Multi-institutional phase II study of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for breast cancer in Japan: Kyoto Radiation Oncology Study Group (UPBEAT study).

PURPOSE: The UK-FAST-Forward study showed that ultra-hypofractionated whole-breast irradiation (ultra-HF-WBI) involving five fractions of 26 Gy radiation over 1 week was not inferior to HF-WBI. However, it is not used in Japan due to safety concerns. In April 2022, we commenced a multi-institutional, single-arm, phase II trial. Our aim is to confirm the safety of ultra-HF-WBI after breast-conserving surgery (BCS) for breast cancer in Japanese women. METHOD: We plan to enroll 98 patients from 13 institutions. The primary endpoint is the proportion of late adverse events of grades ≥2 within 3 years. DISCUSSION: We believe that this highly promising clinical study can positively impact the Japanese guidelines for breast cancer treatment. The results will help us decide whether or not ultra-HF-WBI can be used as a more convenient alternative to WBI. REGISTRATION NUMBER AND DATE: This trial was registered in the UMIN Clinical Trials Registry (UMIN000047080) on March 4, 2022.

Intraoperative hemodialysis during open-heart surgery in patients with severe chronic kidney disease: a retrospective cohort study.

BACKGROUND: Acute kidney injury and chronic kidney disease (CKD) after cardiac surgery are associated with poor renal prognosis and increased mortality. The impact of intraoperative hemodialysis (IHD) on postoperative renal function remains unknown. We aimed to evaluate the utility of IHD during open-heart surgery in patients with severe non-dialysis-dependent chronic kidney disease (CKD-NDD) and its association with clinical outcomes. METHODS: This was a single-center retrospective cohort study that employed IHD during non-emergency open-heart surgery in patients with CKD stage G4 or G5. Patients who underwent emergent surgery, chronic dialysis, and/or kidney transplantation were excluded. We retrospectively compared the clinical characteristics and outcomes between patients from the IHD and non-IHD groups. The primary outcomes were 90-day mortality and postoperative initiation of renal replacement therapy (RRT). RESULTS: Twenty-eight patients were categorized into the IHD group and 33 into the non-IHD group. When comparing the IHD and non-IHD groups, men accounted for 60.7 vs. 50.3% of patients, the mean patient age was 74.5 (standard deviation [SD] 7.0) vs. 72.9 (SD 9.4) years (p = 0.744), and the proportion of patients with CKD G4 was 67.9 vs. 84.9% (p = 0.138). Regarding clinical outcomes, no significant differences were observed in the 90-day mortality (7.1 vs. 3.0%; p = 0.482) and 30-day RRT (17.9 vs. 30.3%; p = 0.373) rates between the groups. Among the patients with CKD G4, the IHD group had significantly lower 30-day RRT rates than the non-IHD group (0 vs. 25.0%; p = 0.032). RRT initiation was less likely for patients with CKD G4 (odds ratio 0.07, 95% confidence interval [CI] 0.01-0.37; p = 0.002); however, IHD did not significantly decrease the incidence of poor clinical outcomes (odds ratio 0.20, 95% CI 0.04-1.07; p = 0.061). CONCLUSIONS: IHD during open-heart surgery in patients with CKD-NDD did not improve their clinical outcomes with regards to postoperative dialysis. However, for patients with CKD G4, IHD may be useful for postoperative cardiac management.

Crystal Structure of Pyrrolysyl-tRNA Synthetase from a Methanogenic Archaeon ISO4-G1 and Its Structure-Based Engineering for Highly-Productive Cell-Free Genetic Code Expansion with Non-Canonical Amino Acids.

Pairs of pyrrolysyl-tRNA synthetase (PylRS) and tRNAPyl from Methanosarcina mazei and Methanosarcina barkeri are widely used for site-specific incorporations of non-canonical amino acids into proteins (genetic code expansion). Previously, we achieved full productivity of cell-free protein synthesis for bulky non-canonical amino acids, including Nε-((((E)-cyclooct-2-en-1-yl)oxy)carbonyl)-L-lysine (TCO*Lys), by using Methanomethylophilus alvus PylRS with structure-based mutations in and around the amino acid binding pocket (first-layer and second-layer mutations, respectively). Recently, the PylRS·tRNAPyl pair from a methanogenic archaeon ISO4-G1 was used for genetic code expansion. In the present study, we determined the crystal structure of the methanogenic archaeon ISO4-G1 PylRS (ISO4-G1 PylRS) and compared it with those of structure-known PylRSs. Based on the ISO4-G1 PylRS structure, we attempted the site-specific incorporation of Nε-(p-ethynylbenzyloxycarbonyl)-L-lysine (pEtZLys) into proteins, but it was much less efficient than that of TCO*Lys with M. alvus PylRS mutants. Thus, the first-layer mutations (Y125A and M128L) of ISO4-G1 PylRS, with no additional second-layer mutations, increased the protein productivity with pEtZLys up to 57 ± 8% of that with TCO*Lys at high enzyme concentrations in the cell-free protein synthesis.

