Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies.

Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. "Overlap" refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. "Complementation" refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.

Transmural variation in microvascular remodeling following percutaneous revascularization of a chronic coronary stenosis in swine.

Remodeling of the coronary microcirculation is known to occur distal to a chronic coronary stenosis, but the reversibility of these changes and their functional significance on maximum myocardial perfusion before and after revascularization is unknown. Accordingly, swine instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium underwent percutaneous coronary intervention (PCI; n = 8) and were compared with animals with a persistent stenosis (n = 8), as well as sham controls (n = 6). Stenotic animals demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio (37.8 ± 3.3 vs. 28.3 ± 1.3% in sham, P = 0.04), reduced lumen area per arteriole (597 ± 88 vs. 927 ± 113 µm2, P = 0.04), and a compensatory increase in arteriolar density (9.4 ± 1.0 vs. 5.3 ± 0.4 arterioles/mm2, P < 0.01). As a result, vasodilated flow immediately after PCI was similar to normally perfused remote regions (5.1 ± 1.0 vs. 4.8 ± 0.9 ml·min-1·g-1, P = 0.87). When assessed 1-mo after PCI, increases in wall thickness-to-lumen diameter (42.2 ± 3.3%) and reductions in lumen area per arteriole (638 ± 59 µm2) remained unchanged, but arteriolar density returned to normal (5.2 ± 0.5 arterioles/mm2). As a result, maximum subendocardial flow during adenosine declined and was lower than remote regions (2.6 ± 0.3 vs. 5.9 ± 1.1 ml·min-1·g-1, P = 0.01). There was no microvascular remodeling in subepicardial arterioles, and maximum perfusion remained unchanged. These data demonstrate that subendocardial microvascular remodeling occurs distal to a chronic epicardial stenosis. The regression of arteriolar density without increases in luminal area may precipitate stress-induced subendocardial ischemia in the absence of a physiologically significant stenosis.NEW & NOTEWORTHY Swine with a chronic coronary stenosis exhibit subendocardial microvascular remodeling distal to a critical stenosis characterized by an increase in arteriolar wall thickness and reduction in lumen area with a compensatory increase in arteriolar density. The present study is the first to demonstrate that subendocardial arteriolar density normalizes 1-mo after revascularization, but the lumen area of individual arterioles remains reduced. This leads to a reduction in maximal subendocardial perfusion at this time point despite initial normalization of vasodilator reserve after revascularization. This pattern of chronic microvascular structural remodeling could contribute to recurrent subendocardial ischemia in the absence of coronary restenosis during tachycardia and increases in myocardial oxygen demand.

Nonocclusive multivessel intracoronary infusion of allogeneic cardiosphere-derived cells early after reperfusion prevents remote zone myocyte loss and improves global left ventricular function in swine with myocardial infarction.

