which is equivalent to an infinitely wide network with a proper initialization and an infinitesimal learning rate. It is shown that the NTK does not correctly capture the depth dependence of the generalization performance, which indicates the importance of the feature learning rather than the lazy learning., Comment: 13+4 pages

Recent studies have demonstrated that noise in stochastic gradient descent (SGD) is closely related to generalization: A larger SGD noise, if not too large, results in better generalization. Since the covariance of the SGD noise is proportional to $\eta^2/B$, where $\eta$ is the learning rate and $B$ is the minibatch size of SGD, the SGD noise has so far been controlled by changing $\eta$ and/or $B$. However, too large $\eta$ results in instability in the training dynamics and a small $B$ prevents scalable parallel computation. It is thus desirable to develop a method of controlling the SGD noise without changing $\eta$ and $B$. In this paper, we propose a method that achieves this goal using ``noise enhancement'', which is easily implemented in practice. We expound the underlying theoretical idea and demonstrate that the noise enhancement actually improves generalization for real datasets. It turns out that large-batch training with the noise enhancement even shows better generalization compared with small-batch training., Comment: 9 pages

The outcomes of intensity-modulated proton craniospinal irradiation (ipCSI) are unclear. We evaluated the clinical benefit of our newly developed ipCSI system that incorporates two gantry-mounted orthogonal online X-ray imagers with a robotic six-degrees-of-freedom patient table. Nine patients (7-19 years old) were treated with ipCSI. The prescribed dose for CSI ranged from 23.4 to 36.0 Gy (relative biological effectiveness) in 13-20 fractions. Four adolescent and young adult (AYA) patients (15 years or older) were treated with vertebral-bodysparing ipCSI (VBSipCSI). Myelosuppression following VBSipCSI was compared with that of eight AYA patients treated with photon CSI at the same institution previously. The mean homogeneity index (HI) in the nine patients was 0.056 (95% confidence interval: 0.044-0.068). The mean time from the start to the end of all beam delivery was 37 min 39 s +/- 2 min 24 s (minimum to maximum: 22 min 49 s - 42 min 51 s). The nadir white blood cell, hemoglobin, and platelet levels during the 4 weeks following the end of the CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0071, 0.0453, 0.0024, respectively). The levels at 4 weeks after the end of CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0023, 0.0414, 0.0061). Image-guided ipCSI was deliverable in a reasonable time with sufficient HI. Using VBSipCSI, AYA patients experienced a lower incidence of serious acute hematological toxicity than AYA patients treated with photon CSI.

The outcomes of intensity-modulated proton craniospinal irradiation (ipCSI) are unclear. We evaluated the clinical benefit of our newly developed ipCSI system that incorporates two gantry-mounted orthogonal online X-ray imagers with a robotic six-degrees-of-freedom patient table. Nine patients (7-19 years old) were treated with ipCSI. The prescribed dose for CSI ranged from 23.4 to 36.0 Gy (relative biological effectiveness) in 13-20 fractions. Four adolescent and young adult (AYA) patients (15 years or older) were treated with vertebral-bodysparing ipCSI (VBSipCSI). Myelosuppression following VBSipCSI was compared with that of eight AYA patients treated with photon CSI at the same institution previously. The mean homogeneity index (HI) in the nine patients was 0.056 (95% confidence interval: 0.044-0.068). The mean time from the start to the end of all beam delivery was 37 min 39 s +/- 2 min 24 s (minimum to maximum: 22 min 49 s - 42 min 51 s). The nadir white blood cell, hemoglobin, and platelet levels during the 4 weeks following the end of the CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0071, 0.0453, 0.0024, respectively). The levels at 4 weeks after the end of CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0023, 0.0414, 0.0061). Image-guided ipCSI was deliverable in a reasonable time with sufficient HI. Using VBSipCSI, AYA patients experienced a lower incidence of serious acute hematological toxicity than AYA patients treated with photon CSI.

Background : The usefulness of the Microcuff^(R) pediatric endotracheal tube (Microcuff^(R) PET) has been reported from other countries, but few reports include Japanese children because Microcuff^(R) PET was recently introduced in Japan in 2015. Therefore, we compared the tube exchange ratio and postoperative complications between Microcuff^(R) PET and uncuffed tubes in Japanese children. / Methods : We conducted a single center retrospective cohort study with approval from our ethics committee. Patients aged 2 to 8 years, who underwent general anesthesia with endotracheal intubation between October 2015 and September 2017, were included....

Background : The usefulness of the Microcuff^(R) pediatric endotracheal tube (Microcuff^(R) PET) has been reported from other countries, but few reports include Japanese children because Microcuff^(R) PET was recently introduced in Japan in 2015. Therefore, we compared the tube exchange ratio and postoperative complications between Microcuff^(R) PET and uncuffed tubes in Japanese children. / Methods : We conducted a single center retrospective cohort study with approval from our ethics committee. Patients aged 2 to 8 years, who underwent general anesthesia with endotracheal intubation between October 2015 and September 2017, were included....

