Long-term survival outcomes and quality of life of image-guided proton therapy for operable stage I non-small cell lung cancer: A phase 2 study.

BACKGROUND AND PURPOSE: This study evaluated long-term efficacy, safety, and changes in quality of life (QOL) of patients after image-guided proton therapy (IGPT) for operable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This single-institutional prospective phase 2 study enrolled patients with operable histologically confirmed stage IA or IB NSCLC (7th edition of UICC). The prescribed dose was 66 Gy relative biological effectiveness equivalents (GyRBE) in 10 fractions for peripheral lesions, or 72.6 GyRBE in 22 fractions for central lesions. The primary endpoint was the 3-year overall survival (OS). The secondary endpoints included disease control, toxicity, and changes in QOL score. RESULTS: We enrolled 43 patients (median age: 68 years; range, 47-79 years) between July 2013 to January 2021, of whom 41 (95 %) had peripheral lesions and 27 (63 %) were stage IA. OS, local control, and progression-free survival rates were 95 % (95 % CI: 83-99), 95 % (82-99), and 86 % (72-94), respectively, at 3 years, and 83 % (66-92), 95 % (82-99), and 77 % (60-88), respectively, at 7 years. Four patients (9 %) developed grade 2, and one patient (2 %) developed grade 3 radiation pneumonitis. No other grade 3 or higher adverse events were observed. In the QOL analysis, global QOL remained favorable; however, approximately 40 % of patients reported dyspnea at 3 and 24 months. CONCLUSION: Our findings suggest that IGPT provides effective disease control and survival in operable stage I NSCLC, particularly for peripheral lesions. Moreover, toxicity associated with IGPT was minimal, and patients reported favorable QOL.

Lobectomy versus proton therapy for stage I non-small cell lung cancer.

OBJECTIVE: Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC). In recent years, an increasing number of patients with lung cancer have been treated using proton therapy (PT). We conducted a propensity score-matched analysis to compare the treatment outcomes of these 2 modalities. METHODS: We retrospectively reviewed data from 275 patients with histologically confirmed clinical stage I NSCLC who underwent lobectomy (n = 206) or PT (n = 69) at our institution from July 2013 to December 2020. The end points were overall survival (OS), cause-specific survival, recurrence-free survival (RFS), local control, regional lymph node control, and distant control. Propensity score matching was performed to reduce selection bias in the 2 groups. RESULTS: The matched cohort consisted of 59 patients who underwent lobectomy and 59 patients who underwent PT with a median follow-up period of 50 months. There were no significant differences in OS (P = .26), cause-specific survival (P = .33), RFS (P = .53), local control (P = .41), regional lymph node control (P = .98), and distant control (P = .31). In the lobectomy and PT groups, the 5-year OS rate was 85.8% and 79.1%, respectively, the RFS rate was 82.3% and 77.8%, and the local control rate was 92.1% and 96.6%. CONCLUSIONS: We found no difference in survival or disease control between lobectomy and PT in patients with histologically confirmed clinical stage I NSCLC. Despite these findings, the potential for unmeasured confounding factors remains, and randomized control trials are needed to better compare these treatment modalities.

Outcomes of proton therapy for non-small cell lung cancer in patients with interstitial pneumonia.

BACKGROUND: Interstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP. METHODS: Twenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66-74 Grays (relative biological effectiveness) in 10-37 fractions. RESULTS: The median follow-up period was 21.1 months [interquartile range (IQR), 15.6-37.3] for all patients and 37.2 months (IQR, 24.0-49.9) for living patients. The median patient age was 77 years (IQR, 71-81). The median planning target volume was 112.0 ml (IQR, 56.1-246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57-95), 30% (15-47), and 45% (26-62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients' quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months. CONCLUSIONS: PT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.

Patient-Reported Quality of Life Outcomes after Moderately Hypofractionated and Normofractionated Proton Therapy for Localized Prostate Cancer.