Intracoronary cardiosphere-derived cells (icCDCs) infused into the infarct-related artery reduce scar volume but do not improve left ventricular (LV) ejection fraction (LVEF). We tested the hypothesis that this reflects the inability of regional delivery to prevent myocyte death or promote myocyte proliferation in viable myocardium remote from the infarct. Swine (n = 23) pretreated with oral cyclosporine (200 mg/day) underwent a 1-h left anterior descending coronary artery (LAD) occlusion, which reduced LVEF from 61.6 ± 1.0 to 45.3 ± 1.5% 30 min after reperfusion. At that time, animals received global infusion of allogeneic icCDCs (n = 8), regional infusion of icCDCs restricted to the LAD using the stop-flow technique (n = 8), or vehicle (n = 7). After 1 mo, global icCDCs increased LVEF from 44.8 ± 1.9 to 60.8 ± 3.8% (P < 0.05) with no significant change after LAD stop-flow icCDCs (44.8 ± 3.6 to 50.9 ± 3.1%) or vehicle (46.5 ± 2.5 to 47.7 ± 2.6%). In contrast, global icCDCs did not alter infarct volume (%LV mass) assessed at 2 days (11.2 ± 2.3 vs. 12.6 ± 2.3%), whereas it was reduced after LAD stop-flow icCDCs (7.1 ± 1.1%, P < 0.05). Histopathological analysis of remote myocardium after global icCDCs demonstrated a significant increase in myocyte proliferation (147 ± 32 vs. 14 ± 10 nuclei/106 myocytes, P < 0.05) and a reduction in myocyte apoptosis (15 ± 9 vs. 46 ± 10 nuclei/106 myocytes, P < 0.05) that increased myocyte nuclear density (1,264 ± 39 vs. 1,157 ± 33 nuclei/mm2, P < 0.05) and decreased myocyte diameter (13.2 ± 0.2 vs. 14.5 ± 0.3 µm, P < 0.05) compared with vehicle-treated controls. In contrast, remote zone changes after regional LAD icCDCs were no different from vehicle. These data indicate that changes in global LVEF after icCDCs are dependent upon preventing myocyte loss and hypertrophy in myocardium remote from the infarct. These arise from stimulating myocyte proliferation and reducing myocyte apoptosis indicating the importance of directing cell therapy to viable remote regions.NEW & NOTEWORTHY Administration of allogeneic cardiosphere-derived cells to the entire heart via global intracoronary infusion shortly after myocardial infarction favorably influenced left ventricular ejection fraction by preventing myocyte death and promoting myocyte proliferation in remote, noninfarcted myocardium in swine. In contrast, regional intracoronary cell infusion did not significantly affect remote zone myocyte remodeling. Global cell administration targeting viable myocardium remote from the infarct may be an effective approach to prevent adverse ventricular remodeling after myocardial infarction.

Reirradiation for recurrent head and neck cancers using charged particle or photon radiotherapy.

OBJECTIVE: To examine the outcomes of reirradiation for recurrent head and neck cancers using different modalities. METHODS: This retrospective study included 26 patients who received charged particle radiotherapy (CP) and 150 who received photon radiotherapy (117 CyberKnife radiotherapy [CK] and 36 intensity-modulated radiotherapy [IMRT]). Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. RESULTS: Higher prescribed doses were used in CP than photon radiotherapy. The 1­year overall survival (OS) rates were 67.9% for CP and 54.1% for photon radiotherapy (p = 0.15; 55% for CK and 51% for IMRT). In multivariate Cox regression, the significant prognostic factors for better survival were nasopharyngeal cancer, higher prescribed dose, and lower tumor volume. IPTW showed a statistically significant difference between CP and photon radiotherapy (p = 0.04). The local control rates for patients treated with CP and photon radiotherapy at 1 year were 66.9% (range 46.3-87.5%) and 67.1% (range 58.3-75.9%), respectively. A total of 48 patients (27%) experienced toxicity grade ≥3 (24% in the photon radiotherapy group and 46% in the CP group), including 17 patients with grade 5 toxicity. Multivariate analysis revealed that younger age and a larger planning target volume (PTV) were significant risk factors for grade 3 or worse toxicity. CONCLUSION: CP provided superior survival outcome compared to photon radiotherapy. Tumor volume, primary site (nasopharyngeal), and prescribed dose were identified as survival factors. Younger patients with a larger PTV experienced toxicity grade ≥3.

Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium.