[Successful Atrial Plication in Improving Respiratory Failure due to Bilateral Giant Atria].

Giant atria may trigger respiratory failure, which often requires surgical intervention. We report a patient who presented with respiratory failure due to bilateral giant atria. The patient was a 75-year-old woman with rheumatic heart disease. She had undergone mitral valve replacement and tricuspid annuloplasty at another hospital 17 years ago but recently developed respiratory dysfunction. Compression to the lungs by enlarged atria was diagnosed as the main cause of respiratory dysfunction. Hence, the anterior-to-posterior left atrial wall was plicated by para-annular and superior-half plication, respectively, and the right atrial wall was excised into an ellipse shape. Tricuspid valvuloplasty was performed on four sets of eight artificial chordae with CV5 sutures and an annuloplasty ring. Respiratory failure was alleviated after the surgery.

Effects of colorectal endoscopic submucosal dissection on postoperative abdominal symptoms: a prospective observational study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective procedure to resect large superficial gastrointestinal neoplasms. In gastric ESD, several studies showed the relationship between postoperative abdominal symptoms and endoscopic treatment. However, the influence of colorectal ESD on abdominal symptoms after treatment is still unknown. To the best of our knowledge, this is the first prospective multicenter study performed to investigate the impact of colorectal ESD on postoperative abdominal symptoms. This study aimed to clarify the association between change of abdominal symptoms and ESD. METHODS: This study was a prospective multicenter observational trial that enrolled 141 out of 171 patients who underwent colorectal ESD and answered the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire from March 2015 to August 2019. We evaluated abdominal symptoms in the patients using the GSRS questionnaire before ESD and a few weeks after ESD. RESULTS: Comparing the GSRS before and after ESD, overall scores changed from 1.58 ± 0.58 to 1.48 ± 0.48, and the five subscales (reflux syndrome, abdominal pain, indigestion syndrome, diarrhea syndrome, and constipation syndrome) were slightly improved. Overall scores, indigestion syndrome, and constipation syndrome were statistically significantly different before and after ESD (P < 0.05). CONCLUSIONS: In GSRS, a score of ≥ 3 is often treated as a clinically significant symptom. Therefore, our findings indicated that there was no clinically significant difference. For this reason, colorectal ESD does not affect postoperative abdominal symptoms and is considered a minimally invasive treatment. The analysis of the impact of colon ESD on gastrointestinal symptoms UMIN000016914.

Multi-institutional feasibility study of intensity-modulated radiotherapy with chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients. RESULTS: Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively. CONCLUSION: The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Crystal structures of the human adiponectin receptors.

Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 Å resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.

A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Prognostic implications of preoperative chronic kidney disease and anemia in patients undergoing coronary artery bypass graft surgery.

PURPOSE: Chronic kidney disease (CKD) and anemia are independent preoperative risk factors for coronary artery bypass graft (CABG) surgery. We evaluated the implications of the coexistence of these two factors and their associated prognosis for CABG surgery. METHODS: We analyzed, retrospectively, consecutive patients who underwent elective CABG surgery between 2004 and 2014. The patients were classified into four groups depending on the presence or absence of preoperative CKD and anemia. We assessed the major adverse cardiac and cerebrovascular event (MACCE), defined as composite outcomes of cardio- and cerebrovascular death, revascularization through surgery or percutaneous intervention, hospitalization for congestive heart failure, and cerebral infarction. RESULTS: The study population consisted of 510 patients (73 % male; median age 71 years old), followed up for a median period of 2.8 years. Multivariate analysis indicated that neither the CKD/no-anemia group [hazard ratio (HR) 0.98, 95 % confidence interval (CI) 0.39-2.51, P = 0.973] nor the no-CKD/anemia group (HR 1.20, 95 % CI 0.69-2.09, P = 0.512) had significantly poorer prognoses than the no-CKD/no-anemia group. However, the CKD/anemia group had a significantly higher risk of a MACCE (HR 2.01, 95 % CI 1.01-3.98, P = 0.046). CONCLUSION: The presence of both CKD and anemia in patients undergoing CABG for coronary artery disease is synergistically associated with a worse outcome.

