Proton beam therapy for hepatocellular carcinoma with bile duct invasion.

AIM: Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. METHODS: Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. RESULTS: The median follow-up time was 23.4 months (range, 7.9-54.3). The median age was 71 years (range, 58-90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5-8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. CONCLUSIONS: PBT was feasible with tolerable toxicities for the treatment of BDIHCC.

Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress.

Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G2/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G2/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.

A case of massive hemoptysis caused by lung cancer saved by V-V ECMO and hemostasis achieved by radiotherapy.

Massive hemoptysis is one of the fatal complications of lung cancer. There is no established standard treatment method for it, and it often causes sudden suffocation, and some cases may be difficult to save. A 63-year-old man was admitted to the hospital with dyspnea, and developed massive hemoptysis from lung cancer shortly after admission. The tumor had obstructed the right main bronchus and had invaded the right pulmonary artery. Surgery and interventional radiology were judged impossible. The patient was successfully saved by the introduction of Veno-Venous Extra Corporeal Membrane Oxygenation (V-V ECMO), and hemostasis was obtained by radiotherapy. Two months after completion of radiotherapy, he was weaned off the ventilator and discharged on his own. He died of increased peritoneal dissemination and other complications 1 year and 1 month later, but no recurrence of hemoptysis was noted until his death. We experienced a case of massive hemoptysis in which V-V ECMO and radiation therapy succeeded in saving life and stopping bleeding. The use of V-V ECMO by emergency care teams and multimodality therapy, including radiotherapy, were effective for massive hemoptysis from lung cancer.

Tumor Response on Diagnostic Imaging after Proton Beam Therapy for Hepatocellular Carcinoma.

BACKGROUND: Follow-up after treatment for hepatocellular carcinoma (HCC) can be mostly performed using dynamic CT or MRI, but there is no common evaluation method after radiation therapy. The purpose of this study is to examine factors involved in tumor reduction and local recurrence in patients with HCC treated with proton beam therapy (PBT) and to evaluate HCC shrinkage after PBT. METHODS: Cases with only one irradiated lesion or those with two lesions irradiated simultaneously were included in this study. Pre- and post-treatment lesions were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) by measuring the largest diameter. RESULTS: The 6-, 12-, and 24-month CR + PR rates after PBT were 33.1%, 57.5%, and 76.9%, respectively, and the reduction rates were 25.1% in the first 6 months, 23.3% at 6-12 months, and 14.5% at 13-24 months. Cases that reached CR/PR at 6 and 12 months had improved OS compared to non-CR/non-PR cases. CONCLUSIONS: It is possible that a lesion that reached SD may subsequently transition to PR; it is reasonable to monitor progress with periodic imaging evaluations even after 1 year of treatment.

Total Synthesis of the Sesquiterpene (-)-Merrillianin.

The first total synthesis of (-)-merrillianin (1), which is a natural sesquiterpene with a tricyclic structure having a cyclopentane ring and five- and seven-membered lactone parts, is demonstrated. This asymmetric total synthesis enabled the absolute stereostructure determination of naturally occurring (-)-1.

Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan.

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.

Moderately hypofractionated proton beam therapy for localized prostate cancer: 5-year outcomes of a phase II trial.

The usefulness of moderately hypofractionated radiotherapy for localized prostate cancer has been extensively reported, but there are limited studies on proton beam therapy (PBT) using similar hypofractionation schedules. The aim of this prospective phase II study is to confirm the safety of a shortened PBT course using 70 Gy relative biological effectiveness (RBE) in 28 fractions. From May 2013 to June 2015, 102 men with localized prostate cancer were enrolled. Androgen deprivation therapy was administered according to risk classification. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.0. Of the 100 patients ultimately evaluated, 15 were classified as low risk, 43 as intermediate risk, and 42 as high risk. The median follow-up time of the surviving patients was 96 months (range: 60-119 months). The 5-year cumulative incidences of grade 2 gastrointestinal/genitourinary adverse events were 1% (95% CI: 0.1-6.9) and 4% (95% CI: 1.5-10.3), respectively; no grade ≥ 3 gastrointestinal/genitourinary adverse events were observed. The current study revealed a low incidence of late adverse events in prostate cancer patients treated with moderately hypofractionated PBT of 70 Gy (RBE) in 28 fractions, indicating the safety of this schedule.