We retrospectively evaluated the three-year patient-reported quality of life (QOL) after moderately hypofractionated proton therapy (MHPT) for localized prostate cancer in comparison with that after normofractionated PT (NFPT) using the Expanded Prostate Cancer Index Composite-50. Patients who received MHPT (60-63 Gy (relative biological effectiveness equivalents; RBE)/20-21 fractions) (n = 343) or NFPT (74-78 Gy (RBE)/37-39 fractions) (n = 296) between 2013 and 2016 were analyzed. The minimum clinically important difference (MCID) threshold was defined as one-half of a standard deviation of the baseline value. The median follow-up was 56 months and 83% completed questionnaires at 36 months. Clinically meaningful score deterioration was observed in the urinary domain at 1 month in both groups and in the sexual domain at 6-36 months in the NFPT group, but not observed in the bowel domain. At 36 months, the mean score change for urinary summary was -0.3 (MHPT) and -1.6 points (NFPT), and that for bowel summary was +0.1 and -2.0 points; the proportion of patients with MCID was 21% and 24% for urinary summary and 18% and 29% for bowel summary. Overall, MHPT had small negative impacts on QOL over three years, and the QOL after MHPT and NFPT was similar.

DAPL1 is a novel regulator of testosterone production in Leydig cells of mouse testis.

Leydig cells in the testes produce testosterone in the presence of gonadotropins. Therefore, male testosterone levels must oscillate within a healthy spectrum, given that elevated testosterone levels augment the risk of cardiovascular disorders. We observed that the expression of death-associated protein-like 1 (DAPL1), which is involved in the early stages of epithelial differentiation and apoptosis, is considerably higher in the testes of sexually mature mice than in other tissues. Accordingly, Dapl1-null mice were constructed to evaluate this variation. Notably, in these mice, the testicular levels of steroidogenic acute regulatory protein (StAR) and serum testosterone levels were significantly elevated on postnatal day 49. The findings were confirmed in vitro using I-10 mouse testis-derived tumor cells. The in vivo and in vitro data revealed the DAPL1-regulated the expression of StAR involving altered transcription of critical proteins in the protein kinase A and CREB/CREM pathways in Leydig cells. The collective findings implicate DAPL1 as an important factor for steroidogenesis regulation, and DAPL1 deregulation may be related to high endogenous levels of testosterone.

Spot Scanning Proton Therapy for Sinonasal Malignant Tumors.

PURPOSE: Treatment of sinonasal malignant tumors is challenging, and evidence to establish a standard treatment is limited. Our objective was to evaluate the efficacy and safety of spot scanning proton therapy (SSPT) for sinonasal malignant tumors. PATIENTS AND METHODS: We retrospectively analyzed patients with sinonasal malignant tumors (T1-4bN0-2M0) who underwent SSPT between May 2014 and September 2019. The prescription dose was typically either 60 GyRBE in 15 fractions or 60.8 GyRBE in 16 fractions for mucosal melanoma and 70.2 GyRBE in 26 fractions for other histologic subtypes. Endpoints included local control (LC), progression-free survival, overall survival (OS), and incidence of toxicity. Prognostic factors were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Of 62 enrolled patients, the common histologic subtypes were mucosal melanoma (35%), squamous cell carcinoma (27%), adenoid cystic carcinoma (16%), and olfactory neuroblastoma (10%). Locally advanced stages were common (T3 in 42% and T4 in 53%). Treatment-naïve tumors and postsurgical recurrent tumors accounted for 73% and 27%, respectively. No patient had previous radiotherapy. The median follow-up was 17 months (range, 6-66) for all patients and 21.5 months (range, 6-66) for survivors. The 2-year LC, progression-free survival, and OS rates of all patients were 92%, 50%, and 76%, respectively. Univariate analysis revealed histology as a prognostic factor for OS, being higher in adenoid cystic carcinoma and olfactory neuroblastoma than in other tumors. Sixteen grade ≥3 late toxicities were observed in 12 patients (19%), including 11 events resulting in visual impairment; the most common was cataract. There was 1 grade 4 toxicity, and there were no grade 5 toxicities. CONCLUSION: SSPT was well tolerated and yielded good LC for sinonasal malignant tumors. Although we consider SSPT to be a leading treatment modality, further studies are required to establish its status as a standard treatment.

A Phase 2 Study of Image-Guided Proton Therapy for Operable or Ablation-Treatable Primary Hepatocellular Carcinoma.