Endovascular Treatment of Aortoduodenal Syndrome.

PURPOSE: Duodenal obstruction caused by aneurysmal dilatation of the abdominal aorta is a rare clinical entity that is traditionally treated by open aneurysm repair, aneurysmorrhaphy, and duodenal release. We present here the case of aortoduodenal syndrome treated by endovascular therapy. CASE REPORT: A 73-year-old man diagnosed simultaneously with sigmoidovesical fistula and an abdominal aortic aneurysm (AAA) underwent resection of the sigmoid colon followed by colostomy. On postoperative day 34, the patient experienced nausea and vomiting. Computed tomography revealed the AAA causing duodenal obstruction by direct compression. We chose endovascular therapy for treating the AAA rather than graft replacement because of the risk of infection by the colostomy orifice. Postoperatively, the patient reacquired the ability to eat. However, postoperative computed tomography revealed that the diameter of the AAA had not changed. CONCLUSIONS: We considered that the decreased intra-aneurysmal pressure caused a release of duodenal obstruction.

Expression, purification, crystallization, and preliminary X-ray crystallographic studies of the human adiponectin receptors, AdipoR1 and AdipoR2.

The adiponectin receptors (AdipoR1 and AdipoR2) are membrane proteins with seven transmembrane helices. These receptors regulate glucose and fatty acid metabolism, thereby ameliorating type 2 diabetes. The full-length human AdipoR1 and a series of N-terminally truncated mutants of human AdipoR1 and AdipoR2 were expressed in insect cells. In small-scale size exclusion chromatography, the truncated mutants AdipoR1Δ88 (residues 89-375) and AdipoR2Δ99 (residues 100-386) eluted mostly in the intact monodisperse state, while the others eluted primarily as aggregates. However, gel filtration chromatography of the large-scale preparation of the tag-affinity-purified AdipoR1Δ88 revealed the presence of an excessive amount of the aggregated state over the intact state. Since aggregation due to contaminating nucleic acids may have occurred during the sample concentration step, anion-exchange column chromatography was performed immediately after affinity chromatography, to separate the intact AdipoR1Δ88 from the aggregating species. The separated intact AdipoR1Δ88 did not undergo further aggregation, and was successfully purified to homogeneity by gel filtration chromatography. The purified AdipoR1Δ88 and AdipoR2Δ99 proteins were characterized by thermostability assays with 7-diethylamino-3-(4-maleimidophenyl)-4-methyl coumarin, thin layer chromatography of bound lipids, and surface plasmon resonance analysis of ligand binding, demonstrating their structural integrities. The AdipoR1Δ88 and AdipoR2Δ99 proteins were crystallized with the anti-AdipoR1 monoclonal antibody Fv fragment, by the lipidic mesophase method. X-ray diffraction data sets were obtained at resolutions of 2.8 and 2.4 Å, respectively.

Baseline correction of a correlation model for improving the prediction accuracy of infrared marker-based dynamic tumor tracking.

We previously found that the baseline drift of external and internal respiratory motion reduced the prediction accuracy of infrared (IR) marker-based dynamic tumor tracking irradiation (IR Tracking) using the Vero4DRT system. Here, we proposed a baseline correction method, applied immediately before beam delivery, to improve the prediction accuracy of IR Tracking. To perform IR Tracking, a four-dimensional (4D) model was constructed at the beginning of treatment to correlate the internal and external respiratory signals, and the model was expressed using a quadratic function involving the IR marker position (x) and its velocity (v), namely function F(x,v). First, the first 4D model, F1st(x,v), was adjusted by the baseline drift of IR markers (BDIR) along the x-axis, as function F'(x,v). Next, BDdetect, that defined as the difference between the target positions indicated by the implanted fiducial markers (Pdetect) and the predicted target positions with F'(x,v) (Ppredict) was determined using orthogonal kV X-ray images at the peaks of the Pdetect of the end-inhale and end-exhale phases for 10 s just before irradiation. F'(x,v) was corrected with BDdetect to compensate for the residual error. The final corrected 4D model was expressed as Fcor(x,v) = F1st{(x-BDIR),v}-BDdetect. We retrospectively applied this function to 53 paired log files of the 4D model for 12 lung cancer patients who underwent IR Tracking. The 95th percentile of the absolute differences between Pdetect and Ppredict (|Ep|) was compared between F1st(x,v) and Fcor(x,v). The median 95th percentile of |Ep| (units: mm) was 1.0, 1.7, and 3.5 for F1st(x,v), and 0.6, 1.1, and 2.1 for Fcor(x,v) in the left-right, anterior-posterior, and superior-inferior directions, respectively. Over all treatment sessions, the 95th percentile of |Ep| peaked at 3.2 mm using Fcor(x,v) compared with 8.4 mm using F1st(x,v). Our proposed method improved the prediction accuracy of IR Tracking by correcting the baseline drift immediately before irradiation.