A systematic review and meta-analysis of radiotherapy and particle beam therapy for skull base chondrosarcoma: TRP-chondrosarcoma 2024.

Introduction: Chondrosarcoma is a rare malignant bone tumor. Particle beam therapy (PT) can concentrate doses to targets while reducing adverse events. A meta-analysis based on a literature review was performed to examine the efficacy of PT and photon radiotherapy for skull base chondrosarcoma. Methods: The meta-analysis was conducted using 21 articles published from 1990 to 2022. Results: After PT, the 3- and 5-year overall survival (OS) rates were 94.1% (95% confidence interval [CI]: 91.0-96.2%) and 93.9% (95% CI: 90.6-96.1%), respectively, and the 3- and 5-year local control rates were 95.4% (95% CI: 92.0-97.4%) and 90.1% (95% CI: 76.8-96.0%), respectively. Meta-regression analysis revealed a significant association of PT with a superior 5-year OS rate compared to three-dimensional conformal radiotherapy (p < 0.001). In the studies used in the meta-analysis, the major adverse event of grade 2 or higher was temporal lobe necrosis (incidence 1-18%, median 7%). Conclusion: PT for skull base chondrosarcoma had a good outcome and may be a valuable option among radiotherapy modalities. However, high-dose postoperative irradiation of skull base chondrosarcoma can cause adverse events such as temporal lobe necrosis.

Proton Beam Therapy for Treating Patients with Hepatocellular Carcinoma with Major Portal Vein Tumor Invasion: A Single Center Retrospective Study.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor prognosis and is generally not indicated for surgery. Proton beam therapy (PBT) may offer an alternative treatment. In this study, long-term outcomes were examined in 116 patients (median age 66 years, 100 males) with HCC with advanced PVTT (Vp3 or Vp4) who received PBT from April 2008 to March 2018. Of these patients, 63 received PBT as definitive treatment and 53 as palliative treatment. The representative dose was 72.6 Gy (RBE) in 22 fractions. Eight patients died in follow-up, including 72 due to tumor progression. The 5-year overall survival (OS) rate was 18.0% (95% CI 9.8-26.2%) and the 5-year local control (LC) rate was 86.1% (74.9-97.3%). In multivariate analyses, performance status and treatment strategy were significantly associated with OS. The median follow-up period for survivors with definitive treatment was 33.5 (2-129) months, and the 5-year OS rate was 25.1% (12.9-37.3%) in these cases. The median survival time after definitive irradiation was >20 months. The 5-year OS rate was 9.1% (0-19.7%) for palliative irradiation. These results compare favorably with those of other therapies and suggest that PBT is a useful option for cases of HCC with advanced PVTT that cannot undergo surgery, with an expected survival benefit and good local control. Determining the optimal indication for this treatment is a future challenge.

Systematic Review and Meta-Analysis of Particle Beam Therapy versus Photon Radiotherapy for Skull Base Chordoma: TRP-Chordoma 2024.

[Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4-93.3%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6543; 80.0% (95% CI: 75.7-83.6%) vs. 89.5% (95% CI: 83.0-93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5-76.7%) vs. 40.2% (95% CI: 31.6-48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001). The rates of brain necrosis were 8-50% after PT and 0-4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings.

Late Changes in Renal Volume and Function after Proton Beam Therapy in Pediatric and Adult Patients: Children Show Significant Renal Atrophy but Deterioration of Renal Function Is Minimal in the Long-Term in Both Groups.

