Dose Escalation

Eligible participants will undergo intake procedures and baseline evaluations at the clinic the day before dosing. The next day, participants will be randomized to, and receive, either Nezavist SDD oral suspension or placebo vehicle (4 cohorts of escalating doses of Nezavist with 6 Nezavist subjects and 2 placebo subjects in each cohort). Participants will remain in the clinic for at least an additional 48-hours for safety assessments and blood collections to determine plasma levels of Nezavist, then will be discharged from the clinic and return for follow-up safety tests 72-hours later.

Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with radiochemotherapy with curative intent. If the field-set UP margins are broad, the consequence may be that quality of life is impaired. The study group of Nutting et al. (2023) investigated this year whether dysphagia-optimized intensity-modulated radiotherapy can reduce the radiation dose to structures associated with dysphagia and aspiration and improve swallowing function compared to standard IMRT (Nutting C, Finneran L, Roe J, Petkar I, Rooney K, Hall E; DARS Triallist Group. Dysphagia-optimized intensity-modulated radiotherapy versus standard radiotherapy in patients with pharyngeal cancer - Authors' reply. Lancet Oncol. 2023 Oct;24(10):e398. doi: 10.1016/S1470-2045(23)00457-6. PMID: 37797636.) The study group concluded that the results suggest that dysphagia-optimized IMRT improves patient-reported swallowing function compared to standard IMRT. DO-IMRT should be considered the new standard of care for patients receiving radiotherapy for pharyngeal cancer, and ART could further improve outcomes. Thus, in this trial we analyze ART in head and neck cancer in a prospective randomized trial.

Online-adaptive radiotherapy (ART) makes it possible to adapt the dose distribution to the anatomical changes online immediately before each radiation fraction. Adaptive radiotherapy is a further development of image-guided radiotherapy (IGRT), which is now standard in radiotherapy. Here, a cone-beam CT (CBCT) is also performed at the beginning of each fraction, which is used to position the patients in relation to the radiation field arrangement of the initial radiation plan approved for the series. In contrast to ART, with IGRT the radiation plan cannot be adapted to deformations in the body from radiation fraction to radiation fraction, e.g. due to different rectum and bladder fillings. In ART mode, the online adaptive treatment plan for the current treatment is then selected and approved by the specialist online onboard in all cases in which the current target volume for the tumor expansion is not sufficiently covered by the initial treatment plan pre-planned for the series with its planned tolerances, or surrounding normal tissue is exposed too much. If the ART plan does not show any clear dosimetric advantages over the reference plan, especially if the initial plan covers the target volume of the day well, there are no dose increases and the normal tissues are spared as intended, the initial radiation plan from the planning CT can also be used as in IGRT. The aim of this study is to treat at least 15 patients with locally advanced gynecological carcinoma (mainly cervical carcinoma, endometrial carcinoma, vaginal carcinoma), who are to receive definitive radiotherapy at the Department for Radiotherapy at the University Hospital Essen, in ART mode on the Ethos therapy device over an initial 10 radiation fractions. The dose distribution is always compared with the adaptive and the initial plan for the radiation series on the anatomy of the day by the specialist and medical physics expert. The aim of this study is to prospectively investigate what percentage of patients benefit from ART when using standard PTV margins and how to recognize the corresponding patients early in the series. Secondarily, it will be investigated in what proportion of patients the risk organ burden and the safety margins around the clinical target volume can be reduced with ART compared to IGRT and how large this reduction can be. The EORTC and CTC AE toxicitiy scales and further assessment scales will be evaluated in order to quantify objective and subjective side effects.