A new manual dispensing system for in meso membrane protein crystallization with using a stepping motor-based dispenser.

A reliable and easy to use manual dispensing system has been developed for the in meso membrane protein crystallization method. The system consists of a stepping motor-based dispenser with a new microsyringe system for dispensing, which allows us to deliver any desired volume of highly viscous lipidic mesophase in the range from ~50 to at least ~200 nl. The average, standard deviation, and coefficient of variation of 20 repeated deliveries of 50 nl cubic phase were comparable to those of a current robotic dispensing. Moreover, the bottom faces of boluses delivered to the glass crystallization plate were reproducibly circular in shape, and their centers were within about 100 µm from the center of the crystallization well. The system was useful for crystallizing membrane and soluble proteins in meso.

Prevalence and the long-term prognosis of functional mitral regurgitation in Japanese patients with symptomatic heart failure.

Functional mitral regurgitation (FMR) is a common and critical condition in patients with heart failure (HF); however, the prevalence and clinical outcome of FMR in Japanese real-world clinical practice remain unclear. Within a single hospital-based cohort in the Shinken Database 2004-2011, which comprised all new patients (n = 17,517) who visited the Cardiovascular Institute, we followed symptomatic HF patients. A total of 1,701 patients were included: 104 FMR patients (who had moderate to severe FMR) and 1,597 non-FMR patients (who had none or mild FMR). FMR patients had lower rates of hypertension and dyslipidemia, but higher rates of dilated cardiomyopathy, atrial fibrillation, and New York Heart Association functional class III/IV. FMR patients had higher levels of brain natriuretic peptide and lower left ventricular function. Use of cardiovascular drugs was more common among FMR patients. Kaplan-Meier curves revealed that the incidences of all-cause death, cardiovascular death, and admission for HF were significantly higher in FMR patients. The adjusted Cox regression analysis showed that significant FMR was associated with higher incidences of all-cause death [hazard ratio (HR) 2.179, 95 % confidence interval (CI) 1.266-3.751; P = 0.005], cardiovascular death (HR 2.371, 95 % CI 1.157-4.858; P = 0.018), and admission for HF (HR 1.819, 95 % CI 1.133-2.920; P = 0.013). FMR was common in Japanese symptomatic HF patients and was associated with adverse long-term outcomes. Establishing optimal therapeutic strategies for FMR is warranted.

Development of a dose verification system for Vero4DRT using Monte Carlo method.

Vero4DRT is an innovative image-guided radiotherapy system employing a C-band X-ray head with gimbal mechanics. The purposes of this study were to propose specific MC models of the linac head and multileaf collimator (MLC) for the Vero4DRT and to verify their accuracy. For a 6 MV photon beam delivered by the Vero4DRT, a simulation code was implemented using EGSnrc. The linac head model and the MLC model were simulated based on its specification. Next, the percent depth dose (PDD) and beam profiles at depths of 15, 100, and 200 mm were simulated under source-to-surface distance of 900 and 1000 mm. Field size was set to 150 × 150 mm2 at a depth of 100 mm. Each of the simulated dosimetric metrics was then compared with the corresponding measurements by a 0.125 cc ionization chamber. After that, intra- and interleaf leakage, tongue-and-groove, and rounded-leaf profiles were simulated for the static MLC model. Meanwhile, film measurements were performed using EDR2 films under similar conditions to simulation. The measurement for the rounded-leaf profile was performed using the water phantom and the ionization chamber. The leaf physical density and abutting leaf gap were adjusted to obtain good agreement between the simulated intra- and interleaf leakage profiles and measurements. For the MLC model in step-and-shoot cases, a pyramid and a prostate IMRT field were simulated, while film measurements were performed using EDR2. For the linac head, exclusive of MLC, the difference in PDD was < 1.0% after the buildup region. The simulated beam profiles agreed to within 1.3% at each depth. The MLC model has been shown to reproduce dose measurements within 2.5% for static tests. The MLC is made of tungsten alloy with a purity of 95%. The leaf gap of 0.015 cm and the MLC physical density of 18.0 g/ cm3, which provided the best agreement between the simulated and measured leaf leakage, were assigned to our MC model. As a result, the simulated step-and-shoot IMRT dose distributions agreed with the film measurements to within 3.3%, with exception of the penumbra region. We have developed specific MC models of the linac head and the MLC in the Vero4DRT system. The results have demonstrated that our MC models have high accuracy. 