RATIONALE: Allogeneic bone marrow-derived mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs) have each entered clinical trials, but a direct comparison of these cell types has not been performed in a large animal model of hibernating myocardium. OBJECTIVE: Using completely blinded methodology, we compared the efficacy of global intracoronary allogeneic MSCs (icMSCs, ≈35×10(6)) and CDCs (icCDCs, ≈35×10(6)) versus vehicle in cyclosporine-immunosuppressed swine with a chronic left anterior descending coronary artery stenosis (n=26). METHODS AND RESULTS: Studies began 3 months after instrumentation when wall thickening was reduced (left anterior descending coronary artery % wall thickening [mean±SD], 38±11% versus 83±26% in remote; P<0.01) and similar among groups. Four weeks after treatment, left anterior descending coronary artery % wall thickening increased similarly after icCDCs and icMSCs, whereas it remained depressed in vehicle-treated controls (icMSCs, 51±13%; icCDCs, 51±17%; vehicle, 34±3%, treatments P<0.05 versus vehicle). There was no change in myocardial perfusion. Both icMSCs and icCDCs increased left anterior descending coronary artery myocyte nuclear density (icMSCs, 1601±279 nuclei/mm(2); icCDCs, 1569±294 nuclei/mm(2); vehicle, 973±181 nuclei/mm(2); treatments P<0.05 versus vehicle) and reduced myocyte diameter (icMSCs, 16.4±1.5 µm; icCDCs, 16.8±1.2 µm; vehicle, 20.2±3.7 µm; treatments P<0.05 versus vehicle) to the same extent. Similar changes in myocyte nuclear density and diameter were observed in the remote region of cell-treated animals. Cell fate analysis using Y-chromosome fluorescent in situ hybridization demonstrated rare cells from sex-mismatched donors. CONCLUSIONS: Allogeneic icMSCs and icCDCs exhibit comparable therapeutic efficacy in a large animal model of hibernating myocardium. Both cell types produced equivalent increases in regional function and stimulated myocyte regeneration in ischemic and remote myocardium. The activation of endogenous myocyte proliferation and regression of myocyte cellular hypertrophy support a common mechanism of cardiac repair.

Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

BACKGROUND: Radiotherapy is an effective treatment for the postoperative loco-regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer. METHODS: We retrospectively investigated 35 patients treated for a postoperative loco-regional recurrence of esophageal cancer with local field radiotherapy between December 2008 and March 2016. The median irradiation dose was 60 Gy (range: 50-67.5 Gy). Thirty-one (88.6%) patients received concurrent chemotherapy. RESULTS: The median follow-up period was 18 months (range: 5-94 months). The 2-year overall survival was 55.7%, with a median survival time of 29.9 months. In the univariate analysis, the maximal diameter ≤20 mm (P = 0.0383), solitary lesion (P = 0.0352), and the complete remission after treatment (P = 0.00411) had a significantly better prognosis. A total of 27 of 35 patients (77.1%) had progressive disease (loco-regional failure [n = 9], distant metastasis [n = 7], and both loco-regional failure and distant metastasis [n = 11]). No patients had Grade 3 or greater mucositis. CONCLUSION: Local field radiotherapy is a considerable treatment option for postoperative loco-regional recurrence of esophageal cancer.

Clinical Usefulness of the Platelet-to Lymphocyte Ratio in Patients with Angiosarcoma of the Face and Scalp.

Angiosarcoma of the face and scalp (ASFS) is an extremely aggressive tumor that frequently metastasizes, often leading to death. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers that predict outcome of various cancers. We aimed to examine the relationship between pretreatment inflammatory markers and ASFS outcome. We included 17 patients with ASFS and a control group of 56 age- and gender-matched healthy individuals. Total white blood counts, neutrophil, lymphocyte, monocyte, and platelet counts were recorded; NLR, PLR, and LMR were calculated. Kaplan-Meier curves were used to calculate overall survival (OS) and distant metastasis-free survival (DMFS). Optimal cut-off values for each inflammatory marker were calculated using receiver operating curve analysis. Median follow-up was 22 months (range, 6-75). There was a statistically significant difference in absolute neutrophil counts and NLR between patient and control groups. Two-year OS and DMFS rates were 41% and 35%, respectively. In patients with tumors < 10 cm, PLR was highly correlated with DMFS, with the 2-year DMFS for those with a high PLR being 50% compared with 100% for those with a low PLR (p = 0.06). This study suggests that PLR is superior to NLR and LMR, and is a clinically useful marker in patients with ASFS with small tumors.

Myocardial and Serum Galectin-3 Expression Dynamics Marks Post-Myocardial Infarction Cardiac Remodelling.

