The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration.

Circulating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. First, it is roughly linked to urinary inorganic phosphate excretion. Second, expression of renal Npt2a and Npt2c, and intestinal Npt2b proteins also exhibit a dynamic daily oscillation. Analyses of Npt2a, Npt2b, and Npt2c knockout mice revealed the importance of renal inorganic phosphate reabsorption and cellular inorganic phosphate shifts in the daily oscillation. Third, experiments in which nicotinamide and a specific Nampt inhibitor (FK866) were administered in the active and rest phases revealed that the Nampt/NAD+ system is involved in renal inorganic phosphate excretion. Additionally, for cellular shifts, liver-specific Nampt deletion disturbed the daily oscillation of plasma phosphate during the rest but not the active phase. In systemic Nampt+/- mice, NAD levels were significantly reduced in the liver, kidney, and intestine, and the daily oscillation (active and rest phases) of the plasma phosphate concentration was attenuated. Thus, the Nampt/NAD+ system for Npt2 regulation and cellular shifts to tissues such as the liver play an important role in generating daily oscillation of plasma inorganic phosphate levels.

Particle therapy for clinically diagnosed stage I lung cancer: comparison with pathologically proven non-small cell lung cancer.

BACKGROUND: The purpose of the present study was to present the treatment outcomes of particle therapy for indeterminate pulmonary nodules (IPNs) diagnosed as stage I non-small cell lung cancer, including a comparative analysis involving pathologically proven lung cancer (PPLC). MATERIAL AND METHODS: A total of 54 patients (57 lesions) who underwent particle therapy for IPNs were enrolled in this study. Median patient age was 76 (range 52-87) years. T-classification was: T1a, 30; T1b, 16; and T2a, 11. Particle therapy using protons or carbon ions was delivered at total doses of 52.8-80 Gy equivalent in 4-26 fractions. The PPLC cohort included 111 patients. RESULTS: The median follow-up time was 41 (range 7-90) months. For all IPN patients, the three-year overall survival, progression-free survival, local control and distant progression-free survival rates were 90%, 72%, 94% and 79%, respectively. Grade 2 toxicities were radiation pneumonitis (19%), dermatitis (9%), rib fracture (2%), chest wall pain (2%) and neuropathy (2%). No ≥grade 3 toxicities were observed. In univariate analysis, the IPN group showed significantly better survival relative to the PPLC group. However, after adjustment for baseline imbalances between these two groups in multivariate analysis, pathological confirmation did not correlate with survival. CONCLUSIONS: Particle therapy for IPNs provided favorable outcomes with minimal toxicities, which may be comparable to those for PPLC patients. Further studies are needed to clarify the optimal management of IPN patients.

Unexpected radiation laryngeal necrosis after carbon ion therapy using conventional dose fractionation for laryngeal cancer.

Carbon ion therapy is a type of radiotherapy that can deliver high-dose radiation to a tumor while minimizing the dose delivered to organs at risk. Moreover, carbon ions are classified as high linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. A 73-year-old man with glottic squamous cell carcinoma, T3N0M0, refused laryngectomy and received carbon ion therapy of 70 Gy (relative biological effectiveness) in 35 fractions. Three months after the therapy, the patient had an upper airway inflammation, and then laryngeal edema and pain occurred. Five months after the therapy, the airway stenosis was severe and computed tomography showed lack of the left arytenoid cartilage and exacerbation of laryngeal necrosis. Despite the treatment, 5 and a half months after the therapy, the laryngeal edema and necrosis had become even worse and the surrounding mucosa was edematous and pale. Six months after the therapy, pharyngolaryngoesophagectomy and reconstruction with free jejunal autograft were performed. The surgical specimen pathologically showed massive necrosis and no residual tumor. Three years after the carbon ion therapy, he is alive without recurrence. The first reported laryngeal squamous cell carcinoma case treated with carbon ion therapy resulted in an unexpected radiation laryngeal necrosis. Tissue damage caused by carbon ion therapy may be difficult to repair even for radioresistant cartilage; therefore, hollow organs reinforced by cartilage, such as the larynx, may be vulnerable to carbon ion therapy. Caution should be exercised when treating tumors in or adjacent to such organs with carbon ion therapy.

