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The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Purpose: To quantitatively evaluate how much the doses to organs at risk are affected in the prone position compared to the supine position in the proton therapy (PT) for prostate cancer. Materials and Methods: Fifteen consecutive patients with clinically localized prostate cancer underwent treatment planning computed tomography scans in both the supine and prone positions. The clinical target volume (CTV) consisted of the prostate gland plus the seminal vesicles. The PT plans were designed using the standard lateral opposed fields with passively scattered proton beams for both treatment positions. The prescribed dose for each plan was set to 78 Gy (Relative biological effectiveness)/39 fractions to 50% of the planning target volume. Dose-volume metrics of the rectum and bladder in the two treatment positions were analyzed. Results: It was confirmed that all the parameters of D05, D10, D20, D30, Dmean, and V90 examined in the rectum were significantly reduced in the prone position. There was no significant difference between the two positions in the bladder dose except for Dmean. The distance between the CTV and the rectum tended to increase with the patient in the prone position; at the prostate level, however, the maximum change was approximately 5 mm, and there was significant variation between cases. Conclusions: We confirmed that the rectal doses were significantly lower in the prone compared with the supine position in PT. Although uncertain, the prone position could be an effective method to reduce the rectal dose in PT.

Radiation therapy (RT) is commonly used for the treatment of prostate cancer, with intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT) being the utilized modalities. This case report outlines the treatment course of a recurrent prostate cancer lesion in the right perineal musculature managed with proton therapy following IMRT. A 64-year-old Japanese man, diagnosed with prostate cancer and categorized as high risk according to the National Comprehensive Cancer Network guidelines, underwent six months of androgen deprivation therapy, which included bicalutamide and degarelix acetate. Six months after completing 78 Gy in 39 fractions of IMRT, the patient reported perineal to anal pain. Laboratory tests showed an elevated serum prostate-specific antigen (PSA) level, and pelvic MRI showed a mass lesion in the right perineal musculature. Consequently, the patient was diagnosed with recurrent prostate cancer. Thereafter, the patient underwent eight cycles of systemic chemotherapy with docetaxel; however, his pain progressively worsened. Subsequently, the treatment was switched to 12 cycles of cabazitaxel, which led to gradual pain relief. The patient received PBT at 60 Gy relative biological effectiveness in 30 fractions for the recurrent lesion. Five years after PBT, pelvic MRI showed no mass lesions in the prostate or surrounding tissues. The PSA levels remained low, less than 0.008 ng/ml, and there were no apparent late complications.

The T-box transcription factor TBX5 plays essential roles in cardiac and limb development. Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities. In this study, we identified a WW-domain-containing transcriptional regulator TAZ as a potent TBX5 coactivator. TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF. YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription, possibly by forming a heterodimer with TAZ. TBX5 lacks a PY motif, which mediates the association of other proteins with TAZ, and interacts with TAZ through multiple domains including its carboxyl-terminal structure. Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ. These findings reveal key roles for TAZ and YAP in the control of TBX5-dependent transcription and suggest the involvement of these coactivators in cardiac and limb development.

To examine the efficacy and toxicity of particle beam therapy (PT) for biliary duct carcinoma (BDC) and compare the outcomes between extrahepatic BDC (eBDC) and intrahepatic BDC (iBDC). We analyzed multi-institutional data from May 2009 to December 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS) and toxicity. We included 150 patients with unresectable BDC treated with PT using a median prescribed dose of 70.2 GyRBE (range, 44-77 GyRBE) in 25 fractions (range, 10-38 fractions). With a median follow-up of 13.0 months, median survival time (MST) was 21 months, and 2-year OS was 44.8%. For eBDC and iBDC, the MSTs were 20 and 23 months, respectively. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Vascular invasion, prescribed dose and serum tumor marker level (carcinoembryonic antigen: CEA) were identified as poor prognostic factors for OS. A higher radiation dose EQD2 ≥ 67 Gy showed superior OS, with a hazard ratio of 0.341. The radiation dose of PT is an important predisposing factor for overall survival. The MST for patients with eBDC given a higher radiation dose was 25 months, compared to 15 months for those given the lower dose and 23 months for patients with iBDC (all iBDC given higher doses). iBDC and eBDC duct carcinomas showed equivalent outcomes with PT, especially when treated with a high radiation dose. In detailed analysis, baseline CEA level in iBDC, and radiation dose and GTV in eBDC were statistically significant predicators for OS. Acute and late toxicity grade ≥3 occurred in 2.2% and 2.7% of patients, respectively, including two late grade-5 toxicities. In conclusion, PT showed good efficacy for BDC, both eBDC and iBDC, with a low incidence of severe toxicity.

