Maximum Dose Research Articles

Dosimetric comparison of ZAP-X, Gamma Knife, and CyberKnife stereotactic radiosurgery for single brain metastasis.

To evaluate the dosimetric characteristics of ZAP-X stereotactic radiosurgery (SRS) for single brain metastasis by comparing with two mature SRS platforms. Thirteen patients with single brain metastasis treated with CyberKnife (CK) G4 were selected retrospectively. The prescription dose for the planning target volume (PTV) was 18-24Gy for 1-3 fractions. The PTV volume ranged from 0.44 to 11.52cc.Treatment plans of thirteen patients were replanned using the ZAP-X plan system and the Gamma Knife (GK) ICON plan system with the same prescription dose and organs at risk (OARs) constraints. The prescription dose of PTV was normalized to 70% for both ZAP-X and CK, while it was 50% for GK. The dosimetric parameters of three groups included the plan characteristics (CI, GI, GSI, beams, MUs, treatment time), PTV (D2, D95, D98, Dmin, Dmean, Coverage), brain tissue (volume of 100%-10% prescription dose irradiation V100%-V10%, Dmean) and other OARs (Dmax, Dmean),all of these were compared and evaluated. All data were read and analyzed with MIM Maestro. One-way ANOVA or a multisample Friedman rank sum test was performed, where p < 0.05 indicated significant differences. The CI of GK was significantly lower than that of ZAP-X and CK. Regarding the mean value, ZAP-X had a lower GI and higher GSI, but there was no significant difference among the three groups. The MUs of ZAP-X were significantly lower than those of CK, and the mean value of the treatment time of ZAP-X was significantly shorter than that of CK. For PTV, the D95, D98, and target coverage of CK were higher, while the mean of Dmin of GK was significantly lower than that of CK and ZAP-X. For brain tissue, ZAP-X showed a smaller volume from V100% to V20%; the statistical results of V60% and V50% showed a difference between ZAP-X and GK, while the V40% and V30% showed a significant difference between ZAP-X and the other two groups; V10% and Dmean indicated that GK was better. Excluding the Dmax of the brainstem, right optic nerve and optic chiasm, the mean value of all other OARs was less than 1Gy. For the brainstem, GK and ZAP-X had better protection, especially at the maximum dose. For the SRS treating single brain metastasis, all three treatment devices, ZAP-X system, CyberKnife G4 system, and GammaKnife system, could meet clinical treatment requirements. The newly platform ZAP-X could provide a high-quality plan equivalent to or even better than CyberKnife and Gamma Knife, with ZAP-X presenting a certain dose advantage, especially with a more conformal dose distribution and better protection for brain tissue. As the ZAP-X systems get continuous improvements and upgrades, they may become a new SRS platform for the treatment of brain metastasis.

International consensus on methotrexate dosing for patients with atopic dermatitis: An eDelphi study.

Despite the widespread off-label use of methotrexate (MTX) for the treatment of atopic dermatitis (AD), there is limited high-quality evidence on dosing regimens and existing guidelines do not provide clear recommendations regarding dosing strategies. The aim of this study was to achieve international consensus among AD experts to standardize the dosing regimen for MTX treatment in adults and children with AD. An electronic Delphi (eDelphi) study was conducted from October 2021 to September 2022. Recruitment was conducted through dermatology societies and AD interest groups. Participation was open to dermatologists and dermatology residents experienced in treating AD patients with MTX. The study consisted of three online rounds. The first round was informed by a systematic review of relevant literature, and subsequent rounds were adjusted based on the results of the previous round. Participants voted on 19 proposals using a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree). Consensus was achieved when at least 70% of participants agreed, and less than 15% disagreed. Proposals that did not reach consensus in the first three rounds were discussed in a consensus meeting, where consensus was defined as less than 30% disagreement. In total, 152 participants completed Round 1, 104 (68%) completed all survey rounds, and 43 (28%) joined the consensus meeting. Consensus was achieved on 7 proposals in Round 1, 4 in Round 2 and 6 in Round 3. The final 2 proposals reached consensus during the consensus meeting. Consensus topics include test dose, start dose, maximum dose, administration route, dosing schedule, management of stopping treatment, treatment duration and folic acid supplementation. This eDelphi study achieved consensus on 19 proposals related to MTX dosing for adults and children with AD. These results aim to guide prescribing decisions and encourage a standardized global approach to MTX use in AD.