Epstein‑Barr virus‑associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric cancer characterized by clinicopathological features including lymphoepithelioma‑like histology. Aberrant expression of activation‑induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen‑related nuclear factor κB (NF‑κB) signaling in Helicobacter pylori‑associated gastric cancer. To elucidate whether or not AID expression is relevant to carcinogenesis in EBVaGC, immunohistochemical expression of AID and AID‑regulatory factors between EBVaGC and EBV‑non‑associated gastric carcinoma (GC) were evaluated, each using 15 cases of GC with lymphoid stroma (GCLS) and other types of GC. Aberrant expression of AID, NF‑κB and paired box 5 (PAX5) were significantly decreased in EBVaGC (0/11, 1/11 and 1/11) compared with in EBV‑non‑associated GC (7/19, 12/19 and 11/19) (P=0.025, 0.005 and 0.01, respectively); however, no significant difference in c‑Myb proto‑oncogene expression was identified. AID expression was also decreased in EBV‑associated GCLS (0/10) compared with in EBV‑non‑associated GCLS (3/5). Unexpectedly, decreased expression of NF‑κB and PAX5 was observed in GCLS (1/15 and 2/15) compared with in GC without LS (12/15 and 10/15) (P<0.001 and P=0.003, respectively). Decreased AID expression observed in EBVaGC is consistent with the reported molecular characterization of hypermethylation and rare somatic gene mutation in EBVaGC. Only PAX5 was identified to be significantly associated with venous invasion (P=0.022). The results of the present study suggest that pathogen‑induced AID expression may be irrelevant to carcinogenesis of EBVaGC, whereas it contributes to carcinogenesis in certain types of EBV‑non‑associated GC.

This is a report of a single-institution prospective study evaluating the safety of a spot-scanning dedicated, small 360-degree gantry, synchrotron-based proton beam therapy (PBT) system. Data collection was performed for 56 patients with 59 treatment sites who received proton beam therapy at Hokkaido University Hospital between March 2014 and July 2015. Forty-one patients were male and 15 were female. The median age was 66 years. The primary lesion sites were prostate (n = 17), bone/soft tissue (n = 10), liver (n = 7), lung (n = 6), central nervous system (n = 5), colon (n = 2), pancreas (n = 2), kidney (n = 2) and others (n = 5). Chemotherapy was administered in 11 patients. The prescribed total dose was from 20 to 76 GyE (Radiobiological equivalent dose, RBE = 1.1), with the median dose of 65 GyE in 4 to 35 fractions. No PBT-related Common Terminology Criteria for Adverse Events Grade 4 or 5 toxicities were observed; the incidence of early PBT-related Grade 4 adverse events was 0% (95% confidence interval 0 to 6.38%). The most common Grade 3 toxicities were hematologic toxicity (12.5%) unlikely to be related to the PBT. One patient developed a left femoral neck fracture (Grade 3) at 14.5 months after PBT for chondrosarcoma of the left pelvis. The pathological findings showed no other malignancies, suggesting that it was possibly related to the PBT. In conclusion, the spot-scanning dedicated, synchrotron-based PBT system is feasible, but further studies on its long-term safety and efficacy are warranted.

This is a report of a single-institution prospective study evaluating the safety of a spot-scanning dedicated, small 360-degree gantry, synchrotron-based proton beam therapy (PBT) system. Data collection was performed for 56 patients with 59 treatment sites who received proton beam therapy at Hokkaido University Hospital between March 2014 and July 2015. Forty-one patients were male and 15 were female. The median age was 66 years. The primary lesion sites were prostate (n = 17), bone/soft tissue (n = 10), liver (n = 7), lung (n = 6), central nervous system (n = 5), colon (n = 2), pancreas (n = 2), kidney (n = 2) and others (n = 5). Chemotherapy was administered in 11 patients. The prescribed total dose was from 20 to 76 GyE (Radiobiological equivalent dose, RBE = 1.1), with the median dose of 65 GyE in 4 to 35 fractions. No PBT-related Common Terminology Criteria for Adverse Events Grade 4 or 5 toxicities were observed; the incidence of early PBT-related Grade 4 adverse events was 0% (95% confidence interval 0 to 6.38%). The most common Grade 3 toxicities were hematologic toxicity (12.5%) unlikely to be related to the PBT. One patient developed a left femoral neck fracture (Grade 3) at 14.5 months after PBT for chondrosarcoma of the left pelvis. The pathological findings showed no other malignancies, suggesting that it was possibly related to the PBT. In conclusion, the spot-scanning dedicated, synchrotron-based PBT system is feasible, but further studies on its long-term safety and efficacy are warranted.