To compare late renal effects in pediatric and adult patients with malignancies after PBT involving part of the kidney. A retrospective study was conducted to assess changes in renal volume and function in 24 patients, including 12 children (1-14 years old) and 12 adults (51-80 years old). Kidney volumes were measured from CT or MRI images during follow-up. Dose-volume histograms were calculated using a treatment planning system. In children, the median volume changes for the irradiated and control kidneys were -5.58 (-94.95 to +4.79) and +14.92 (-19.45 to +53.89) mL, respectively, with a relative volume change of -28.38 (-119.45 to -3.87) mL for the irradiated kidneys. For adults, these volume changes were -22.43 (-68.7 to -3.48) and -21.56 (-57.26 to -0.16) mL, respectively, with a relative volume change of -5.83 (-28.85 to +30.92) mL. Control kidneys in children exhibited a marked increase in size, while those in adults showed slight volumetric loss. The percentage of irradiated volume receiving 10 Gy (RBE) (V10) and 20 Gy (RBE) (V20) were significantly negatively associated with the relative volume change per year, especially in children. The CKD stage based on eGFR for all patients ranged from 1 to 3 and no cases with severe renal dysfunction were found before or after PBT. Late effects on the kidneys after PBT vary among age groups. Children are more susceptible than adults to significant renal atrophy after PBT. V10 and V20 might serve as predictors of the degree of renal atrophy after PBT, especially in children. PBT has a minimal impact on deterioration of renal function in both children and adults.

Particle beam therapy versus photon radiotherapy for extrahepatic biliary cancer-systemic review and meta-analysis.

Particle beam therapy (PT) is a potentially promising approach to the treatment of extrahepatic biliary cancer (EBC) because of its unique dose distribution using the Bragg peak. However, the superiority of PT to photon radiotherapy (XT) remains unclear. Therefore, we conducted a systematic review and meta-analysis to compare PT and XT for the treatment of EBC. The primary endpoint was overall survival (OS), which was pooled using a random-effects model. Nine articles comprising a total of 1558 patients (seven XT articles, n = 1488 patients; two PT articles, n = 70 patients) were screened. In addition, we compared the outcomes of XT and PT with the outcomes available from a prospective data registry (proton-net). The 1-year OS probability rates were 55, 65 and 72% for the XT group, PT group and PT registry, respectively. The 2-year OS probability rates were 26, 38 and 38% for the XT group, PT group and PT registry, respectively. The 3-year OS probability rates were 12, 35 and 18% for the XT group, PT group and PT registry, respectively. Although the difference between the 1-year OS rates of the XT group and PT registry was statistically significant, no other significant superiority was observed among these groups. In conclusion, the efficacy of PT was not superior to that of XT during this meta-analysis.

Analysis of the cost-effectiveness of proton beam therapy for unresectable pancreatic cancer in Japan.

BACKGROUND: Proton beam therapy (PBT) has recently been included in Japan's social health insurance benefits package. This study aimed to determine the cost-effectiveness of PBT for unresectable, locally advanced pancreatic cancer (LAPC) as a replacement for conventional photon radiotherapy (RT). METHODS: We estimated the incremental cost-effectiveness ratio (ICER) of PBT as a replacement for three-dimensional conformal RT (3DCRT), a conventional photon RT, using clinical evidence in the literature and expense complemented by expert opinions. We used a decision tree and an economic and Markov model to illustrate the disease courses followed by LAPC patients. Effectiveness was estimated as quality-adjusted life years (QALY) using utility weights for the health state. Social insurance fees were calculated as the costs. The stability of the ICER against the assumptions made was appraised using sensitivity analyses. RESULTS: The effectiveness of PBT and 3DCRT was 1.67610615 and 0.97181271 QALY, respectively. The ICER was estimated to be ¥5,376,915 (US$46,756) per QALY. According to the suggested threshold for anti-cancer therapy from the Japanese authority of ¥7,500,000 (US$65,217) per QALY gain, such a replacement would be considered cost-effective. The one-way and probabilistic sensitivity analyses demonstrated stability of the base-case ICER. CONCLUSION: PBT, as a replacement for conventional photon radiotherapy, is cost-effective and justifiable as an efficient use of finite healthcare resources. Making it a standard treatment option and available to every patient in Japan is socially acceptable from the perspective of health economics.