Background This study aimed to determine the optimal bladder volume (BV) for hypofractionated proton therapy in prostate cancer (PC). Materials and methods Two hundred patients with PC were enrolled in this study and classified into low-, intermediate-, and high-risk groups. Treatment planning was performed by assuming a hypofractionated schedule of 63 Gy (relative biological effectiveness) in 21 fractions. The dose indices of the bladder (V and V ) were calculated and classified into four groups according to the BV. A cutoff value with a 95% confidence interval was calculated on the basis of the mean and standard deviation of the dose indices. These values were compared with the dose constraints (V < 15 % and V < 30 %). Results The dose indices were higher in the high-risk group than in the other risk groups. The cutoff value exceeded dose constraints in the low- and intermediate-risk groups with a BV of ≦ 149 cc. Additionally, the cutoff value exceeded the dose constraint in the high-risk group with a BV of ≦ 199 cc. In all the cases, the group with a BV of ≧ 200 cc was below the dose constraint. Conclusions In this study, the relationship between the dose and volume of the bladder in hypofractionated PT for PC was evaluated using a 95% CI to determine the optimal BV. The BV should be changed for each risk group, and a larger BV is required for a high-risk group than for other risk groups.

Breast cancer infrequently metastasizes to the sternum as solitary metastasis. We experienced successful treatment with proton beam therapy for a case of sternal metastasis of breast cancer. This case demonstrates for the first time the role of proton therapy in the treatment of oligometastatic sternal metastasis with limited tolerance of normal tissue due to previous photon irradiation. A 40-year-old Japanese female presented with lumpiness in her left breast. The patient was diagnosed with breast cancer (cT1N0M0, cStage IA) and underwent partial mastectomy with axillary lymph node dissection. After the mastectomy, the patient received radiation therapy with 50 Gy in 25 fractions for initial irradiation of the left breast. After the initial irradiation of 50 Gy, the patient received 10 Gy in five fractions of a sequential boost for the tumor bed to a total dose of 60 Gy. Although the patient was administered tamoxifen after radiation therapy, solitary sternal metastasis occurred 6 months after radiation therapy. She refused chemotherapy and requested proton beam therapy for her sternal metastasis. The daily proton beam therapy fractions were 2.5 relative biological effectiveness, receiving a total dose of 70 Gy relative biological effectiveness. An acute side effect of grade 2 dermatitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. occurred during proton beam therapy, but there was no acute or late complication of more than grade 3. At 3 years after proton beam therapy, the patient remains in complete remission without surgery or chemotherapy. Proton beam therapy for solitary sternal metastasis of breast cancer is considered to be a therapeutic option.