Particle radiotherapy using protons or carbon ions for unresectable locally advanced head and neck cancers with skull base invasion.

OBJECTIVE: To study the oncological outcome of the patients with unresectable locally advanced primary head and neck cancers invading the skull base, treated with particle radiotherapy. METHODS: Fifty-seven patients with unresectable primary head and neck cancers invading the skull base received proton or carbon ion radiotherapy as definitive treatment at Hyogo Ion Beam Medical Center between 2003 and 2009. Forty-seven patients were treated with proton radiotherapy and 10 patients were treated with carbon ion radiotherapy. A retrospective review was performed with clinical charts and recorded imagings. RESULTS: With a median follow-up of 32 months, the 3-year actual survival and local progression-free rates of all the patients were 61 and 56%, respectively. The 3-year actual survival rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 83, 44, 75, 0 and 38%, respectively. The 3-year actual local control rates of adenoid cystic carcinoma, squamous cell carcinoma, olfactory neuroblastoma, adenocarcinoma and malignant melanoma were 63, 31, 83, 50 and 0%, respectively. Distant metastasis was observed in 13 of 25 patients in adenoid cystic carcinoma, two of 14 patients in squamous cell carcinoma, one of six patients with olfactory neuroblastoma, two of four patients with adenocarcinoma, three of four patients with malignant melanoma and two of three patients with undifferentiated carcinoma. Mucositis and dermatitis were seen as acute toxicities. The most common late toxicity was visual disorder. Grades 2, 3 and 4 visual disorders were observed in seven, five and two patients, respectively. CONCLUSIONS: Proton and carbon ion radiotherapy resulted in satisfactory local control in patients with locally advanced unresectable primary head and neck cancers invading the skull base.

[Sodium-dependent inorganic phosphate transporters and biomineralization].

Phosphate (Pi), one of most abundant anions in living organisms, plays a crucial role in biomineralization. An adequate plasma Pi concentration is required to maintain the calcium × phosphate ion product within a range sufficient for physiological bone mineralization, but an increase in the calcium × phosphate product in extracellular fluids above a certain threshold can predispose to extraskeletal calcification. Membrane transport systems for Pi transport are key elements in maintaining homeostasis of Pi in organisms. Members of two families of solute carrier (SLC) proteins (SLC20 and SLC34) act as Na⁺ -dependent, secondary-active cotransporters to transport Pi across cell membranes in mammals. This review summarizes the role of SLC20 and SCL34 proteins on biomineralization.

[Analysis of the safety and efficacy of percutaneous isolated hepatic perfusion after particle therapy for advanced hepatocellular carcinoma].

Here, we report the efficacy of dual treatment with hepatic resection and percutaneous isolated hepatic perfusion (PIHP) for advanced hepatocellular carcinoma( HCC). Recently, we introduced treatment with combined particle therapy and PIHP for unresectable HCC in cases of insufficient liver function. The purpose of this study was to evaluate the safety and efficacy of PIHP for local control in the liver after particle therapy. From 2006 to 2013, 6 patients underwent particle therapy for the main lesion and subsequent PIHP for remnant liver lesions. Their mean age was 64 years, and the mean size of the main lesion was 6.2 cm (range, 2.0-10.8 cm). All patients had liver cirrhosis. After particle therapy, PIHP was performed by hepatic arterial infusion of 100 mg/m2 of doxorubicin and 30 mg/m2 of mitomycin C. With regard to side effects, neutropenia occurred in all patients but no serious hepatobiliary injury was observed. The response rate for PIHP was 50% (partial response: 3 and stable disease: 3). The mean overall survival time was 26.9 months after particle therapy. In conclusion, even after particle therapy, PIHP is a safe treatment and is associated with a good local control rate for remnant HCCs. Further accumulation of data is needed to evaluate the efficacy of this treatment strategy in terms of prognosis.