Children scheduled for general anesthesia were randomly divided into two groups based on age: Group T consisted of toddlers aged 1 - 3 years old, and Group P consisted of preschool children aged 3 - 6 years old. The initial dose for both groups was dexmedetomidine 1μg/kg and esketamine 0.5mg/kg. The sedation depth of the children was assessed using the Ramsay Sedation Scale. An unbiased coin - flipping design was adopted: after esketamine 0.5mg/kg was administered intranasally via a nasal dropper, dexmedetomidine 1μg/kg was given intranasally. The adjusted dose of dexmedetomidine was 0.25μg/kg. If the sedation of the previous child failed, the intranasal dose of dexmedetomidine for the next child would be increased by 0.25μg/kg. If the sedation of the previous child was successful, a card would be drawn to decide the induction dose for the next patient. A total of 20 cards, which were identical in appearance, were prepared. The probability of administering the same dose was 19/20 (95%), and the probability of reducing the dose for the next patient by 0.25μg/kg was 1/20 (5%). After drug administration, an anesthesiologist who was unaware of the medication usage would rate the sedation level using the Ramsay Sedation Scale every 5 minutes. The non - invasive blood pressure (NIBP), heart rate (HR), respiratory rate (RR), and blood oxygen saturation (SpO2) were recorded before drug administration (0 minutes, baseline) and at 5, 10, 15, 20, 25, and 30 minutes after drug administration.The onset time was defined as the time from intranasal administration to an RSS score of ≥ 4. Thirty minutes after intranasal administration, an experienced nurse who was unaware of the intranasal drug dose performed intravenous cannulation. The emotional state was assessed using the Emotional State Scale (ESS - 4) during intravenous cannulation. Successful intravenous cannulation was defined as an ESS - 4 score of ≤ 2 during cannulation, regardless of whether the intravenous infusion catheter was successfully inserted.The Pediatric Anesthesia Emergence Delirium (PAED) scale was used to assess the degree of emergence delirium in children. The onset time of sedation (the time to reach an RSS score of ≥4 after intranasal drug administration), surgical time (from the start to the end of the surgery), and awakening time (from the closure of the sevoflurane vaporizer to an Aldrete score of 9 or above) were recorded.

Potential subjects will consist of parturients who present for scheduled elective cesarean deliveries. Patients will be recruited and consented for the study pre-operatively and if they display Grade 3 or 4 shivering at the time of delivery then they will be enrolled in the study. Doses of dexmedetomidine will be selected according to a sequential up-and-down method, using a biased coin design to find the estimated dose at which 90% of patients would have desired effect - cessation of shivering within 5 minutes of medication administration. An anesthesia physician not involved in patient care or assessment will prepare the dexmedetomidine for intravenous use. Anesthesia will be initiated with spinal anesthesia with our institution's typical dosing of 1.6 mL 0.75% bupivacaine with dextrose, 15 mcg fentanyl, and 150 mcg morphine. Shivering will be graded using a five-point scale as outlined by Crossley and Mahajan. Members of the anesthesia team caring for women in the study will be educated on the grading scales. * Grade 0: no shivering; * Grade 1: one or more of the following: piloerection, peripheral vasoconstriction, peripheral cyanosis, but without visible muscle activity; Grade 2: visible muscle activity confined to one muscle group; * Grade 3: visible muscle activity in more than one muscle group; * Grade 4: gross muscle activity involving the whole body

Do peripheral nerve blocks work shorter if you are on opioids? Background: Peripheral nerve blocks effectively alleviate postoperative pain. Animal studies and human research indicate that opioid tolerance results in reduced effectiveness of local analgesics. This applies to both central nerve blockade and infiltration anaesthesia. The impact on peripheral nerve block in humans has not been evaluated. The aim of the study is to assess the onset time and duration of a radial nerve block in opioid tolerant individuals compared to opioid naive individuals. We hypothesise that peripheral nerve blocks cause shorter sensory and motor block in opioid-tolerant compared to opioid-naive counterparts. Methods: Twenty opioid-tolerant individuals will be matched by sex and age with opioid-naïve counterparts. Participants will undergo an ultrasound-guided radial nerve block. The onset time and duration of motor and sensory blockade will be tested and measured. The primary outcome is difference in duration of sensory nerve blockade between the two groups. The secondary outcomes include the onset time of sensory blockade, onset time of motor blockade, and difference in duration of motor nerve blockade. Perspectives: The data from this study will provide evidence for the duration of peripheral nerve block in opioid tolerant individuals and support if a specific postoperative protocol for opioid tolerant individuals is needed or it should be of special attention.