Background: Olfactory neuroblastoma (ONB) is a rare tumor originating from olfactory epithelium. Here we retrospectively analyzed the long-term treatment outcomes and toxicity of radiotherapy for ONB patients for whom computed tomography (CT) and three-dimensional treatment planning was conducted to reappraise the role of radiotherapy in the light of recent advanced technology and chemotherapy. Methods: Seventeen patients with ONB treated between July 1992 and June 2013 were included. Three patients were Kadish stage B and 14 were stage C. All patients were treated with radiotherapy with or without surgery or chemotherapy. The radiation dose was distributed from 50 Gy to 66 Gy except for one patient who received 40 Gy preoperatively. Results: The median follow-up time was 95 months (range 8-173 months). The 5-year overall survival (OS) and relapse-free survival (RFS) rates were estimated at 88% and 74%, respectively. Five patients with stage C disease had recurrence with the median time to recurrence of 59 months (range 7-115 months). Late adverse events equal to or above Grade 2 in CTCAE v4.03 were observed in three patients. Conclusion: Multimodal therapy including radiotherapy with precise treatment planning based on CT simulation achieved an excellent local control rate with acceptable toxicity and reasonable overall survival for patients with ONB.

Introduction: We retrospectively evaluated the efficacy of three-dimensional conformal radiotherapy (3D-CRT) for spinal schwannoma. Methods: Nine patients with spinal schwannoma were treated with 3D-CRT. All patients had a paravertebral or intraosseous component. Tumor sizes ranged from 0.8 to 8.7 cm, with a median of 3.5 cm. The prescribed dose was 50 Gy in 25 fractions at the isocenter, except for 1 patient who received 66 Gy in 33 fractions for a large sacral tumor. The follow-up period ranged from 20 to 137 months, with a median of 72 months. Results: Tumor shrinkage within 3 mm occurred in 4 patients and tumor expansion within 3 mm occurred in 3. One tumor showed neither expansion nor shrinkage at the last follow-up. One patient experienced transient expansion by 8 mm in diameter at 12 months after the completion of radiotherapy (35-43 mm), and then the tumor size remained unchanged for 7 years. No severe late toxicity a parts per thousand yen grade 3 was observed. Conclusions: Only 1 of 9 tumors showed transit expansion over 3 mm after 3D-CRT, and severe late radiation toxicity was not observed. Use of 3D-CRT should be considered a treatment option for spinal schwannoma.

Background: Olfactory neuroblastoma (ONB) is a rare tumor originating from olfactory epithelium. Here we retrospectively analyzed the long-term treatment outcomes and toxicity of radiotherapy for ONB patients for whom computed tomography (CT) and three-dimensional treatment planning was conducted to reappraise the role of radiotherapy in the light of recent advanced technology and chemotherapy. Methods: Seventeen patients with ONB treated between July 1992 and June 2013 were included. Three patients were Kadish stage B and 14 were stage C. All patients were treated with radiotherapy with or without surgery or chemotherapy. The radiation dose was distributed from 50 Gy to 66 Gy except for one patient who received 40 Gy preoperatively. Results: The median follow-up time was 95 months (range 8-173 months). The 5-year overall survival (OS) and relapse-free survival (RFS) rates were estimated at 88% and 74%, respectively. Five patients with stage C disease had recurrence with the median time to recurrence of 59 months (range 7-115 months). Late adverse events equal to or above Grade 2 in CTCAE v4.03 were observed in three patients. Conclusion: Multimodal therapy including radiotherapy with precise treatment planning based on CT simulation achieved an excellent local control rate with acceptable toxicity and reasonable overall survival for patients with ONB.

Introduction: We retrospectively evaluated the efficacy of three-dimensional conformal radiotherapy (3D-CRT) for spinal schwannoma. Methods: Nine patients with spinal schwannoma were treated with 3D-CRT. All patients had a paravertebral or intraosseous component. Tumor sizes ranged from 0.8 to 8.7 cm, with a median of 3.5 cm. The prescribed dose was 50 Gy in 25 fractions at the isocenter, except for 1 patient who received 66 Gy in 33 fractions for a large sacral tumor. The follow-up period ranged from 20 to 137 months, with a median of 72 months. Results: Tumor shrinkage within 3 mm occurred in 4 patients and tumor expansion within 3 mm occurred in 3. One tumor showed neither expansion nor shrinkage at the last follow-up. One patient experienced transient expansion by 8 mm in diameter at 12 months after the completion of radiotherapy (35-43 mm), and then the tumor size remained unchanged for 7 years. No severe late toxicity a parts per thousand yen grade 3 was observed. Conclusions: Only 1 of 9 tumors showed transit expansion over 3 mm after 3D-CRT, and severe late radiation toxicity was not observed. Use of 3D-CRT should be considered a treatment option for spinal schwannoma.

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.