PURPOSE: Because most previous data on proton therapy for hepatocellular carcinoma (HCC) were retrospectively collected from inoperable or previously treated cases, our aim was to evaluate the outcome of image-guided proton therapy (IGPT) for operable or radiofrequency ablation-treatable primary HCC. METHODS AND MATERIALS: This phase 2 study prospectively investigated the efficacy and safety of IGPT and quality of life (QoL) after IGPT for operable/ablatable HCC. The primary endpoint was overall survival, and the secondary endpoints were local control, incidence of grade ≥3 adverse events, and changes in QoL. Toxicities were evaluated with Common Terminology Criteria for Adverse Events, version 4.0. QoL scores were assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0, and Quality of Life Questionnaire-Hepatocellular Carcinoma/Primary Liver Cancer Module. IGPT was performed using respiratory-gated techniques. RESULTS: Forty-five patients (median age: 68 years; range, 36-80 years) were enrolled between June 2013 and February 2016; 38 were considered operable and 14 were indicated for radiofrequency ablation. The major underlying liver diseases were hepatitis B (n = 16), hepatitis C (n = 13), alcoholic hepatitis (n = 3), and nonalcoholic fatty liver disease (n = 13). The Child-Pugh score was A5 in 32 patients, A6 in 9 patients, and B7 in 4 patients. Thirty-seven patients with a peripherally located tumor were given 66 Gy relative biological effectiveness in 10 fractions, and 8 patients with a centrally located tumor received 72.6 Gy relative biological effectiveness in 22 fractions. The median follow-up period of surviving patients was 60 months (range, 42-75 months). Two- and 5-year overall survival rates were 84% (95% confidence interval [CI], 74%-95%) and 70% (95% CI, 56%-84%), respectively, and local control rates were 95% (95% CI, 89%-100%) and 92% (95% CI, 84%-100%), respectively. Grade 3 radiation-induced liver disease was observed in 1 patient. No significant changes were noted in QoL scores 1 year after treatment, except for body image. CONCLUSIONS: Although the primary endpoint did not meet statistical significance as planned in the study design, IGPT is a safe and effective treatment for solitary primary HCC and may become a treatment option.

Changes in sexual function and serum testosterone levels in patients with prostate cancer after image-guided proton therapy.

Since sexual function and testosterone levels after image-guided proton therapy (IGPT) have not yet been examined in detail, we prospectively evaluated changes before and after IGPT. Among patients treated with IGPT with or without combined androgen blockade (CAB) therapy between February 2013 and September 2014, patients who agreed to participate in the study and were followed up for >3 years after IGPT were evaluated. Serum testosterone levels were regularly measured together with prostate-specific antigen (PSA) levels before and after IGPT. The Erection Hardness Score (EHS) and the sexual domain summary, function subscale and bother subscale of the sexual domain in the Expanded Prostate Cancer Index Composite (EPIC) were assessed. There were 38 low-risk, 46 intermediate-risk and 43 high- or very-high-risk patients (NCCN classification). Although serum testosterone levels in low-risk patients did not decrease after IGPT, reductions were observed in the average EHS and the sexual domain summary score of the EPIC. In intermediate-, high- and very-high-risk patients, testosterone and PSA levels both increased following the termination of CAB after IGPT, and the average EHS increased. The sexual domain summary score gradually increased, but not above minimally important differences. In intermediate-risk patients, the function subscale increased from 4.4 to 14.8 (P < 0.05) 12 months after IGPT and reached a plateau after 60 months. The results of the present study would suggest the potential of IGPT, and further prospective studies to directly compare IGPT with other modalities are warranted.

Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring.

Although dioxins and related chemicals have been suspected to disrupt child development, their toxic mechanism remains poorly understood. Our previous studies in rat fetuses revealed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, suppresses fetal synthesis of pituitary growth hormone (GH) that is essential for development. This study examined the hypothesis that attenuating GH expression in fetuses triggers developmental disorders. Treating pregnant rats with 1 µg/kg TCDD reduced the circulating level of GH and its downstream factor, insulin-like growth factor-1 (IGF-1), in the offspring only during the fetal and early neonatal stages. Although maternal TCDD exposure resulted in low body weight and length at babyhood and defects in the learning and memory ability at adulthood, GH supplementation in TCDD-exposed fetuses restored or tended to restore the defects including IGF-1 downregulation. Moreover, maternal TCDD exposure decreased the number of GH-positive cells during the fetal/neonatal stage. A microarray analysis showed that TCDD reduced the expression of death-associated protein-like 1 (DAPL1), a cell cycle-dependent proliferation regulator, in the fetal pituitary gland. In addition, TCDD treatment attenuated proliferating cells and cyclin mRNA expression in the fetal pituitary gland. Aryl hydrocarbon receptor (AHR)-knockout fetuses were insensitive to TCDD treatment, indicating that the TCDD-induced reduction in DAPL1 and GH mRNAs expression was due to AHR activation. Finally, DAPL1 knockdown suppressed GH and cyclin D2 expression in fetal pituitary cells. These results provide a novel evidence that dioxin suppresses GH-producing cell proliferation and GH synthesis due to partly targeting DAPL1, thereby impairing offspring development.