A case of acute exacerbation of idiopathic pulmonary fibrosis after proton beam therapy for non-small cell lung cancer.

There have been no reports describing acute exacerbations of idiopathic pulmonary fibrosis after particle radiotherapy for non-small cell lung cancer. The present study describes the case of a 76-year-old Japanese man with squamous cell carcinoma of the lung that relapsed in the left upper lobe 1 year after right upper lobectomy. He had been treated with oral prednisolone 20 mg/day every 2 days for idiopathic pulmonary fibrosis, and the relapsed lung cancer was treated by proton beam therapy, which was expected to cause the least adverse effects on the idiopathic pulmonary fibrosis. Fifteen days after the initiation of proton beam therapy, the idiopathic pulmonary fibrosis exacerbated, centered on the left upper lobe, for which intensive steroid therapy was given. About 3 months later, the acute exacerbation of idiopathic pulmonary fibrosis had improved, and the relapsed lung cancer became undetectable. Clinicians should be aware that an acute exacerbation of idiopathic pulmonary fibrosis may occur even in proton beam therapy, although proton beam therapy appears to be an effective treatment option for patients with idiopathic pulmonary fibrosis.

Risk factors for recurrence and re-recurrence of ovarian endometriomas after laparoscopic excision.

AIM: Since ovarian endometrioma is frequently diagnosed in women of reproductive age, laparoscopic excision of the endometrioma is performed for most cases. However, endometriomas frequently recurs even after repeated surgical procedures. The aim of our study is to identify risk factors for recurrence and re-recurrence of endometriomas after the first and second laparoscopic excision. MATERIAL & METHODS: We retrospectively evaluated 173 patients who had a minimum of one year postoperative follow-up after the laparoscopic excision of endometriomas. Ten and eight factors were evaluated to assess their effect on the risk of recurrence and re-recurrence, respectively. Factors were analyzed using univariate and the Cox regression test. RESULTS: The overall rate of recurrence and re-recurrence were 45.1% and 45.5%, respectively. A high revised American Society for Reproductive Medicine score (1997) was associated with an increased risk of recurrence. Only postoperative pregnancy was associated with a decreased risk of recurrence. Short periods of normal menstruation without pregnancy or gonadotrophin-releasing hormone analogues from first surgery to recurrence were associated with higher rate of re-recurrence. CONCLUSIONS: A high revised American Society for Reproductive Medicine score was a risk factor, and postoperative pregnancy was protective against recurrence. The patient with short periods of normal menstruation without pregnancy or gonadotrophin-releasing hormone analogues from first surgery to recurrence had a high risk of re-recurrence.

Proton Therapy for Localized Prostate Cancer: Long-Term Results From a Single-Center Experience.

PURPOSE: Although proton therapy is controversial, it has been used to treat localized prostate cancer over the past 2 decades. The purpose of this study is to examine the long-term efficacy and toxicity of proton therapy for localized prostate cancer. METHODS AND MATERIALS: This was a retrospective observational study of 2021 patients from 2003 to 2014 at a single institution. Patients were classified using the risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019. Ninety-eight percent of the patients received 74 Gy (relative biological effectiveness) in 37 fractions. Fifty-one and 6% of the patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The outcomes were the time of freedom from biochemical relapse and the time to late toxicity by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The outcomes were estimated using the Kaplan-Meier method and were analyzed using multivariable Cox proportional hazards models. RESULTS: The median follow-up period was 84 months (interquartile range, 60-110). The 5- and 10-year freedom from biochemical relapse rates were 100% and 100%, 99% and 88%, 93% and 86%, 90% and 79%, 88% and 68%, and 76% and 63% for the very low, low, favorable intermediate, unfavorable intermediate, high, and very high-risk groups, respectively. Patients with higher risk experienced biochemical relapse after shorter periods. The 5-year rates of grade 2 or higher late genitourinary and gastrointestinal toxicity were 2.2% and 4.0%, respectively. The results of multivariable analyses indicate that younger patients more often experienced biochemical relapse. CONCLUSIONS: This study demonstrates the favorable biochemical controls of proton therapy even in advanced localized prostate cancer patients with a low incidence of late toxicities, supporting the feasibility of conducting prospective clinical trials. The risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019, are useful to classify patients with localized prostate cancer. Our findings might suggest the necessity to develop a treatment strategy that accounts for the patient's age.

