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Therapeutic Advances in... 2023In patients attempting to discontinue their antidepressant medication, there have been no prospective studies on patterns of withdrawal as a function of the rate of...
BACKGROUND
In patients attempting to discontinue their antidepressant medication, there have been no prospective studies on patterns of withdrawal as a function of the rate of antidepressant reduction during the tapering trajectory, and moderators thereof.
OBJECTIVE
To investigate withdrawal as a function of gradual dose reduction.
DESIGN
Prospective cohort study.
METHODS
The sampling frame consisted of 3956 individuals in the Netherlands who received an antidepressant tapering strip between 19 May 2019 and 22 March 2022 in routine clinical practice. Of these, 608 patients, majorly with previous unsuccessful attempts to stop, provided daily ratings of withdrawal in the context of reducing their antidepressant medications (mostly venlafaxine or paroxetine), using hyperbolic tapering strips offering daily tiny reductions in dose.
RESULTS
Withdrawal in daily-step hyperbolic tapering trajectories was limited, and inverse to the rate of taper. Female sex, younger age, presence of one or more risk factors and faster rate of reduction over shorter tapering trajectories were associated with more withdrawal and differential course over time. Thus, sex and age differences were less marked early in the course of the trajectory, whereas differences associated with risk factors and shorter trajectories tended to peak early in the trajectory. There was evidence that tapering in weekly larger steps (mean per-week dose reduction: 33.4% of previous dose), in comparison with daily tiny steps (mean per-day dose reduction: 4.5% of previous dose or 25.3% per week), was associated with more withdrawal in trajectories of 1, 2 or 3 months, particularly for paroxetine and the group of other (non-paroxetine, non-venlafaxine) antidepressants.
CONCLUSION
Antidepressant hyperbolic tapering is associated with limited, rate-dependent withdrawal that is inverse to the rate of taper. The demonstration of multiple demographic, risk and complex temporal moderators in time series of withdrawal data indicates that antidepressant tapering in clinical practice requires a personalised process of shared decision making over the entire course of the tapering period.
PubMed: 37200818
DOI: 10.1177/20451253231171518 -
Scientific Reports Apr 2022Reproductive sterility is the basis of the sterile insect technique (SIT) and essential for its success in the field. Numerous factors that influence dose-response in...
Reproductive sterility is the basis of the sterile insect technique (SIT) and essential for its success in the field. Numerous factors that influence dose-response in insects have been identified. However, historically the radiation dose administered has been considered a constant. Efforts aiming to standardize protocols for mosquito irradiation found that, despite carefully controlling many variable factors, there was still an unknown element responsible for differences in expected sterility levels of insects irradiated with the same dose and handling protocols. Thus, together with previous inconclusive investigations, the question arose whether dose really equals dose in terms of biological response, no matter the rate at which the dose is administered. Interestingly, the dose rate effects studied in human nuclear medicine indicated that dose rate could alter dose-response in mammalian cells. Here, we conducted experiments to better understand the interaction of dose and dose rate to assess the effects in irradiated mosquitoes. Our findings suggest that not only does dose rate alter irradiation-induced effects, but that the interaction is not linear and may change with dose. We speculate that the recombination of reactive oxygen species (ROS) in treatments with moderate to high dose rates might minimize indirect radiation-induced effects in mosquitoes and decrease sterility levels, unless dose along with its direct effects is increased. Together with further studies to identify an optimum match of dose and dose rate, these results could assist in the development of improved methods for the production of high-quality sterile mosquitoes to enhance the efficiency of SIT programs.
Topics: Animals; Humans; Infertility; Insecta; Mammals; Pupa; Radiation Dosage
PubMed: 35422488
DOI: 10.1038/s41598-022-10027-z -
Cancer Reports (Hoboken, N.J.) Jan 2022High-dose-rate brachytherapy (HDR BRT) has been enjoying rapid acceptance as a treatment modality offered to selected prostate cancer patients devoid of risk group,... (Review)
Review
BACKGROUND
High-dose-rate brachytherapy (HDR BRT) has been enjoying rapid acceptance as a treatment modality offered to selected prostate cancer patients devoid of risk group, employed either in monotherapy setting or combined with external beam radiation therapy (EBRT) and is currently one of the most active clinical research areas.