Treatment with liraglutide or naltrexone-bupropion in patients with genetic obesity: a real-world study

Rare genetic obesity commonly features early-onset obesity, hyperphagia, and therapy-resistance to lifestyle interventions. Pharmacotherapy is often required to treat hyperphagia and induce weight loss. We describe clinical outcomes of glucagon-like peptide-1 analogue liraglutide or naltrexone-bupropion treatment in adults with molecularly confirmed genetic obesity (MCGO) or highly suspected for genetic obesity without definite diagnosis (HSGO). We conducted a real-world cohort study at the Obesity Center CGG at Erasmus University Center, Rotterdam, Netherlands, between March 19, 2019, and August 14, 2023. All patients with MCGO and HSGO who were treated with either liraglutide or naltrexone-bupropion were included. Liraglutide 3mg and naltrexone-bupropion were administered according to the manufacturer's protocol. Treatment evaluation occurred short-term, after 12 weeks on maximum or highest-tolerated dose, preceded by the 4-5 week dose escalation phase. Differences in anthropometrics, body composition, metabolic markers, self-reported appetite, eating behaviour, and quality of life (QoL) were evaluated. Ninety-eight adults were included in the analysis: 23 patients with MCGO and 75 patients with HSGO, with median BMI of 42.0kg/m2 (IQR 38.7-48.2) and 43.7kg/m2 (IQR 38.0-48.7), respectively. After liraglutide treatment, median weight at evaluation significantly decreased compared to baseline in both groups:-4.7% (IQR-6.0 to-1.5) in patients with MCGO and-5.2% (IQR-8.1 to-3.5) in patients with HSGO. Additionally, improvements were observed in appetite, fat mass, fasting glucose, and HbA1c in both patients with MCGO and with HSGO. Patients with HSGO also reported significant improvements in several domains of QoL and eating behaviour. In patients with MCGO and HSGO treated with naltrexone-bupropion, mean weight at evaluation significantly differed from baseline:-5.2%±5.8 in patients with MCGO and-4.4%±4.7 in patients with HSGO. Appetite, fat mass, and waist circumference significantly decreased in both groups. Obesity-related comorbidities improved in significant proportions of patients treated with liraglutide or naltrexone-bupropion. In conclusion, our short-term findings show potential of liraglutide and naltrexone-bupropion as treatment options for adults with (a clinical phenotype of) genetic obesity. MB, EvdA, and EvR are supported by the Elisabeth Foundation, a non-profit foundation supporting academic obesity research.

Results of Stereotactic Body Radiotherapy With CyberKnife-M6 for Primary and Metastatic Lung Cancer.

The aim of the study was to evaluate the efficacy of stereotactic body radiotherapy (SBRT) using the CyberKnife-M6 (CK-M6) with lung optimized treatment (LOT) module in patients with primary lung cancer and lung metastases. Forty-two lesions from 35 patients were treated between 2019 and 2022. Four-dimensional computed tomography images were obtained when the patients were in a free breathing modality. Tracking modality was selected prospectively according to the visibility of the target. The median prescribed dose was 48 Gy in four fractions (fx) (28 - 55 Gy/1- 7 fx). The median age was 68 years (47 - 82 years), and 43% of cases were adenocarcinoma. The median lesion size was 15 mm (6 - 36 mm). Complete, partial and stable responses were obtained as 26%, 62%, and 9.5% at a median of 2 months (1 - 6 months), and 35.5%, 47.5% and 5% at the 12th month evaluation, respectively. Grade 3 and higher toxicity was not observed in any case. The mean and 2-year overall survival (OS) was 31.5 months and 54%, and the local recurrence-free survival (LRFS) was 29.6 months and 51%, respectively. In univariate analysis, target lesion type, complete response (CR), and higher esophagus maximum dose were favorable factors for OS and LRFS (P < 0.05). The CR at 12th month evaluation remained significant in multivariate analysis in terms of OS (hazard ratio = 8.602, 95% confidence interval: 1.05 - 70.01; P = 0.044). A mean LRFS of 29.6 months and OS of 31.5 months were obtained in patients with primary and metastatic lung cancer. With a median treatment time of 25 min, motion-managed strategy with CK-M6-LOT-based SBRT is an effective, safe, and comfortable treatment method for lung cancer.

Efficient use of penile Doppler ultrasound for investigating men with erectile dysfunction.