Supratentorial glioblastoma treated with radiotherapy: use of the Radiation Therapy Oncology Group recursive partitioning analysis grouping for predicting survival.

OBJECTIVE: This study aimed to evaluate the usefulness of recursive partitioning analysis model established by the Radiation Therapy Oncology Group for predicting the survival of patients with supratentorial glioblastoma treated with radiotherapy and to determine prognostic factors for the subgroups of this prognostic model. METHODS: A total of 108 glioblastoma patients treated with radiotherapy between January 1987 and December 2005 were retrospectively reviewed. Recursive partitioning analysis classes III, IV, V and VI included 8, 29, 32 and 39 patients, respectively. These classes were divided into two subgroups: a good prognostic group containing classes III-IV and a poor prognostic group containing classes V-VI. The median radiation dose was 60 Gy. Seventy-five patients received chemotherapy and/or immunotherapy. RESULTS: The overall survival differed significantly among classes III, IV, V and VI, with median survival times of 34, 15, 11 and 7 months, respectively. Among the good prognostic group, patients with basal ganglia invasion showed poorer survival outcomes than patients without basal ganglia invasion. Among the poor prognostic group, patients with tumor sizes of <5 cm and patients treated with nimustine hydrochloride showed better survival outcomes than those with tumor sizes of > or =5 cm and those without treatment with nimustine hydrochloride, respectively. CONCLUSIONS: This study confirms the prognostic value of the recursive partitioning analysis grouping. Basal ganglia invasion could be a useful predictive factor for survival in the good prognostic group, whereas tumor size and treatment with nimustine hydrochloride could be useful predictive factors in the poor prognostic group.

Improvement in impaired ocular accommodation by parietal acupoint therapy to relieve neck stiffness: a case report.

OBJECTIVES: Neck stiffness could lead to impaired ocular accommodation. We report two cases that visual function was improved by relieving neck stiffness. CASE PRESENTATION: (Case 1) A 34-year-old female complained of neck stiffness and visual problems after computer work. She was treated by parietal acupoint therapy (PAPT), which is a new scalp micro-acupuncture system. The evaluation of accommodative micro-fluctuations (the Fk-map) showed that increased bilateral ciliary muscle tension in the middle to near distance was relieved bilaterally, accompanied by relief of neck stiffness after treatment. (Case 2) A 43-year-old female complained of a visual problem with pressure pain on the bilateral posterior cervical muscles. Performing with PAPT improved impaired ciliary muscle tension noticeably with relief of neck stiffness after treatment. CONCLUSIONS: This is the first report on the improvement of impaired ocular accommodation with treating neck stiffness by using PAPT.

[5-FU based chemoradiotherapy for unresectable locally advanced pancreatic cancer].