Exploring factors associated with bleeding events after open heart surgery in patients on dialysis - effects of the presence or absence of warfarin therapy.

BACKGROUND: Perioperative management of patients on dialysis is critical for controlling bleeding and thrombotic risk, in addition to infection control. Postoperative anticoagulation is often difficult to control, and different institutions have different policies. Therefore, in this study, we aimed to investigate factors associated with postoperative bleeding events and whether warfarin (WF) therapy affects the incidence of postoperative bleeding events, total mortality, and stroke. METHODS: Patients who were admitted to the cardiovascular surgery department and underwent valve replacement or plasty were included, and those who underwent mechanical valve introduction were excluded. Thirty-nine patients were included in the study. The primary endpoint was to identify factors associated with the composite endpoint of postoperative bleeding events, and the secondary endpoint was to determine the effect size of WF therapy on postoperative bleeding events, all-cause mortality, and stroke and the strength of association between the crossed endpoints. The strength of the association between the crossed items was examined. RESULTS: Low body weight (p = 0.038) was identified as a factor associated with the primary endpoint of postoperative bleeding events. The secondary endpoint of whether or not patients received WF therapy was largely unrelated to bleeding events, all-cause mortality, and postoperative stroke up to 90 days after surgery. CONCLUSIONS: Preliminary studies suggest that low body weight is a risk factor for postoperative bleeding events in patients on dialysis, although further exploration of other factors will be necessary with the accumulation of similar cases.

Correlation Between Dosimetric Parameters and Local Control in Definitive Radiotherapy for Head and Neck Cancers.

BACKGROUND/AIM: Radiotherapy (RT) outcomes are generally reported based on stage, patient background, and concomitant chemotherapy. This study aimed to investigate the effects of the prescribed dose to gross tumor volume (GTV) and the calculation algorithm on local control in definitive RT for head and neck (H&N) cancers using follow-up images after RT. PATIENTS AND METHODS: This study included 154 patients with H&N cancers treated by Volumetric Modulated Arc Therapy at the Kobe City Medical Center General Hospital. Patients were classified into those receiving definitive RT (70 Gy of irradiation) and those not receiving it. Follow-up images were used to categorize the patients into the responders and non-responders groups. In the non-responders group, follow-up images were imported into the treatment planning system, and the contours of the residual or recurrent areas (local failure) were extracted and fused with computed tomography-simulated images for treatment planning. Dose evaluation parameters included maximum dose, dose administered to 1% of the volume, dose administered to 50% of the volume, dose administered to 99% of the volume (D99%), and minimum dose (Dmin) administered to the GTV. The doses to the GTV were compared between responders and non-responders. RESULTS: D99% exhibited significant differences between local failure and responders and between local failure and non-responders. Dmin showed significant differences between responders and non-responders and between responders and local failure. CONCLUSION: This study emphasizes the importance of verifying dose distribution in all slices of treatment planning, highlighting the need for precise assessment of the dose to the GTV in head and neck cancers.

Population-based asymmetric margins for moving targets in real-time tumor tracking.