RECENT FINDINGS
This review encompasses all the current evidence to support the use of HDR BRT in various clinical scenario and shines light to the HDR BRT rationale, as an ultimately conformal dose delivery method enabling safe dose escalation to the prostate.
CONCLUSION
Valid long-term data, both in regard to the oncologic outcomes and toxicity profile, support the current clinical indication spectrum of HDR BRT. At the same time, this serves as solid, rigid ground for emerging therapeutic applications, allowing the technique to remain in the spotlight alongside stereotactic radiosurgery.
Topics: Brachytherapy; Dose Fractionation, Radiation; Humans; Male; Prostatic Neoplasms
PubMed: 34164950
DOI: 10.1002/cnr2.1450 -
Frontiers in Oncology 2022To evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment.
PURPOSES
To evaluate the plan quality and robustness of both dose and dose rate of proton pencil beam scanning (PBS) transmission FLASH delivery in lung cancer treatment.
METHODS AND MATERIALS
An in-house FLASH planning platform was used to optimize 10 lung cancer patients previously consecutively treated with proton stereotactic body radiation therapy (SBRT) to receive 3 and 5 transmission beams (Trx-3fds and Trx-5fds, respectively) to 34 Gy in a single fraction. Perturbation scenarios (n=12) for setup and range uncertainties (5 mm and 3.5%) were introduced, and dose-volume histogram and dose-rate-volume histogram bands were generated. Conventional proton SBRT clinical plans were used as a reference. RTOG 0915 dose metrics and 40 Gy/s dose rate coverage (V) were used to assess the dose and dose rate robustness.
RESULTS
Trx-5fds yields a comparable iCTV D of 105.3%, whereas Trx-3fds resulted in inferior D of 111.9% to the clinical SBRT plans with D of 105.6% (p<0.05). Both Trx-5fds and Trx-3fds plans had slightly worse dose metrics to organs at risk than SBRT plans. Trx-5fds achieved superior dosimetry robustness for iCTV, esophagus, and spinal cord doses than both Trx-3fds and conventional SBRT plans. There was no significant difference in dose rate robustness for V coverage between Trx-3fds and Trx-5fds. Dose rate distribution has similar distributions to the dose when perturbation exists.
CONCLUSION
Transmission plans yield overall modestly inferior plan quality compared to the conventional proton SBRT plans but provide improved robustness and the potential for a toxicity-sparing FLASH effect. By using more beams (5- versus 3-field), both dose and dose rate robustness for transmission plans can be achieved.
PubMed: 36059710
DOI: 10.3389/fonc.2022.970602 -
Cancer Science Nov 2023Rectal cancer is a common malignancy that requires multidisciplinary treatment. By utilizing the dose-response relationship in rectal cancer radiotherapy, increasing the... (Review)
Review
Rectal cancer is a common malignancy that requires multidisciplinary treatment. By utilizing the dose-response relationship in rectal cancer radiotherapy, increasing the radiotherapy dose can improve clinical complete remission rates. High-dose rate endorectal brachytherapy (HDREBT) is a novel technique that delivers high doses of radiotherapy directly to the tumor via an endorectal applicator, sparing the adjacent normal tissues from excessive radiation exposure. HDREBT includes contact X-ray brachytherapy and high-dose-rate intracavitary brachytherapy. We introduce the latest developments in applicators and imaging techniques for HDREBT in rectal cancer and summarize the current evidence on the efficacy, safety, and feasibility of HDREBT as a neoadjuvant, definitive, or palliative treatment option for all stages of rectal cancer patients. We also discuss the potential advantages and challenges of HDREBT in achieving organ preservation and improving the quality of life of rectal cancer patients. HDREBT has shown promising results in achieving high complete response rates, enabling nonoperative management, improving organ preservation rates, and providing effective palliation in rectal cancer patients. More studies are needed to optimize its dose and fractionation schemes in different clinical scenarios.