Twenty-one patients with unresectable locally advanced pancreatic cancer were evaluated in this retrospective analysis. They received extra-beam radiotherapy(50.4-54 Gy/28-30 fractions)with concurrent continuous infusion of 5-FU(250 mg/m(2)day)between December 1999 and April 2007. The radiation field included primary tumor and adjacent lymph nodes. Twenty patients(95%)completed chemoradiotherapy, although one patient quit radiotherapy due to vomiting. No lethal side effects were observed. The response rate was 10%. One of the patients judged to have stable disease underwent resection after maintenance chemotherapy. The median progression free survival and the median overall survival were 6.4 and 12 months, respectively. In eleven patients(52%), the initial sites of disease progression were local or peritoneum without liver metastases, suggesting systemic effects of this treatment. In conclusion, 5-FU based chemoradiotherapyis well tolerated and provides definite benefits against unresectable locally advanced pancreatic cancer.

Utility of Laparoscopic Uterine Myomectomy as a Treatment for Infertility with No Obvious Cause Except for Uterine Fibroids.

OBJECTIVES: Uterine fibroids are capable of causing infertility, but there are no definite criteria for which laparoscopic uterine myomectomy (LM) is known to be beneficial. To investigate the usefulness of LM, we examined pregnancy rates in patients with infertility with no obvious cause except for the presence of uterine fibroids. MATERIALS AND METHODS: We retrospectively reviewed the clinical records at Suzuki Memorial Hospital between June 2010 and August 2014. We found 60 eligible patients (LM group, 46; non-LM group, 14). The criteria for performing LM were a maximal fibroid diameter of 40 mm or more or the presence of >4 fibroids. RESULTS: The duration of infertility before the first visit was significantly longer in the LM group; although there was no significant difference in the mean patient age and body mass index. Pregnancy was achieved in 45.7% of patients (21/46) in the LM group and 28.6% (4/14) in the non-LM group. There were no pregnancies in patients with >10 fibroids. The postoperative pregnancy rate in the LM group was comparable to previously reported pregnancy rates. CONCLUSIONS: Our criteria for performing LM in patients with no obvious cause for infertility except for uterine fibroids seem appropriate, especially when the fibroids are large and the number of fibroids is between 4 and 9. However, our results suggest that the effectiveness of LM is low in patients with 10 or more uterine fibroids.

Treatment outcomes of proton or carbon ion therapy for skull base chordoma: a retrospective study.

BACKGROUND: The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. METHODS: All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan-Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up was 71.5 months (range, 14-175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. CONCLUSIONS: Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable.

Total body irradiation followed by bone marrow transplantation: comparison of once-daily and twice-daily fractionation regimens.

PURPOSE: The purpose of this study was to evaluate the results of two sequential total body irradiation (TBI) regimens, especially focusing on pulmonary complications. MATERIALS AND METHODS: Patients with malignant disease who underwent TBI followed by bone marrow transplantation were retrospectively reviewed. There were 86 patients (51 males, 35 females). Altogether, 36 patients were treated on twice-daily fractions of 2 Gy for 3 days to a total 12 Gy (group A). Another 50 patients were treated on once-daily fractions of 2.4 or 3.0 Gy for 4 or 5 days to a total 12 Gy (group B). RESULTS: The 5-year overall survival rate was 49.2%, and relapse-free survival was 44.3%. There were no significant differences between the two groups regarding overall survival (P = 0.1237) or relapse-free survival (P = 0.1548). Two patients in group A had interstitial pneumonitis of grade 3 or higher severity compared with three patients in group B. There was no significant difference between patients in group A (5-year probability rate was 7.6%) and patients in group B (5-year probability rate was 13.9%) (P = 0.9519). CONCLUSION: We concluded that our once-daily TBI regimen is feasible and had the benefit of reducing the complexity of TBI. We believe that further investigation of the TBI regimen is needed.

Efficacy of Parietal Acupoint Therapy: Scalp Acupuncture for Neck/Shoulder Stiffness with Related Mood Disturbance.