Lung cancer ranks among the most commonly occurring cancer types globally and has the highest mortality rate. Non-small-cell lung cancer (NSCLC) is the predominant form, accounting for more than 85% of cases. Because symptoms often manifest late, many patients present with locally advanced disease (LA-NSCLC) at diagnosis. The cornerstone treatment for unresectable LA-NSCLC consists of a combination of systemic therapy and radiotherapy followed by immunotherapy. Radiotherapy is preceded by a labor- and time-intensive treatment preparation process. This process first requires diagnostic imaging, such as PET-CT, followed by treatment-planning imaging using a dedicated breathing-guided four-dimensional (4D) planning CT. Subsequently, the tumor and surrounding organs at risk (OARs) must be contoured and independently reviewed by radiation oncologists according to internationally recommended guidelines. Commercial convolutional neural networks (CNNs) are currently used to support this contouring process. These models perform voxel-wise classification to label anatomical structures based on prior training data. A widely used commercial CE-marked application for OAR contouring is Syngo.via®. After contouring, dosimetric treatment planning is performed. Plan creation begins with an optimization step followed by a dose calculation, aiming to achieve an acceptable balance between target coverage and OAR sparing. A commonly used CE-marked knowledge-based planning tool that streamlines this process is RapidPlan®. This system provides estimates of achievable dose distributions and guides dosimetrists and medical physicists toward high-quality plan generation. All preparatory steps are executed on the planning CT, which represents only a single anatomical snapshot at one moment in time. Once preparation is complete, the radiotherapy course begins. Treatments are delivered daily over a period of up to seven weeks. Throughout this timeframe, both tumor and intrathoracic anatomical changes may occur, causing the initial contours and treatment plan to no longer match the patient's anatomy on the day of treatment. Adaptive radiotherapy (ART), in which the original plan is modified in response to anatomical changes, can therefore be beneficial. Clinical studies have demonstrated that patients with NSCLC may benefit from frequent treatment-plan adaptations in cases of tumor regression or intrathoracic shifts during the treatment course. Improvements in progression-free survival and overall survival have been reported, and routine mid-treatment offline ART is recommended for LA-NSCLC. However, despite the evidence, very limited number of patients will receive adaptive radiotherapy. The extensive labor associated with contouring and treatment planning remains a major barrier to broad implementation of ART for all eligible patients. Several contemporary tools have the potential to accelerate the adaptive process. In the present study, the investigators intend to prospectively perform mid-treatment adaptations in 30 patients with LA-NSCLC. These patients will undergo a repeated planning CT followed by renewed contouring and treatment planning, mirroring the pre-treatment workflow. This approach enables initial evaluation of the time efficiency of modern contouring and planning tools in an adaptive setting. All tools used are CE-marked and currently applied as part of standard clinical practice on the initial planning CT. Quality checks and manual reviews by medical physicists and physicians will be identical to pre-treatment procedures. For enrolled patients, the resulting treatment plan accounts for anatomical changes and may enhance tumor coverage and OAR protection. A retrospective phase will begin after completion of all treatments. This phase will investigate the feasibility of incorporating state-of-the-art position-verification imaging-namely cone-beam CTs (CBCTs)-as a replacement for repeated planning CTs. If feasible, repeated 4DCT acquisition could be avoided, sparing patients additional imaging doses and reducing the burden of extra appointments. It will be essential to determine whether current contouring and planning tools can be applied effectively to CBCT data. The prospective workflow described above will serve as the benchmark for time efficiency and contouring and planning quality. This comparison will help determine whether transitioning from repeated 4DCTs to CBCTs within an ART workflow is viable and advantageous. In the prospective ART workflow, the repeated 4D planning CT will be acquired, followed by automated OAR contouring using Syngo.via® and manual delineation of tumor lesions. Treatment planning will then be performed with RapidPlan®, which enhances optimization and reduces inter-observer variability. If the resulting adapted plan provides a dosimetric advantage, it will be implemented for the remainder of the radiotherapy course. Plan-verification procedures will mirror those used in pre-treatment planning, including approval by the responsible physicians and medical physicists. Time measurements will be recorded at each workflow step to serve as ground-truth data for the retrospective phase. In the retrospective evaluation, the investigators will assess the performance of a CBCT-based ART workflow. Instead of a repeated 4DCT, daily CBCT images-acquired routinely for position verification-will be used. CBCT image quality for radiotherapy planning will be verified and converted into a synthetic CT using dedicated CE-marked software (MIM®). Synthetic CT generation improves the accuracy of dose calculations. Automated OAR contouring using Syngo.via® and MIM® will then be performed, followed by manual tumor delineation. Subsequent treatment planning will again be carried out using RapidPlan®. This process will evaluate the extent to which CBCT or synthetic CT can support adaptive treatment planning. As in the prospective phase, time registration will occur at all workflow stages.