Vasculogenic erectile dysfunction is the most common type of erectile dysfunction, and penile Doppler ultrasound (PDUS) is a useful tool to assess erectile hemodynamics in the clinician's effort to discuss prognosis and management strategies with the patient. We herein describe the PDUS protocol used at our center, including indications, technique, and data interpretation. We describe our institutional experience with PDUS and discuss it in the context of a contemporary review of the literature for this investigation. Our institutional PDUS protocol. To perform PDUS properly, adequate training, equipment, setting, technique, and interpretation are critical. The accuracy of PDUS is entirely predicated on achieving complete cavernosal smooth muscle relaxation. A redosing protocol optimizes the reliability and reproducibility of the hemodynamic data acquired during PDUS. A rigidity-based assessment is performed, and patients are scanned according to the erection rigidity achieved (full hardness) or by administration of maximum dose of the vasoactive agent. Peak systolic velocity is considered a measure of arterial inflow (normal, >30cm/s), while end diastolic velocity evaluates the veno-occlusive mechanism (normal, <5cm/s). After the procedure, the patient is evaluated to confirm detumescence. If the patient has a persistent penetration rigidity erection, intracavernosal phenylephrine is administered; however, if detumescence is not achieved with intracavernosal phenylephrine injections alone, corporal aspiration is potentially performed. PDUS is a valuable minimally invasive tool for erectile hemodynamics assessment and an accurate assessment of such, provided that complete cavernosal smooth muscle relaxation is achieved.

In Silico Comparison of Three Different Beam Arrangements for Intensity-Modulated Proton Therapy for Postoperative Whole Pelvic Irradiation of Prostate Cancer

Background and purpose: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. The aim of this study was to evaluate three different intensity-modulated proton therapy (IMPT) beam arrangements when treating the prostate bed and pelvis in the postoperative setting. Materials and Methods: Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (IMPT2B) (opposed laterals), three-field (IMPT3B) (opposed laterals inferiorly matched to a posterior–anterior beam superiorly), and four-field (IMPT4B) (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. The prescription was 50 Gy radiobiological equivalent (GyE) to the pelvis and 70 GyE to the prostate bed. Comparisons were made using paired two-sided Wilcoxon signed-rank tests. Results: CTV coverages were met for all IMPT plans, with 99% of CTVs receiving ≥ 100% of prescription doses. All organ at risk (OAR) objectives were met with IMPT3B and IMPT4B plans, while several rectum objectives were exceeded by IMPT2B plans. IMPT4B provided the lowest doses to OARs for the majority of analyzed outcomes, with significantly lower doses than IMPT2B +/− IMPT3B for bladder V30–V50 and mean dose; bowel V15–V45 and mean dose; sigmoid maximum dose; rectum V40–V72.1, maximum dose, and mean dose; femoral head V37–40 and maximum dose; bone V40 and mean dose; penile bulb mean dose; and skin maximum dose. Conclusion: This study is the first to compare proton beam arrangements when treating the prostate bed and pelvis. four-field plans provided better sparing of the bladder, bowel, and rectum than 2- and three-field plans. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer.

Two Case Reports of Coronary Spastic Angina Accompanied by the Menstrual Cycle

Abstract Background Coronary spastic angina (CSA) in premenopausal women is not frequent but has also been suggested to be associated with estrogen decline during the menstrual cycle and sometimes becomes refractory and difficult to control. We experienced two premenopausal women with CSA that showed the involvement of the menstrual cycle. Case Summary Case 1: 41 years-old-woman had ST-segment elevation and chest pain during urosepsis, just two days after the onset of menstruation. The acetylcholine stress test was performed according to the menstrual cycle and multiple coronary spasms were induced. Case 2: 40 years-old-woman had refractory chest pain as a symptom of premenstrual syndrome (PMS). Coronary angiography on drugs at the maximum dose revealed spontaneous multiple coronary spasms. Blood levels of estrogen were normal, suggesting that hormonal change may be involved, and the introduction of low-dose pills made free from angina and the reduction of drug dose. Discussion In premenopausal female angina pectoris, estrogen may play a role, it is important to ask about the menstrual cycle and history of PMS. Besides, the timing of catheterization in premenopausal women with suspected CSA should be considered. Low-dose pills may be effective in some cases, and active medical collaboration with other departments such as gynecology is desirable.