Objectives: Yamamoto New Scalp Acupuncture is a quick and effective microsystem of acupuncture used for treating various symptoms for which the somatotopic area is the scalp. This article describes Parietal Acupoint Therapy (PAPT), which is another approach, using a different scalp somatotopy, and to evaluate PAPT's effect on neck/shoulder stiffness and related mood disturbances. Materials and Methods:Subjects: Forty-six volunteers suffering from chronic neck/shoulder stiffness with various symptoms (headache, dizziness, and related mood disturbance) participated in this study and were randomly divided into 2 groups: treatment (26 subjects) and control (20 subjects). Interventions: PAPT, PC points, and PL points were used. Outcome Measures: Immediately before and after treatment, to evaluate the patients' psychobiologic and mood states, salivary alpha amylase (sAA) levels were determined and the Profile of Mood States Second Edition (POMS 2)-Short Form scale was administered. Neck/shoulder stiffness was evaluated using a visual analogue scale (VAS) score immediately before and after, and at 3 and 7 days post-therapy. Results: sAA levels were not significantly different in either group after versus before the intervention. There were significant decreases in mean scores in the POMS 2 subscales Anger/Hostility (P < 0.001), Confusion/Bewilderment (P < 0.001), Depression/Dejection (P < 0.01), Fatigue/Inertia (P < 0.001), Tension/Anxiety (P < 0.001), and Total Mood Disturbance (P < 0.001) post-therapy in the treatment group, but not in the control group. The mean VAS score significantly improved in the treatment group post-therapy, which persisted during the observation period. Conclusions: PAPT treatment on PC points ameliorated neck/shoulder stiffness and related mood disturbance. PAPT has the potential to be as effective as other scalp acupuncture types.

Particle Therapy Using Protons or Carbon Ions for Unresectable or Incompletely Resected Bone and Soft Tissue Sarcomas of the Pelvis.

PURPOSE: To retrospectively analyze the treatment outcomes of particle therapy using protons or carbon ions for unresectable or incompletely resected bone and soft tissue sarcomas (BSTSs) of the pelvis. METHODS AND MATERIALS: From May 2005 to December 2014, 91 patients with nonmetastatic histologically proven unresectable or incompletely resected pelvic BSTSs underwent particle therapy with curative intent. The particle therapy used protons (52 patients) or carbon ions (39 patients). All patients received a dose of 70.4 Gy (relative biologic effectiveness) in 32 fractions (55 patients) or 16 fractions (36 patients). RESULTS: The median patient age was 67 years (range 18-87). The median planning target volume (PTV) was 455 cm3 (range 108-1984). The histologic type was chordoma in 53 patients, chondrosarcoma in 14, osteosarcoma in 10, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma in 5, and other in 9 patients. Of the 91 patients, 82 had a primary tumor and 9 a recurrent tumor. The median follow-up period was 32 months (range 3-112). The 3-year rate of overall survival (OS), progression-free survival (PFS), and local control was 83%, 72%, and 92%, respectively. A Cox proportional hazards model revealed that chordoma histologic features and a PTV of ≤500 cm3 were significantly associated with better OS, and a primary tumor and PTV of ≤500 cm3 were significantly associated with better PFS. Ion type and number of fractions were not significantly associated with OS, PFS, or local control. Late grade ≥3 toxicities were observed in 23 patients. Compared with the 32-fraction protocol, the 16-fraction protocol was associated with significantly more frequent late grade ≥3 toxicities (18 of 36 vs 5 of 55; P<.001). CONCLUSIONS: Particle therapy using protons or carbon ions was effective for unresectable or incompletely resected pelvic BSTS, and the 32-fraction protocol was effective and relatively less toxic. Nevertheless, a longer follow-up period is needed to confirm these results.

Effect of Osteocyte-Ablation on Inorganic Phosphate Metabolism: Analysis of Bone-Kidney-Gut Axis.