Purpose To investigate the impact of different setup methods, vertebral body matching (VM), diaphragm matching (DM), and marker matching (MM), on the dose distribution in proton therapy (PT) for hepatocellular carcinoma (HCC). Materials and Methods Thirty‐eight HCC lesions were studied retrospectively to assess changes in the dose distribution on two computed tomography (CT) scans. One was for treatment planning (1st‐CT), and the other was for dose confirmation acquired during the course of PT (2nd‐CT). The dose coverage of the clinical target volume (CTV‐D98) and normal liver volume that received 30 Gy relative biological effectiveness (RBE) (liver‐V30) were evaluated under each condition. Initial treatment planning on the 1st‐CT was defined as reference, and three dose distributions recalculated using VM, DM, and MM on the 2nd‐CT, were compared to it, respectively. In addition, the relationship between the CTV‐D98 of each method and the distance between the center of mass (COM) of the CTV and the right diaphragm top was evaluated. Results For CTV‐D98, significant differences were observed between the reference and VM and DM, respectively (P = 0.013, P = 0.015). There were also significant differences between MM and VM and DM, respectively (P = 0.018, P = 0.036). Regarding liver‐V30, there was no significant difference in any of the methods, and there were no discernable difference due to the different setup methods. In DM, only two out of 34 cases with a distance from right diaphragm top to COM of CTV of 90 mm or less that CTV‐D98 difference was 5% or more and CTV‐D98 was worse than VM were confirmed. Conclusion Although MM is obviously the most effective method, it is suggested that DM may be particularly effective in cases where the distance from right diaphragm top to COM of CTV of 90 mm or less.

Radical esophagectomy for esophageal squamous cell carcinoma has improved survival, but the rate of recurrence is high. Patients of recurrent esophageal squamous cell carcinoma after failure of chemotherapy have a poor prognosis. We herein report the achievement of long-term survival after definitive proton beam therapy for oligorecurrent esophageal squamous cell carcinoma after failure of chemotherapy. A 60-year-old Japanese man was diagnosed as having squamous cell carcinoma of the lower thoracic esophagus (cT2N0M0, stage IIA). He underwent two courses of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil, and esophagectomy with three-field lymphadenectomy was performed. Microscopic findings after resection showed two lymph node metastases (ypT2N1M0, stage IIB). Five months after resection, a computed tomography scan revealed a solitary liver metastasis in the S4 area. He underwent three courses of chemotherapy with cisplatin and 5-fluorouracil; however, positron emission tomography revealed two lymph node metastases. Surgeons recommended second-line chemotherapy, but the patient refused chemotherapy and requested proton beam therapy. We performed proton beam therapy without chemotherapy for the liver metastasis and lymph node metastases, with total doses of 79.2 and 60 Gy relative biological effectiveness, respectively, according to the tumor location. An acute side effect of grade 1 dermatitis occurred after proton beam therapy, but there was no acute or late complication of more than grade 2. The patient remains in complete remission 5 years after treatment without surgery or chemotherapy. Proton beam therapy exerted a curative effect on oligorecurrent esophageal squamous cell carcinoma. This is the first report on the achievement of long-term survival after definitive proton beam therapy for oligorecurrent esophageal squamous cell carcinoma.

Purpose Anatomical changes, such as shrinkage and aeration, can affect dose distribution in proton therapy (PT) for maxillary sinus carcinoma (MSC). These changes can affect the dose to the target and organs at risk (OARs); however, when these changes occur during PT is unclear. This study aimed to investigate the dosimetric impact of anatomical changes during PT. Materials and Methods Fifteen patients with MSC were enrolled in this study. Initial PT plans were generated based on initial computed tomography (CT) images. Several repeat CT images were obtained to confirm anatomical changes during PT. Evaluation PT plans were generated by copying initial PT plans to repeat CT images. The dose differences of the target and OARs were evaluated by comparing both the plans. Results At 3–4 weeks after the initiation of PT, the target volume reduced by approximately 10% as compared with the initial volume. Consequently, the target volumes gradually varied until the end of treatment. The value of V95 (volume that received 95% of the prescription dose) in the clinical target volume of the evaluation PT plan was similar to that of the initial PT plan. However, the dose to OARs, such as the contralateral optic nerve, contralateral eyeball, brainstem, and optic chiasm, increased significantly from the middle to the later phases of the treatment course. In contrast, there was a slight dose difference in the ipsilateral optic apparatus. Conclusion The trend analysis in this study showed that anatomical changes appeared 3–4 weeks after the start of PT, and the dose to the OARs tended to increase. Therefore, it is recommended to check the status of tumor 3–4 weeks after the start of treatment to avoid the deterioration of dose distribution due to these changes.