BACKGROUND: Acute myocardial infarction (MI) causes significant changes in cardiac morphology and function. Galectin-3 is a novel and potentially therapeutically important mediator of cardiac remodelling. Myocardial and serum galectin-3 expression dynamics in response to the early cardiovascular outcomes after acute MI are not fully elucidated. METHODS: We first performed a comprehensive longitudinal microarray analyses in mice after acute MI. We then measured the serum levels of galectin-3 in a translational porcine model of coronary microembolism-induced post-ischaemic cardiac remodelling. We validated our pre-clinical studies in humans by measuring serum galectin-3 levels of 52 patients with acute ST-elevation MI (STEMI) and 11 healthy controls. We analysed galectin-3 data in relation to the development of major adverse cardiovascular outcomes (MACO). RESULTS: Of the 9,753 genes profiled at infarcted and remote myocardium at eight different time points, dynamic myocardial overexpression of galectin-3 mRNA was detected. In a pig model of diffuse myocardial damage and cardiac remodelling, galectin-3 localised to the areas of tissue damage and myocardial fibrosis, with proportionate increase of their serum galectin-3 expression levels. In humans, increased serum galectin-3 level was associated with in-hospital MACO. CONCLUSIONS: In this translational study, we demonstrated that galectin-3 is dynamically overexpressed in response to acute MI-induced cardiac remodelling. Elevated galectin-3 levels are associated with the development of in-hospital MACO.

Development of an Improved Inhalable Powder Formulation of Pirfenidone by Spray-Drying: In Vitro Characterization and Pharmacokinetic Profiling.

PURPOSE: Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method. METHODS: Spray-dried PFD (SD/PFD) was prepared by spray-drying with L-leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations. RESULTS: Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 µm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose. CONCLUSION: SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD.

New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites.

Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290 nm) and 14,000 M(-1)cm(-1) (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins.

Non-animal photosafety screening for complex cosmetic ingredients with photochemical and photobiochemical assessment tools.

Previously, a non-animal screening approach was proposed for evaluating photosafety of cosmetic ingredients by means of in vitro photochemical and photobiochemical assays; however, complex cosmetic ingredients, such as plant extracts and polymers, could not be evaluated because their molecular weight is often poorly defined and so their molar concentration cannot be calculated. The aim of the present investigation was to establish a photosafety screen for complex cosmetic ingredients by using appropriately modified in vitro photosafety assays. Twenty plant extracts were selected as model materials on the basis of photosafety information, and their phototoxic potentials were assessed by means of ultraviolet (UV)/visible light (VIS) spectral analysis, reactive oxygen species (ROS)/micellar ROS (mROS) assays, and 3T3 neutral red uptake phototoxicity testing (3T3 NRU PT). The maximum UV/VIS absorption value was employed as a judgment factor for evaluating photoexcitability of samples, and the value of 1.0 was adopted as a tentative criterion for photosafety identification. The ROS/mROS assays were conducted at 50 µg/mL, and no false negative prediction was obtained. Furthermore, the ROS/mROS assays at 50 µg/mL had a similar predictive capacity to the ROS/mROS assays in the previous study. A systematic tiered approach for simple and rapid non-animal photosafety evaluation of complex cosmetic ingredients can be constructed using these modified in vitro photochemical assays.

Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention.

Progressive fibrosis is a pathological hallmark of many chronic diseases responsible for organ failure. Although there is currently no therapy on the market that specifically targets fibrosis, the dynamic fibrogenic process is known to be regulated by multiple soluble mediators that may be therapeutically intervened. The failing hamster heart exhibits marked fibrosis and increased expression of secreted Frizzled-related protein 2 (sFRP2) amenable to reversal by mesenchymal stem cell (MSC) therapy. Given the previous demonstration that sFRP2-null mice subjected to myocardial infarction exhibited reduced fibrosis and improved function, we tested whether antibody-based sFRP2 blockade might counteract the fibrogenic pathway and repair cardiac injury. Cardiomyopathic hamsters were injected intraperitoneally twice a week each with 20 µg of sFRP2 antibody. Echocardiography, histology, and biochemical analyses were performed after 1 mo. sFRP2 antibody increased left ventricular ejection fraction from 40 ± 1.2 to 49 ± 6.5%, whereas saline and IgG control exhibited a further decline to 37 ± 0.9 and 31 ± 3.2%, respectively. Functional improvement is associated with a ∼ 50% reduction in myocardial fibrosis, ∼ 65% decrease in apoptosis, and ∼ 75% increase in wall thickness. Consistent with attenuated fibrosis, both MSC therapy and sFRP2 antibody administration significantly increased the activity of myocardial matrix metalloproteinase-2. Gene expression analysis of the hamster heart and cultured fibroblasts identified Axin2 as a downstream target, the expression of which was activated by sFRP2 but inhibited by therapeutic intervention. sFRP2 blockade also increased myocardial levels of VEGF and hepatocyte growth factor (HGF) along with increased angiogenesis. These findings highlight the pathogenic effect of dysregulated sFRP2, which may be specifically targeted for antifibrotic therapy.

Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial.

BACKGROUND: Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. METHODS AND RESULTS: A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, -16.4 to -11.3) and 12.3% (95% confidence interval, -14.9 to -9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, -0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (-11.4%) than in the atorvastatin group (-0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). CONCLUSIONS: Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study.

Inflammatory markers have been associated with increased risk of several cancers, including colon, lung, breast and liver, but the evidence is inconsistent. We conducted a nested case-control study in the longitudinal cohort of atomic-bomb survivors. The study included 224 hepatocellular carcinoma (HCC) cases and 644 controls individually matched to cases on gender, age, city and time and method of serum storage, and countermatched on radiation dose. We measured C-reactive protein (CRP) and interleukin (IL)-6 using stored sera obtained within 6 years before HCC diagnosis from 188 HCC cases and 605 controls with adequate volumes of donated blood. Analyses with adjustment for hepatitis virus infection, alcohol consumption, smoking habit, body mass index (BMI) and radiation dose showed that relative risk (RR) of HCC [95% confidence interval (CI)] in the highest tertile of CRP levels was 1.94 (0.72-5.51) compared to the lowest tertile (p = 0.20). RR of HCC (95% CI) in the highest tertile of IL-6 levels was 5.12 (1.54-20.1) compared to the lowest tertile (p = 0.007). Among subjects with BMI > 25.0 kg/m(2) , a stronger association was found between a 1-standard deviation (SD) increase in log IL-6 and HCC risk compared to subjects in the middle quintile of BMI (21.3-22.9 kg/m(2) ), resulting in adjusted RR (95% CI) of 3.09 (1.78-5.81; p = 0.015). The results indicate that higher serum levels of IL-6 are associated with increased HCC risk, independently of hepatitis virus infection, lifestyle-related factors and radiation exposure. The association is especially pronounced among subjects with obesity.

Comparative dosimetric study of spot-scanning proton therapy versus volumetric-modulated radiation therapy for extrahepatic bile duct cancer.

This study aimed to compare the dose distributions and clarify the dosimetric characteristics of spot-scanning proton therapy (SSPT) and photon volumetric modulated arc therapy (VMAT) for extrahepatic bile duct cancer (EBDC). This retrospective study included 10 patients with EBDC treated with real-time image-gated SSPT. Using the simultaneous integrated boost technique, the 2 prescription dose levels for planning target volumes were 72.6 and 44 Gy, delivered in 22 fractions. Plan quality comparisons were conducted by analyzing various parameters, including homogeneity, conformity, dose to organs at risk, and normal tissue complication probability (NTCP) for radiation-induced liver damage (RILD). The target dose distributions using SSPT were almost equivalent to those achieved using photon VMAT. There was a significant reduction in all liver dose parameters, the NTCP value for RILD, and kidney dose (mean, V12 Gy, and V18 Gy) in SSPT than in photon VMAT. No significant differences were observed in the intestinal doses in the high-dose area. Thus, compared with photon VMAT, SSPT for EBDC significantly reduced radiation doses to the liver and kidneys and has shown potential clinical benefits of reduced radiation-induced toxicity.

Albumin-bilirubin score is a useful predictor of worsening liver reserve after stereotactic body radiation therapy in elderly Japanese patients with hepatocellular carcinoma.