Proton beam therapy for muscle-invasive bladder cancer: A systematic review and analysis with Proton-Net, a multicenter prospective patient registry database.

To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40-41.4 Gy (relative biological effectiveness (RBE) delivered in 20-23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8-36.3 Gy (RBE) delivered in 10-14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57-84.8% in OS, 39-78% in PFS and 51-68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC.

A Retrospective Study of Renal Growth Changes after Proton Beam Therapy for Pediatric Malignant Tumor.

The purpose of this study was to analyze renal late effects after proton beam therapy (PBT) for pediatric malignant tumors. A retrospective study was performed in 11 patients under 8 years of age who received PBT between 2013 and 2018. The kidney was exposed in irradiation of the primary lesion in all cases. Kidney volume and contour were measured on CT or MRI. Dose volume was calculated with a treatment-planning system. The median follow-up was 24 months (range, 11-57 months). In irradiated kidneys and control contralateral kidneys, the median volume changes were -5.63 (-20.54 to 7.20) and 5.23 (-2.01 to 16.73) mL/year; and the median % volume changes at 1 year were -8.55% (-47.52 to 15.51%) and 9.53% (-2.13 to 38.78%), respectively. The median relative volume change for irradiated kidneys at 1 year was -16.42% (-52.21 to -4.53%) relative to control kidneys. Kidneys irradiated with doses of 10, 20, 30, 40, and 50 GyE had volume reductions of 0.16%, 0.90%, 1.24%, 2.34%, and 8.2% per irradiated volume, respectively. The larger the irradiated volume, the greater the kidney volume was lost. Volume reduction was much greater in patients aged 4-7 years than in those aged 2-3 years. The results suggest that kidneys exposed to PBT in treatment of pediatric malignant tumor show continuous atrophy in follow-up. The degree of atrophy is increased with a higher radiation dose, greater irradiated volume, and older age. However, with growth and maturation, the contralateral kidney becomes progressively larger and is less affected by radiation.

Analysis of person-hours required for proton beam therapy for pediatric tumors.

Proton beam therapy (PBT) is effective for pediatric tumors, but patients may require sedation and other preparations, which extend the treatment time. Pediatric patients were classified into sedation and non-sedation cases. Adult patients were classified into three groups based on irradiation from two directions without or with respiratory synchronization and patch irradiation. Treatment person-hours were calculated as follows: (time from entering to leaving the treatment room) × (number of required personnel). A detailed analysis showed that the person-hours required for the treatment of pediatric patients are about 1.4-3.5 times greater than those required for adult patients. With the inclusion of additional time for the preparation of pediatric patients, PBT for pediatric cases is two to four times more labor-intensive than for typical adult cases.

Proton Beam Therapy versus Radiofrequency Ablation for Patients with Treatment-Naïve Single Hepatocellular Carcinoma: A Propensity Score Analysis.