BACKGROUND: Both geometric and dosimetric components are commonly considered when determining the margin for planning target volume (PTV). As dose distribution is shaped by controlling beam aperture in peripheral dose prescription and dose-escalated simultaneously integrated boost techniques, adjusting the margin by incorporating the variable dosimetric component into the PTV margin is inappropriate; therefore, geometric components should be accurately estimated for margin calculations. PURPOSE: We introduced an asymmetric margin-calculation theory using the guide to the expression of uncertainty in measurement (GUM) and intra-fractional motion. The margins in fiducial marker-based real-time tumor tracking (RTTT) for lung, liver, and pancreatic cancers were calculated and were then evaluated using Monte Carlo (MC) simulations. METHODS: A total of 74 705, 73 235, and 164 968 sets of intra- and inter-fractional positional data were analyzed for 48 lung, 48 liver, and 25 pancreatic cancer patients, respectively, in RTTT clinical trials. The 2.5th and 97.5th percentiles of the positional error were considered representative values of each fraction of the disease site. The population-based statistics of the probability distributions of these representative positional errors (PD-RPEs) were calculated in six directions. A margin covering 95% of the population was calculated using the proposed formula. The content rate in which the clinical target volume (CTV) was included in the PTV was calculated through MC simulations using the PD-RPEs. RESULTS: The margins required for RTTT were at most 6.2, 4.6, and 3.9 mm for lung, liver, and pancreatic cancer, respectively. MC simulations revealed that the median content rates using the proposed margins satisfied 95% for lung and liver cancers and 93% for pancreatic cancer, closer to the expected rates than the margins according to van Herk's formula. CONCLUSIONS: Our proposed formula based on the GUM and motion probability distributions (MPD) accurately calculated the practical margin size for fiducial marker-based RTTT. This was verified through MC simulations.

Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study.

BACKGROUND: The applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study. METHODS: We enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis-T3 N0-N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months. RESULTS: Of the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected. CONCLUSIONS: Acute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

Diagnosis of metastases from postoperative differentiated thyroid cancer: comparison between FDG and FLT PET/CT studies.

PURPOSE: To compare positron emission tomography (PET)/computed tomography (CT) studies performed with the glucose analog fluorine 18 ((18)F) fluorodeoxyglucose (FDG) and the cell proliferation tracer (18)F fluorothymidine (FLT) in the diagnosis of metastases from postoperative differentiated thyroid cancer. MATERIALS AND METHODS: The institutional ethics review board approved this prospective study. From March 2010 to February 2012, 20 patients (mean age, 53 years; age range, 22-79 years) with postoperative differentiated thyroid cancer underwent both FDG and FLT PET/CT as a staging work-up before radioiodine therapy. In each patient, 28 anatomic areas were set and analyzed for lymph node and distant metastases. The McNemar exact or χ(2) test was used to examine differences in diagnostic indexes in the detection of lymph node and distant metastases between both tracer PET/CT studies. RESULTS: There were 34 lymph node metastases and/or 73 distant metastases (70 metastases in lung and one each in bone, nasopharynx, and brain) in 13 patients. At patient-based analysis, the sensitivity, specificity, and accuracy were 92% (12 of 13 patients), 86% (six of seven patients), and 90% (18 of 20 patients), respectively, for FDG PET/CT and 69% (nine of 13 patients), 29% (two of seven patients), and 55% (11 of 20 patients) for FLT PET/CT. The accuracy of FDG PET/CT was significantly better than that of FLT PET/CT (P = .023). At lesion-based analysis, the sensitivity, specificity, and accuracy for diagnosing lymph node metastases were 85% (29 of 34 lesions), 99.6% (245 of 246 lesions), and 97.9% (274 of 280 lesions), respectively, for FDG PET/CT and 50% (17 of 34 lesions), 90.7% (223 of 246 lesions), and 85.7% (240 of 280 lesions) for FLT PET/CT. The sensitivity, specificity, and accuracy for diagnosing distant metastases were 45% (33 of 73 lesions), 100% (207 of 207 lesions), and 85.7% (240 of 280 lesions), respectively, for FDG PET/CT and 6.8% (five of 73 lesions), 100% (207 of 207 lesions), and 75.7% (212 of 280 lesions) for FLT PET/CT. The sensitivity (P = .002), specificity (P < .001), and accuracy (P < .001) of FDG PET/CT in the diagnosis of lymph node metastases were superior to those of FLT PET, as were the sensitivity (P < .001) and accuracy (P < .001) in the diagnosis of distant metastases. CONCLUSION: FDG PET/CT is superior to FLT PET/CT in the diagnosis of postoperative differentiated thyroid cancer lymph node and distant metastases. Thus, FDG PET/CT is more suitable than FLT PET/CT for examining recurrence of postoperative differentiated thyroid cancer.