Sex-Related Differences in the Severity of Neonatal Opioid Withdrawal Syndrome: A Single-Center, Retrospective Cohort Study.

Factors associated with the development and expression of Neonatal Opioid Withdrawal Syndrome (NOWS) are poorly understood. There are conflicting data on the role of infant sex in NOWS. Some studies have suggested that infant sex predicts NOWS severity and adverse outcomes, with male infants being more vulnerable. This study aimed to analyze if infant sex is associated with the severity of NOWS among those who require pharmacologic treatment. This is a retrospective cohort study of term and late-preterm infants (≥35 weeks gestation) exposed to in utero opioids, born between September 2006 and August 2022, and required pharmacologic treatment for NOWS. Maternal and infant demographics were collected. Indicators of the severity of NOWS (duration of medical treatment (DOT), duration of hospitalization, maximum dose of opioid treatment, and use of secondary medications) were compared between male and female infants. Standard statistical tests and regression analysis were used to establish the differences in outcomes after accounting for confounders and baseline differences. Out of the 1,074 infants included in the study, 47.9% were female, and 52.1% were male. There was no significant difference in demographic and baseline clinical characteristics between groups except for anthropometry (birth weight, head circumference, and length) and Apgar score at 5 minutes. The median DOT (25 days [14, 39] vs. 23 days [13, 39], p = 0.57), length of hospital stay (31.5 days [20, 44] vs. 28 days [20, 44], p = 0.35), treatment with phenobarbital (24.7 vs. 26.3%, p = 0.56), and clonidine (3.9 vs. 3.8%, p = 0.9) were similar in both groups. The differences remained nonsignificant after adjusting for birth anthropometric measurements, gestational age, 5-minute Apgar score, small for gestational age status, and maternal exposure to benzodiazepines. In this cohort of neonates, sex-related differences were not identified to influence the severity of NOWS among those who required pharmacological treatment. · Vulnerability to NOWS is multifactorial.. · The role of infant sex in the severity of NOWS is not concrete.. · We noted that sex did not impact NOWS severity in those treated..

Mechanical Behaviour of Soil Treated with Chitosan and Calcium Metasilicate Considering the Fungal Growth

Biopolymers have been widely experimented with as organic stabilizers in the last decade for improving soil properties. However, the high nutritional value of some biopolymers like chitin, carrageenan, casein, and chitosan can also promote microbial growth which can affect the improvement in the strength of biopolymer-stabilized soil. This study investigates the mechanical behaviour of clay treated with chitosan at dosages of 0.5, 1.0, 1.5, and 2.0% at various curing periods of 7 d, 28 d, 56 d, and 90 d and also observes the fungal growth, the conditions favourable to fungal growth, and the effect of an inorganic secondary additive on the mechanical behaviour of treated soil. The study shows that fungal growth is higher with the time and dosage of chitosan. The strength of chitosan-treated samples increased with both dosage and age despite the fungal growth observed on the treated soil, as did the fungal growth. On treating the soil with 2% chitosan, the percentage increase in strength was nearly 14.39%, and on the 56th day, it was phenomenally increased to 1534.39%. In an attempt to control the fungal growth, a secondary additive, calcium metasilicate (calsil), was added to various dosages of chitosan-treated soil (CTS). The secondary additive did not completely stop the fungal growth but certainly controlled fungal growth. Chitosan and calsil are hydrophilic, increasing OMC by 67% and 150% for the high CTS and calsil–chitosan-treated soil (CCTS) doses. Calsil coated the soil particles and prevented closer packing under compaction, reducing MDUW by 7.8% and 18% for CTS and CCTS at maximal dosage. The development of hydrated cementitious products made the soil brittle, causing the post-peak strength of CCTS samples to diminish significantly with age. FTIR spectroscopy showed hydrogen bonding strengthening CTS, while XRD revealed cementitious compounds in CCTS. The strength of the soil treated with chitosan and calsil showed a higher strength than soil treated with only chitosan.

A single, maximal dose of celecoxib, ibuprofen, or flurbiprofen does not reduce the muscle signalling response to plyometric exercise in young healthy adults.