In response to kidney damage, osteocytes increase the production of several hormones critically involved in mineral metabolism. Recent studies suggest that osteocyte function is altered very early in the course of chronic kidney disease. In the present study, to clarify the role of osteocytes and the canalicular network in mineral homeostasis, we performed four experiments. In Experiment 1, we investigated renal and intestinal Pi handling in osteocyte-less (OCL) model mice [transgenic mice with the dentin matrix protein-1 promoter-driven diphtheria toxin (DT)-receptor that were injected with DT]. In Experiment 2, we administered granulocyte colony-stimulating factor to mice to disrupt the osteocyte canalicular network. In Experiment 3, we investigated the role of osteocytes in dietary Pi signaling. In Experiment 4, we analyzed gene expression level fluctuations in the intestine and liver by comparing mice fed a high Pi diet and OCL mice. Together, the findings of these experiments indicate that osteocyte ablation caused rapid renal Pi excretion (P < 0.01) before the plasma fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels increased. At the same time, we observed a rapid suppression of renal Klotho (P < 0.01), type II sodium phosphate transporters Npt2a (P < 0.01) and Npt2c (P < 0.05), and an increase in intestinal Npt2b (P < 0.01) protein. In OCL mice, Pi excretion in feces was markedly reduced (P < 0.01). Together, these effects of osteocyte ablation are predicted to markedly increase intestinal Pi absorption (P < 0.01), thus suggesting that increased intestinal Pi absorption stimulates renal Pi excretion in OCL mice. In addition, the ablation of osteocytes and feeding of a high Pi diet affected FGF15/bile acid metabolism and controlled Npt2b expression. In conclusion, OCL mice exhibited increased renal Pi excretion due to enhanced intestinal Pi absorption. We discuss the role of FGF23-Klotho on renal and intestinal Pi metabolism in OCL mice.

Long-term outcomes in patients treated with proton therapy for localized prostate cancer.

The aim of this retrospective study was to report long-term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer-specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow-up period was 70 months (range, 4-145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low-, intermediate-, high-, and very high-risk groups, 5-year FFBR was 99% (95% confidence intervals [CI], 96-100%), 91% (95% CI, 88-93%), 86% (95% CI, 82-89%), and 66% (95% CI, 53-76%), respectively, and 5-year CSS was 100% (95% CI, 100-100%), 100% (95% CI, 100-100%) , 99% (95% CI, 97-100%), and 95% (95% CI, 94-98%), respectively. Patient age, T classification, Gleason score, prostate-specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow-up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high- and very high-risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.

Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: Dose-volume histogram analysis and comparison with conventional chemoradiation.

PURPOSE: The aim of this study was twofold: to determine whether the dose-volume metrics are valuable in predicting radiation pneumonitis (RP) in small-cell lung cancer (SCLC) patients treated with accelerated hyperfractionated radiotherapy and chemotherapy (AHFRT + CT); and to clarify how AHFRT influences the risk of RP in comparison to conventional once-daily radiotherapy and chemotherapy (QDRT + CT). METHODS AND MATERIALS: Study subjects were 43 patients with SCLC treated with AHFRT + CT. Radiotherapy was delivered at 1.5 Gy/fraction (fr) twice daily to 45 Gy/30 fr/3 weeks. We analyzed the relation between RP incidence and several dosimetric factors. We also compared this series data with our previously published data from lung cancer patients treated with QDRT + CT. RESULTS: Radiation pneumonitis Grades 1, 2, and 3 were observed in 28 patients, 7 patients, and 1 patient, respectively. Univariate analysis revealed that the percentage of lung volume receiving more than 15 Gy, 20 Gy, and 30 Gy (V15, V20, V30) and normal tissue complication probability were of predictive value for the development of RP. The 12-month cumulative incidences of RP greater than Grade 2 were 0%, 7.1%, 25%, and 42.9% in patients with a V20 of < or =20%, 21-25%, 26-30%, and > or =31%, respectively. These incidences were lower than that of our patients treated with QDRT + CT. CONCLUSIONS: Dosimetric factors are valuable in predicting RP in SCLC patients treated with AHFRT + CT. Regarding the incidence of RP, AHFRT appears to have some advantage over QDRT.