Image-Guided Proton Therapy for Elderly Patients with Hepatocellular Carcinoma: High Local Control and Quality of Life Preservation.

This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child-Pugh score was A5 in 49 patients, A6 in 15, and B7-9 in 7. Forty-seven patients with a peripherally located tumor were administered 66 gray relative biological effectiveness (GyRBE) in 10 fractions, whereas 24 with a centrally located tumor received 72.6 GyRBE in 22 fractions. The median follow-up period of surviving patients was 33 months (range: 9-68). Two-year overall survival (OS) and local control (LC) rates estimated by the Kaplan-Meier method were 76% (95% confidence interval: 66-87%) and 88% (80-97%), respectively. According to the Common Terminology Criteria for Adverse Events version 4.0, no grade 2 or higher radiation-induced liver disease was observed, and only 1 patient developed grade 3 dermatitis. The quality of life score (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, QLQ-HCC18, and SF-36) did not change after 1 year, except for the three-mental component summary (SF-36, improvement). IGPT is a safe and effective treatment for HCC in elderly patients.

Concurrent Chemo-Proton Therapy Using Adaptive Planning for Unresectable Stage 3 Non-Small Cell Lung Cancer: A Phase 2 Study.

PURPOSE: This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. RESULTS: Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. CONCLUSIONS: CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

Feasibility of transrectal and transperineal fiducial marker placement for prostate cancer before proton therapy.

BACKGROUND: To compare the feasibility of transrectal and transperineal fiducial marker placement for prostate cancer before proton therapy. MATERIALS AND METHODS: From 2013 to 2015, the first 40 prostate cancer patients that were scheduled for proton therapy underwent transrectal fiducial marker placement, and the next 40 patients underwent transperineal fiducial marker placement (the first series). Technical and clinical success and pain scores were evaluated. In the second series (n = 280), the transrectal or transperineal approach was selected depending on the presence/absence of comorbidities, such as blood coagulation abnormalities. Seven patients refused to undergo the procedure. Thus, the total number of patients across both series was 353 (262 and 91 underwent the transrectal and transperineal approach, respectively). Technical and clinical success, complications, marker migration and the distance between the two markers were evaluated. RESULTS: In the first series, the technical and clinical success rates were 100% in both groups. The transrectal group exhibited lower pain scores than the transperineal group. The overall technical success rates of the transrectal and transperineal groups were 100% (262/262) and 99% (90/91), respectively (P > 0.05). The overall clinical success rate was 100% in both groups, and there were no major complications in either group. The migration rates of the two groups did not differ significantly. The mean distance between the two markers was 25.6 ± 7.1 mm (mean ± standard deviation) in the transrectal group and 31.9 ± 5.2 mm in the transperineal group (P < 0.05). CONCLUSION: Both the transrectal and transperineal fiducial marker placement methods are feasible and safe.

Long-term multidisciplinary treatment including proton therapy for a recurrent low-grade endometrial stromal sarcoma and pathologically prominent epithelial differentiation: an autopsy case report.

BACKGROUND: Long-term follow-up reports of low-grade endometrial stromal sarcoma (LGESS) including its clinical course and pathological data are rare. We previously reported the case of a Japanese woman diagnosed with LGESS, who was treated with multidisciplinary therapy. She had been suffering from uterine cervical tumor diagnosed as cervical polyps, or fibroid in statu nascendi, since 24 years old. The patient had survived for 25 years with the disease. This report presents her progress and pathological change since the previous report. CASE PRESENTATION: At age 45, the patient experienced a relapse of the remnant LGESS tumor between the right diaphragm and liver. Although chemotherapy was not effective, the tumor was eliminated by proton therapy. At age 46 years, the remnant tumors outside the irradiated field were resected. The disease was originally diagnosed as "neuroendocrine carcinoma (NEC)" using the surgical specimen. Therefore, cisplatin and irinotecan combination chemotherapy were administered to treat the remnant dissemination. After 4 cycles of chemotherapy, the liver metastases had enlarged and were resected surgically. Consequently, no remnant tumor was visible in the abdominal cavity at the end of the surgery. To determine the origin of NEC, we examined the previously resected specimens obtained from her ileum at age 40 years. A boundary between the LGESS and neuroendocrine tumor grade 2 (NET G2)-like lesion was found in the tumor, indicating that the origin of these tumors was LGESS. After less than 2 years of chemotherapy and undergoing surgery, a relapse of the tumor in the liver induced biliary duct obstruction with jaundice, which was treated with endoscopic retrograde biliary drainage. Although pazopanib prolonged her life for 10 months, she died from sepsis at age 49 years, which was caused by the infection that spread to the liver metastatic tumor via the stented biliary ducts. Autopsy revealed adenocarcinoma-like differentiation of the tumor. CONCLUSION: This LGESS patient has survived for a long time owing to multidisciplinary treatment including proton therapy. The LGESS tumor differentiated to NET G2-like tissue and then further to adenocarcinoma-like tissue during the long-term follow-up.