Non-steroidal anti-inflammatory drugs (NSAIDs) possess analgesic and anti-inflammatory properties by inhibiting cyclooxygenase (COX) enzymes. Conflicting evidence exists on whether NSAIDs influence signaling related to muscle adaptations and exercise with some research finding a reduction in muscle protein synthesis signaling via the AKT-mTOR pathway, changes in satellite cell signaling, reductions in muscle protein degradation, and reductions in cell proliferation. In this study, we determined if a single maximal dose of flurbiprofen (FLU), celecoxib (CEL), ibuprofen (IBU), or a placebo (PLA) affects the short-term muscle signaling responses to plyometric exercise. This was a block randomized, double-masked, crossover design, where 12 participants performed four plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% 1RM. Two hours before exercise, participants consumed a single dose of celecoxib (CEL 200mg), IBU (800mg), FLU (100mg) or PLA with food. Muscle biopsy samples were collected before and 3-h after exercise from the vastus lateralis. Data were analyzed using a repeated measures (RM) ANOVA, ANOVA, or a Friedman test. Significance was considered at p < 0.05. We found no treatment effects on the mRNA expression of PTSG1, PTSG2, MYC, TBP, RPLOP, MYOD1, Pax7, MYOG, Atrogin-1, or MURF1 (all, p > 0.05). We also found no treatment effects on AKT-mTOR signaling or MAPK signaling measured through the phosphorylation status of mTORS2441, mTORS2448, RPS6 235/236, RPS 240/244, 4EBP1, ERK1/2, p38 T180/182 normalized to their respective total abundance (all, p > 0.05). However, we did find a significant difference between MNK1 T197/202 in PLA compared to FLU (p < .05). A single, maximal dose of IBU, CEL, or FLU taken prior to exercise did not affect the signaling of muscle protein synthesis, protein degradation, or ribosome biogenesis three hours after a plyometric training bout.

Process validation and preclinical development of a new PET cerebral blood flow tracer [11C]MMP for initial clinical trials

Background2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [18F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [15O]H2O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[11C]methylamphetamine ([11C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [15O]H2O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [11C]MMP prior to clinical translation.ResultsThe decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low.Conclusions[11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit.

External Radiation Dose to the Shore Crab of Chinnavilai, a High Background Natural Radiation Area

The aim of the study was to determine the activity concentration and radiation dose of radionuclides 226Ra, 228Ra &amp; 40K in shore crab Hemigrapsus Sanguineus, in Chinnavilai, Kayakumari district, Tamil Nadu, India. Gamma spectrometry is used for determine activity concentration and radiation dose of radionuclides (226Ra, 228Ra &amp; 40K.). The total dose values due to both internal and external contributions by all three studied radionuclides fell between 26.51 and 53.19 µGy/day. These values are far below the dose limits (10 mGy/day) prescribed for aquatic animals by the US Department of Energy (2002) and hence the animals are safe, radiologically as far as these radionuclides are concerned. The minimum internal dose for 228Ra in shore crab 0.30 and the external dose 16.42. The total dose for 228Ra in shore crab 16.72. The maximum internal dose for 228Ra in shore crab 0.64 and the external dose 30.03. The total dose for 228Ra in shore crab 30.67.

Reconsidering the usefulness of long-term high-dose buprenorphine

Buprenorphine has been successfully used for decades in the treatment of opioid use disorder, yet there are complexities to its use that warrant attention to maximize its utility. While the package insert of the combination product buprenorphine\naloxone continues to recommend a maximum dose of 16 mg daily for maintenance, the emergence of fentanyl and synthetic analogs in the current drug supply may be limiting the effectiveness of this standard dose. Many practitioners have embraced and appropriately implemented novel practices to mitigate the sequelae of our current crisis. It has become common clinical practice to stabilize patients with 24 - 32 mg of buprenorphine daily at treatment initiation. Many of these patients, however, are maintained on these high doses (&amp;gt;16 mg/d) indefinitely, even after prolonged stability. Although this may be a necessary strategy in the short term, there is little evidence to support its safety and efficacy, and these high doses may be exposing patients to more complications and side effects than standard doses. Commonly known side effects of buprenorphine that are likely dose-related include hyperhidrosis, sedation, decreased libido, constipation, and hypogonadism. There are also complications related to the active metabolite of buprenorphine (norbuprenorphine) which is a full agonist at the mu opioid receptor and does not have a ceiling on respiratory suppression. Such side effects can lead to medical morbidity as well as decreased medication adherence, and we, therefore, recommend that after a period of stabilization, practitioners consider a trial of decreasing the dose of buprenorphine toward standard dose recommendations. Some patients’ path of recovery may never reach this stabilization phase (i.e., several months of adherence to medications, opioid abstinence, and other clinical indicators of stability). Side effects of buprenorphine may not have much salience when patients are struggling for survival and safety, but for those who are fortunate enough to advance in their recovery, the side effects become more problematic and can limit quality of life and adherence.