Introduction: Proton beam therapy (PBT) is known to be an effective locoregional treatment for hepatocellular carcinoma (HCC). However, few comparative studies in treatment-naïve cases have been reported. The aim of this study was to compare the survival outcomes of PBT with those of radiofrequency ablation (RFA) in patients with treatment-naïve solitary HCC. Methods: Ninety-five consecutive patients with treatment-naïve HCC, a single nodule measuring ≤5 cm in diameter, and a Child-Pugh score of ≤8 who were treated with PBT at the University of Tsukuba Hospital between 2001 and 2013 were enrolled in the study. In addition, 836 patients with treatment-naïve HCC treated by RFA at the University of Tokyo Hospital during the same period were analyzed as controls. Recurrence-free survival (RFS) and overall survival (OS) were compared in 83 patient pairs after propensity score matching. Results: The 1-year, 3-year, and 5-year RFS rates were 86.6%, 49.5%, and 35.5%, respectively, in the PBT group and 59.5%, 34.0%, and 20.9% in the RFA group (p = 0.058); the respective OS rates were 97.6%, 77.8%, and 57.1% in the PBT group and 95.1%, 81.7%, and 67.7% in the RFA group (p = 0.16). Regarding adverse effects, no grade 3 or higher adverse events were noted in the PBT; however, two grade 3 adverse events occurred within 30 days of RFA in the RFA group: one hemoperitoneum and one hemothorax. Discussion: After propensity score matching, PBT showed no significant difference in RFS and OS compared to RFA. PBT can be an alternative for patients with solitary treatment-naïve HCC.

Retrospective Analysis of the Areas Responsible for Light Flash and Odor During Proton Beam Therapy and Photon Therapy.

Background Abnormal sensations were frequently experienced by patients who received irradiation of the brain or head and neck region. We have previously suggested correlations with irradiation of the nasal cavity and retina. Purpose We performed a retrospective dose-volume histogram analysis focused on the brain and head and neck tumor to examine the relationship between these abnormal sensations and the details of irradiation. Methods Multivariate logistic regression models were applied for the presence or absence of light flash and odor. Gender, age, radiotherapy method (proton beam therapy vs. photon radiotherapy), dose of retina, optic nerve, chiasmatic gland, pituitary, nasal cavity, oral cavity, frontal lobe, parietal lobe, occipital lobe, temporal lobe, amygdala, and hippocampus were set as candidates of explanatory variables. Results Light flash and odor during radiotherapy have been suggested to be associated with younger age and retina and nasal cavity irradiation. Multivariate analyses including dose-volume histograms indicated that light flash was related to age, chiasmatic gland irradiation, and pituitary dose, and odor was related to age and nasal cavity irradiation. Conclusion Our results indicate that light flash during radiotherapy is caused by irradiation of the visual pathway and that odor is caused by irradiation of the nasal cavity or olfactory bulb.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

Background and purpose: To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). Methods and materials: We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Results: Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5 Gy (RBE) (range, 50-72.6 Gy) in 25 (22-30 fractions). With a median follow-up of 16.3 months, the median survival time was 20.1 months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2 cm >), and a larger tumor diameter (2 cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). Conclusions: This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Inhibition of checkpoint kinase 1 abrogates G2/M checkpoint activation and promotes apoptosis under heat stress.

Hyperthermia induced by heat stress (HS) inhibits the proliferation of cancer cells and induces their apoptosis. However, the mechanism underlying HS-induced apoptosis remains elusive. Here, we demonstrated a novel evidence that checkpoint kinase 1 (Chk1) plays crucial roles in the apoptosis and regulation of cell cycle progression in cells under HS. In human leukemia Jurkat cells, interestingly, the ataxia telangiectasia and Rad-3 related (ATR)-Chk1 pathway was preferentially activated rather than the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway under HS. The selective inhibitors of ATR or Chk1 abrogated HS-induced apoptosis in human leukemia Jurkat cells whereas the inhibition of ATM or Chk2 caused only marginal effects. Inhibition of ATR and Chk1 also abrogated G2/M checkpoint activation by HS in Jurkat cells. The effects of small interfering RNA targeting Chk1 were similar to those of the selective inhibitor of Chk1. In addition, the efficiencies of Chk1 inhibition on G2/M checkpoint abrogation and apoptosis induction were confirmed in the adherent cancer cell lines HeLa, HSC3, and PC3, suggesting that the targeting of Chk1 can be effective in solid tumors cells. In conclusion, these findings indicate a novel molecular basis of G2/M checkpoint activation and apoptosis in cells exposed to HS.