Gestational dioxin exposure suppresses prolactin-stimulated nursing in lactating dam rats to impair development of postnatal offspring.

A number of epidemiological studies have implicated environmental chemicals including dioxins in the induction of negative effects on child development. To clarify the underlying mechanisms, almost all toxicologists have concentrated on effects on the offspring themselves. We examined an alternative hypothesis that gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, targets factors related to maternal childcare to disturb offspring development. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 suppressed maternal licking behavior, a nursing behavior, and mammary gland maturation during the lactational stage, as well as the body weight and short-term memory of postnatal offspring. In support of these findings, maternal production of prolactin, a pituitary hormone essential for nursing including milk production, was decreased during the same period. Intracerebroventricular infusion of prolactin to dioxin-exposed dams restored or tended to restore many of the above defects observed both in mothers and offspring. The TCDD-dependent defects in maternal nursing behaviors can be due to a direct action on aryl hydrocarbon receptor (AHR) of lactating dams, because they did not emerge in AHR-knockout dams or control dams with TCDD-exposed offspring. Further examinations revealed that TCDD induces transforming growth factor ß1 expression, which suppresses prolactin-producing cell proliferation, in a nursing period-specific manner. In agreement with this, the number of prolactin-positive cells in nursing dams was decreased by TCDD. These results provide novel evidence that gestational dioxin exposure attenuates prolactin-stimulated nursing in lactating dams to impair offspring development, and that immaturity of prolactin-producing cells can contribute to them.

Proton therapy for non-squamous cell carcinoma of the head and neck: planning comparison and toxicity.

To investigate optimal treatment planning using proton beams for non-squamous cell carcinoma of the head and neck (NSCHN), the dose distributions of plans involving pencil beam scanning (PBS) with or without a patient-specific aperture system (PSAS), passive-scattering proton therapy (PSPT) and X-ray intensity-modulated radiotherapy (IMRT) were compared. As clinical results, toxicities of PBS with PSAS, including changes in quality of life, were reported. Between April 2014 and August 2016, a total of 30 patients were treated using PBS with PSAS. In 20 patients selected at random, the dose distributions of PBS with or without the PSAS, PSPT and IMRT plans were compared. Neutron exposure by proton therapy was calculated using a Monte Carlo simulation. Toxicities were scored according to CTCAE ver. 4.0. Patients completed EORTC quality of life survey forms (QLQ-C30 and QLQ-HN35) before and 0-12 months after proton therapy. The 95% conformity number of PBS with the PSAS plan was the best, and significant differences were detected among the four plans (P < 0.05, Bonferroni tests). Neutron generation by PSAS was ~1.1-fold higher, but was within an acceptable level. No grade 3 or higher acute dermatitis was observed. Pain, appetite loss and increased weight loss were more likely at the end of treatment, but recovered by the 3 month follow-up and returned to the pretreatment level at the 12 month follow-up. PBS with PSAS reduced the penumbra and improved dose conformity in the planning target volume. PBS with PSAS was tolerated well for NSCHN.

Transient increases in serum α fetoprotein and protein induced by vitamin K antagonist II levels following proton therapy does not necessarily indicate progression of hepatocellular carcinoma.