Transfer factors of 238U, 232Th, 40K, 210Pb to crops and radiation impact assessment in semi-arid environment

AbstractResearch on the safety of staple agricultural food products has always been one of humanity’s priorities and provides input for dose assessment models. Within this important priority, activity concentrations, transfer factors, and radiological effects of 238U, 232Th, 210Pb, and 40K were studied for selected crops in a village close to the NORM area, located in Central Anatolia region of Turkey. The RESRAD-onsite code has been used to assess the total dose rate. The simulation of the risk analysis covered 80 years. The maximum total dose of 0.5 mSv y−1 was obtained at t = 30 years.

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial

The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. Celgene and Acceleron Pharma.

How to Equalize High- and Low-Intensity Endurance Exercise Dose.

Without appropriate standardization of exercise doses, comparing high- (HI) and low-intensity (LI) training outcomes might become a matter of speculation. In athletic preparation, proper quantification ensures an optimized stress-to-recovery ratio. This review aims to compare HI and LI doses by estimating theoretically the conversion ratio, 1:x, between HI and LI: How many minutes, x, of LI are equivalent to 1minute of HI using various quantification methods? A scrutinized analysis on how the dose increases in relation to duration and intensity was also made. An estimation was conducted across 4 categories encompassing 10 different approaches: (1)"arbitrary" methods, (2)physiological and perceptual measurements duringexercise, (3)postexercise measurements, andcomparison to (4a) acute and (4b) chronic intensity-related maximum dose. The first 2 categories provide the most conservative estimation for the HI:LI ratio (1:1.5-1:10), and the third, slightly higher (1:4-1:11). The category (4a) provides the highest estimation (1:52+) and (4b) suggests 1:10 to 1:20. The exercise dose in the majority of the approaches increase linearly in relation to duration and exponentially in relation to intensity. As dose estimations provide divergent evaluations of the HI:LI ratio, the choice of metric will have a large impact on the research designs, results, and interpretations. Therefore, researchers should familiarize themselves with the foundations and weaknesses of their metrics and justify their choice. Last, the linear relationship between duration and exercise dose is in many cases assumed rather than thoroughly tested, and its use should be subjected to closer scrutiny.

Dosimetric impact of intrafraction patient motion on MLC-based 3D-conformal spatially fractionated radiation therapy treatment of large and bulky tumors.

To evaluate the dosimetric impact on spatially fractionated radiation therapy (SFRT) plan quality due to intrafraction patient motion via multi-field MLC-based method for treating large and bulky (≥8cm) unresectable tumors. For large tumors, a cone beam CT-guided 3D conformal MLC-based SFRT method was utilized with 15Gy prescription. An MLC GTV-fitting algorithm provided 1cm diameter apertures with a 2cm center-to-center distance at the isocenter. This generated a highly heterogeneous sieve-like dose distribution within an hour, enabling same-day SFRT treatment. Fifteen previously treated SFRT patients were analyzed (5 head & neck [H&N], 5 chest and lungs, and 5 abdominal and pelvis masses). For each plan, intrafraction motion errors were simulated by incrementally shifting original isocenters of each field in different x-, y-, and z-directions from 1 to 5mm. The dosimetric metrics analyzed were: peak-to-valley-dose-ratio (PVDR), percentage of GTV receiving 7.5Gy, GTV mean dose, and maximum dose to organs-at-risk (OARs). For±1,±2,±3,±4, and±5mm isocenter shifts: PVDR dropped by 3.9%, 3.8%, 4.0%, 4.1%, and 5.5% on average respectively. The GTV(V7.5) remained within 0.2%, and the GTV mean dose remained within 3.3% on average, compared to the original plans. The average PVDR drop for 5mm shifts was 4.2% for H&N cases, 10% for chest and lung, and 2.2% for abdominal and pelvis cases. OAR doses also increased. The maximum dose to the spinal cord increased by up to 17 cGy in H&N plans, mean lung dose (MLD) changed was small for chest/lung, but the bowel dose varied up to 100 cGy for abdominal and pelvis cases. Due to tumor size, location, and characteristics of MLC-based SFRT, isocenter shifts of up to±5mm in different directions had moderate effects on PVDR for H&N and pelvic tumors and a larger effect on chest tumors. The dosimetric impact on OAR doses depended on the treatment site. Site-specific patient masks, Vac-Lok bags, and proper immobilization devices similar to SBRT/SRT setups should be used to minimize these effects.