The prognosis of patients with hepatocellular carcinoma (HCC) is closely related to their liver reserves. The Child-Pugh (CP) score has traditionally been used to evaluate this reserve, with CP Grade B (CP score ≥ 7) associated with a higher risk of radiation-induced liver disease after stereotactic body radiation therapy (SBRT). However, the CP score has limitations, as it does not accurately assess liver reserve capacity. The albumin-bilirubin (ALBI) score has been introduced as a meticulous indicator of liver reserve for the treatment of HCC. We retrospectively evaluated the role of the ALBI score in estimating the worsening liver reserve in 42 patients with HCC treated with SBRT using CyberKnife between 2015 and 2023. The median biologically effective dose (α/ß = 10 Gy) was 100 Gy. For a median follow-up duration of 17.4 months, the 1-year overall survival (OS), local control (LC) and progression-free survival (PFS) rates were 100, 98 and 62%, respectively. Worsening liver reserve was defined as an increase in the modified ALBI grade or CP score within 1 year after SBRT. Univariate and multivariate analyses showed that the baseline ALBI score (≥-2.7 vs <-2.7) was the only significantly different predictor of worsening liver reserve. The OS and LC rates after SBRT for HCC were satisfactory. However, the PFS was poor, and recurrent HCC will require additional treatment. It is clinically important to predict the liver reserve capacity after SBRT, and the baseline ALBI score is a useful predictor.

Re-irradiation for isolated neck recurrence in head and neck tumor: impact of rN category.

Unresectable, isolated lymph node recurrence after radiotherapy is rare but a candidate for re-irradiation. However, severe toxicity is anticipated. Therefore, this study aimed to explore the efficacy and toxicity of re-irradiation in isolated lymph node recurrence of head and neck lesions. We analyzed 46 patients who received re-irradiation for lymph node recurrence without local progression. The primary tumor sites included the oral cavity in 17 patients, the hypopharynx in 12, the oropharynx in seven, the larynx in three, the nasopharynx in two, and other sites. During a median follow-up time of 10 months, the median survival time was 10.6 months, and the 1-year overall survival rate was 45.5%. The 1-year local control and progression-free survival rates were 49.8% and 39.3%, respectively. According to univariate analysis, age (≥ 65 years), the interval between treatment (≥ 12 months), rN category (rN1), and gross tumor volume (GTV < 25 cm3) were predisposing factors for better survival. In the multivariate analysis, the rN category and interval were identified as statistically significant predictors. Late toxicity grade ≥ 3 occurred in four patients (8.6%). These were all Grade 5 carotid blowout syndrome, which associated with tumor invasion of the carotid artery and/ or high doses administration for the carotid artery. Small-volume rN1 tumor that recur after a longer interval is a feasible candidate for re-irradiation. However, strict patient selection and meticulous care for the carotid are required.

The Feasibility of Omission of Postoperative Radiotherapy in Japanese Patients With Early Breast Cancer Treated With Breast-Conserving Surgery.

Background This study was aimed at analyzing the impact of postoperative radiotherapy (PORT) after breast-conserving surgery (BCS) on Japanese patients with early-stage breast cancer and exploring the potential of PORT omission. Materials and methods Data from 794 patients with early-stage breast cancer (T1-2, N0-1), who underwent BCS with (n = 310) or without PORT (n = 484) were retrospectively analyzed. Local control (LC) rate and breast cancer-specific survival (BCSS) were compared between the groups that received and did not receive PORT in the whole cohort and low-risk cohort (i.e., the cohort with negative surgical margin, lymph node negativity, and estrogen receptor positivity, excluding young age of 49 or less), and in low-risk subgroup using propensity-score matching. Results PORT was associated with better LC but not BCSS in the total population. In the low-risk cohort, the incidence of local recurrence in patients without and with PORT was 5.3% and 4.8%, respectively, at 10 years (p = 0.591), and 7.8% and 4.8%, respectively, according to propensity-score matching (p = 0.485). Conclusion PORT improved LC in the total population, but not BCSS or overall survival (OS). In the low-risk group analysis (negative surgical margin, lymph node negativity, estrogen receptor positivity, and age 50 years or more), equivalent LC, BCSS, and OS were found including propensity-matched comparison. Therefore, this study showed that the omission of PORT could be a treatment option for low-risk Japanese patients. Further multi-center prospective studies are warranted to validate these findings and reduce the unnecessary burden of PORT for patients and institutions.

Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.