Transient increases in α-fetoprotein (AFP) and protein induced by vitamin K antagonist II (PIVKA-II), so-called flares, are frequently observed after treatment of hepatocellular carcinoma (HCC). In the present study, changes in AFP and PIVKA-II levels after proton therapy (PT), and the relationship between the flare phenomenon and clinical response were investigated. In 82 patients with stage I/II HCC (59 with no recurrence and 23 with out-of-field recurrence within 1 year), serum AFP and PIVKA-II levels were measured at 1, 3, 6, 9 and 12 months post-PT. AFP and PIVKA-II flares were defined as a >20% increase from the preceding serum level above 20 ng/ml (AFP) or 40 mAU/ml (PIVKA-II), followed by a >20% drop. Among the 59 patients with no recurrence, 3 (5.1%) had an AFP flare, while 23 (39%) had a PIVKA-II flare. The median time to AFP and PIVKA-II flare peaks was 1 and 6 months, respectively. In 4 patients, PIVKA-II flares were observed twice during follow-up. In 1 patient, AFP and PIVKA-II flares were observed simultaneously at 1 month post-PT. The PIVKA-II level pre-PT was significantly higher in the PIVKA-II flare-positive group compared with that in the flare-negative group (P=0.015, odds ratio 4.3, 95% confidence interval, 1.3-14.0). In the 23 patients with out-of-field recurrence, the median increase rate of PIVKA-II (203%) was higher than that in the PIVKA-II-flare-positive group (111%, P=0.035) and the time to recurrence (median, 9 months) was longer than the time to peak AFP level (1 month) in the AFP-flare-positive group (P=0.033). There was no significant association between flares and clinical response. Increases in AFP and PIVKA-II levels following PT should be assessed with caution to avoid misinterpretation of therapeutic outcome.

Effect of a Device-Free Compressed Shell Fixation Method on Hepatic Respiratory Movement: Analysis for Respiratory Amplitude of the Liver and Internal Motions of a Fiducial Marker.

PURPOSE: Suppression of respiratory movement of the liver would be desirable for high-precision radiation therapy for liver tumors. We aimed to investigate the effect of our original device-free compressed shell fixation method and breathing instruction on suppression of respiratory movement. The characteristics of liver motion based on the movement of a fiducial marker were also analyzed. METHODS AND MATERIALS: First, respiratory amplitudes of the liver with the device-free compressed shell were analyzed from the data of 146 patients. The effect of this shell fixing method on liver movement was evaluated. Second, as another cohort study with 166 patients, interfractional internal motion of the liver for patients fixed in the shell was calculated using the fiducial marker coordinate data of images for position setting before daily irradiation. Third, in another 12 patients, intrafractional internal motion was calculated from the fiducial marker coordinate data using x-ray images before and after irradiation. RESULTS: The median respiratory movement without the shell, after fixing with the shell, and after instructing on the breathing method with the shell was 14.2 (interquartile range, 10.7-19.8), 11.5 (8.6-17.5), and 10.4 mm (7.3-15.8), respectively. Systematic and random errors of interfractional internal motion were all ≤2 mm in the left-right and anteroposterior directions and 3.7 and 3.0 mm, respectively, in the craniocaudal direction. Systematic and random errors of intrafractional internal motion were all ≤1.3 mm in the left-right and anteroposterior directions and 0.8 and 2.4 mm, respectively, in the craniocaudal direction. CONCLUSIONS: The device-free compressed shell fixation method was effective in suppressing the respiratory movement of the liver. Irradiation position matching using the fiducial marker can correct the interfractional internal motion on each day, which would contribute to the reduction of the margin to be given around the target.

Clinical outcomes of image-guided proton therapy for histologically confirmed stage I non-small cell lung cancer.

BACKGROUND: Two prospective phase II trials were designed to assess the efficacy and safety of image-guided proton therapy (IGPT) for either medically inoperable or operable stage I non-small cell lung cancer (NSCLC). The present study reports the interim results of these trials. METHODS: Fifty-five patients with histologically confirmed stage I NSCLC (IA in 33 patients and IB in 22 patients; inoperable in 21 patients and operable in 34 patients) who received IGPT between July 2013 and February 2017 were analyzed. The median patient age was 71 years (range: 48-88 years). IGPT with fiducial metallic marker matching was performed for suitable patients, and a respiratory gating method for motion management was used for all treatments. Peripherally located tumors were treated with 66 Gy relative biological effectiveness equivalents (Gy(RBE)) in 10 fractions (n = 49) and centrally located tumors were treated with 72.6 Gy(RBE) in 22 fractions (n = 6). Treatment associated toxicities were evaluated using Common Toxicity Criteria for Adverse Events (v.4.0). RESULTS: Median follow-up was 35 months (range: 12-54 months) for survivors. For all patients, the 3-year overall survival, progression-free survival, and local control rates were 87% (95% confidence interval: 73-94%), 74% (58-85%), and 96% (83-99%), respectively. Fiducial marker matching was used in 39 patients (71%). Grade 2 toxicities observed were radiation pneumonitis in 5 patients (9%), rib fracture in 2 (4%), and chest wall pain in 5 (9%). There were no grade 3 or higher acute or late toxicities. CONCLUSIONS: IGPT appears to be effective and well tolerated for all patients with stage I NSCLC. TRIAL REGISTRATION: Lung-001, 13-02-09 (9), registered 11 June 2013 and Lung-002, 13-02-10 (10), registered 11 June 2013.