Midazolam Indications and Dosing in Palliative Medicine: Results from a Multinational Survey.

Despite sparse evidence and limited guidance on indications, use, and dosing, midazolam is widely used in palliative care. We aimed to describe and compare the use of midazolam in three different countries to improve clinical practice in palliative care. We performed an online survey among palliative care physicians in Norway, Denmark, and the United Kingdom (UK). The focus was indications, dosing, administration, and concomitant drugs. A web-based questionnaire was distributed to members of the respective national palliative medicine associations. The total response rate was 9.4%. Practices in the UK, Norway, and Denmark were overall similar regarding the indications of midazolam for anxiety, dyspnoea, and pain treatment in combination with opioids. However, physicians in the UK used a higher starting dose for anxiety, dyspnoea, and pain treatment compared to Norway and Denmark, as well as a higher maximum dose. Danish physicians preferred, to a higher degree, on-demand midazolam administration. Despite practice similarities in the UK, Norway, and Denmark, differences exist for midazolam dosing and administration in palliative medicine. We demonstrated a lack of consensus on how midazolam should be used in palliative care, setting the stage for future studies on the topic.

Impact of dose distribution by a 3D planning system for brachytherapy with 198Au grains for head and neck cancer.

There has been no study in which the correlation between clinical results and dosimetry based on a 3D treatment planning system in patients with 198Au grains for head and neck cancer was evaluated. Thirty-two patients who were treated with 198Au grains for head and neck cancer were reviewed. Twenty-five patients were treated with brachytherapy alone and seven patients were treated with a combination of brachytherapy and neoadjuvant external beam radiation therapy. With a median observation period of 60 months, the 5-year local control rate was 82.9%. V85Gy of CTV in patients with local recurrence tended to be lower than that in patients without local recurrence (p = 0.07). The maximum dose of the keratinized gingiva in patients in whom bone exposure occurred was significantly higher than that in patients in whom bone exposure did not occur (p = 0.001). Dose distribution with 198Au grains can predict local control and late adverse events.

Long-term toxicity and efficacy of FLASH radiotherapy in dogs with superficial malignant tumors.

FLASH radiotherapy (RT) has emerged as a promising modality, demonstrating both a normal tissue sparing effect and anticancer efficacy. We have previously reported on the safety and efficacy of single fraction FLASH RT in the treatment of oral tumors in canine cancer patients, showing tumor response but also a risk of radiation-induced severe late adverse effects (osteoradionecrosis) for doses ≥35 Gy. Accordingly, the objective in this study was to investigate if single fraction high dose FLASH RT is safe for treating non-oral tumors. Privately-owned dogs with superficial tumors or microscopic residual disease were included. Treatment was generally delivered as a single fraction of 15-35 Gy 10 MeV electron FLASH RT, although two dogs were re-irradiated at a later timepoint. Follow-up visits were conducted up to 12 months post-treatment to evaluate treatment efficiency and adverse effects. Fourteen dogs with 16 tumors were included, of which nine tumors were treated for gross disease whilst seven tumors were treated post-surgery for microscopic residual disease. Four treatment sites treated with 35 Gy had ulceration post irradiation, which was graded as severe adverse effect. Only mild adverse effects were observed for the remaining treatment sites. None of the patients with microscopic disease experienced recurrence (0/7), and all patients with macroscopic disease showed either a complete (5/9) or a partial response (4/9). Five dogs were euthanized due to clinical disease progression. Our study demonstrates that single fraction high dose FLASH RT is generally safe, with few severe adverse effects, particularly in areas less susceptible to radiation-induced damage. In addition, our study indicates that FLASH has anti-tumor efficacy in a clinical setting. No osteoradionecrosis was observed in this study, although other types of high-grade adverse effects including ulcer-formations were observed for the highest delivered dose (35 Gy). Overall, we conclude that osteoradionecrosis following single fraction, high dose FLASH does not appear to be a general problem for non-oral tumor locations. Also, as has been shown previously for oral tumors, 30 Gy appeared to be the maximum safe dose to deliver with single fraction FLASH RT.