This study aims to explore the safety and efficacy of eliminating the PTV expansion margin based on online adaptive stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) or pulmonary oligometastases. In this study, patients will be stratified according to whether they have primary early-stage NSCLC, then randomly assigned in a 1:1 ratio to the study group or the control group. Patients in the study group will receive online adaptive SBRT (without PTV expansion margin), while patients in the control group will receive conventional standard SBRT. After the completion of treatment, patients will be followed up regularly to assess safety and efficacy.

The radiotherapy protocol will include two dose-escalation regimens. The dose in hypoxic tumor volume will be escalated either by conventional RT or stereotactic radiotherapy technique. Concurrent chemotherapy cisplatin will be administered weekly 35-40 mg/m2 or every three weeks 80-100 mg/m2. The parameter of cumulative cisplatin dose of 200 mg/m2 during the whole course of radiotherapy will be also taken into account. Patients will be examined and monitored at least every two weeks. Target volumes and dose and fractionation: Definition of gross tumor volumes (GTV), clinical target volumes (CTV) and planning target volumes (PTV) will follow recommendations of DAHANCA, EORTC and RTOG guidelines. The conventional radiotherapy protocol: Standard fractionation regimen: 70 Gy/54 Gy in 33 fractions GTV primary - CTV - PTV (5+5mm): for dose 70 Gy in 33 fractions GTV LN bulky (\> 3cm) - PTV (5mm): for dose 70 Gy in 33 fractions LN low risk (for elective irradiation) - CTV - PTV (3mm-5mm): for dose 54 Gy in 33 fractions Dose escalated radiotherapy protocol: Dose escalated radiotherapy protocol: 75,9 - 79,2 Gy in 33 fractions GTV hypoxic or any hypoxic LN \> 2cm - PTV (0mm): dose 75,9 - 79,2 Gy in 33 fractions (Contours must be subtracted and reduce by 3mm in case of close relation to the skin, bones or large blood vessels) GTV primary - CTV - PTV (5+5mm): for dose 70 Gy in 33 fractions LN low risk (for elective irradiation) - CTV - PTV (3mm-5mm): for dose 54 Gy in 33 fractions

This is a multicenter, non-inferiority, phase 3, randomized controlled study. This study investigates the role of moderated hypofractionated online adaptive radiotherapy by randomizing patients to this experimental regimen versus the standard of treatment.The purpose of this study is to access safety and efficacy of moderated hypofractionated online adaptive radiotherapy in combination with high-dose-rate brachytherapy in patients with cervical cancer, which based on the previous research (NCT05994300).