The aryl hydrocarbon receptor is indispensable for dioxin-induced defects in sexually-dimorphic behaviors due to the reduction in fetal steroidogenesis of the pituitary-gonadal axis in rats.

Many forms of the toxic effects produced by dioxins and related chemicals take place following activation of the aryl hydrocarbon receptor (AHR). Our previous studies have demonstrated that treating pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic dioxin, attenuates the pituitary expression of gonadotropins to reduce testicular steroidogenesis during the fetal stage, resulting in the impairment of sexually-dimorphic behaviors after the offspring reach maturity. To investigate the contribution of AHR to these disorders, we examined the effects of TCDD on AHR-knockout (AHR-KO) Wistar rats. When pregnant AHR-heterozygous rats were given an oral dose of 1 µg/kg TCDD at gestational day (GD) 15, TCDD reduced the expression of pituitary gonadotropins and testicular steroidogenic proteins in male wild-type fetuses at GD20 without affecting body weight, sex ratio and litter size. However, the same defect did not occur in AHR-KO fetuses. Further, fetal exposure to TCDD impaired the activity of masculine sexual behavior after reaching adulthood only in the wild-type offspring. Also, in female offspring, not only the fetal gonadotropins production but also sexual dimorphism, such as saccharin preference, after growing up were suppressed by TCDD only in the wild-type. Interestingly, in the absence of TCDD, deleting AHR reduced masculine sexual behavior, as well as fetal steroidogenesis of the pituitary-gonadal axis. These results provide novel evidence that 1) AHR is required for TCDD-produced defects in sexually-dimorphic behaviors of the offspring, and 2) AHR signaling plays a role in gonadotropin synthesis during the developmental stage to acquire sexual dimorphism after reaching adulthood.

Acute toxicity of image-guided hypofractionated proton therapy for localized prostate cancer.

BACKGROUND: Hypofractionated proton therapy (HFPT) is expected to become an effective treatment approach for localized prostate cancer (PCa). The purpose of this study was to evaluate differences in acute toxicity among patients with localized PCa treated with either conventional fractionated proton therapy (CFPT) or HFPT. METHODS: A total of 526 eligible patients treated with proton therapy between February 2013 and May 2016 in three phase II trials were analyzed. We prescribed 74 gray relative biological effectiveness equivalents [Gy (RBE)]/37 fractions for low-risk patients and 78 Gy (RBE)/39 fractions for intermediate- and high-risk patients in the CFPT group (n = 254) and 60 Gy (RBE)/20 fractions for low-risk and 63 Gy (RBE)/21 fractions for intermediate- and high-risk patients in the HFPT group (n = 272). Patients were evaluated for acute toxicity with the Common Terminology Criteria for Adverse Events, version 4.0, and urinary quality-of-life change using the International Prostate Symptom Score (IPSS). RESULTS: No grade ≥3 acute toxicity was observed in either group. Among acute genitourinary toxicities, grade 2 rates were 15% (n = 38) in CFPT and 5.9% (n = 16) in HFPT (P ≤ 0.001). The median baseline IPSSs of the CFPT and HFPT groups were 7 (0-29) and 6 (0-31), respectively (P = 0.70). One-month post-treatment scores were 9 (0-32) and 11 (0-32), respectively (P = 0.036), and 6-month post-treatment scores were 7 (0-30) and 7 (0-33), respectively (P = 0.88). There were no significant differences in acute gastrointestinal toxicity between the two groups. CONCLUSION: Our results demonstrated the safety of HFPT for localized PCa patients in terms of acute toxicity.