Topics: Humans; Brachytherapy; Quality of Life; Radiotherapy Dosage; Rectal Neoplasms; Rectum
PubMed: 37702196
DOI: 10.1111/cas.15959 -
Medical Physics Jun 2023Conformality has been a key requirement in radiation therapy for cancer to minimize normal tissue toxicity while maintaining tumor control. Since 2014, there has been... (Review)
Review
Conformality has been a key requirement in radiation therapy for cancer to minimize normal tissue toxicity while maintaining tumor control. Since 2014, there has been great interest in ultra-high dose rate (UHDR), "FLASH," radiation therapy to enhance this therapeutic window. In multiple pre-clinical studies, it was seen that normal tissue demonstrated less damage due to radiation of various modalities when the same dose was delivered at ultra-high mean dose rates exceeding ∼40 Gy/s while tumor control remained indifferent to changes in dose rate. The scientific community has large-scale interdisciplinary studies to investigate this potentially breakthrough technique to enhance treatment options for cancer. FLASH studies have been performed using a number of modalities and delivery techniques for many pre-clinical models. There have been several studies reporting evidence of the FLASH effect as well as technological developments relating to UHDR studies. There is sustained interest and motivation for this topic as well as many questions that are yet to be answered. We provide a short overview to highlight some of the major work and challenges to advance research in FLASH radiotherapy.
Topics: Humans; Neoplasms; Motivation; Radiotherapy Dosage
PubMed: 36758965
DOI: 10.1002/mp.16271 -
Medical Physics Jul 2022Higher dose rates, a trend for radiotherapy machines, can be beneficial in shortening treatment times for radiosurgery and mitigating the effects of motion. Recently,...
Higher dose rates, a trend for radiotherapy machines, can be beneficial in shortening treatment times for radiosurgery and mitigating the effects of motion. Recently, even higher doses (e.g., 100 times greater) have become targeted because of their potential to generate the FLASH effect (FE). We refer to these physical dose rates as ultra-high (UHDR). The complete relationship between UHDR and the FE is unknown. But UHDR systems are needed to explore the relationship further and to deliver clinical UHDR treatments, where indicated. Despite the challenging set of unknowns, the authors seek to make reasonable assumptions to probe how existing and developing technology can address the UHDR conditions needed to provide beam generation capable of producing the FE in preclinical and clinical applications. As a preface, this paper discusses the known and unknown relationships between UHDR and the FE. Based on these, different accelerator and ionizing radiation types are then discussed regarding the relevant UHDR needs. The details of UHDR beam production are discussed for existing and potential future systems such as linacs, cyclotrons, synchrotrons, synchrocyclotrons, and laser accelerators. In addition, various UHDR delivery mechanisms are discussed, along with required developments in beam diagnostics and dose control systems.
Topics: Cyclotrons; Particle Accelerators; Radiation Oncology; Radiosurgery; Radiotherapy Dosage; Synchrotrons
PubMed: 35403262
DOI: 10.1002/mp.15659 -
Cancers Jul 2023Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor... (Review)
Review
Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as Gafchromic EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment.
PubMed: 37568699
DOI: 10.3390/cancers15153883 -
Prostate International Sep 2023Around 40 years have passed since a modern low-dose-rate (LDR) brachytherapy for prostate cancer was introduced. LDR brachytherapy has become one of the definitive... (Review)
Review
Around 40 years have passed since a modern low-dose-rate (LDR) brachytherapy for prostate cancer was introduced. LDR brachytherapy has become one of the definitive treatment options besides radical prostatectomy (RP) and external beam radiation therapy (EBRT). LDR brachytherapy has several advantages over EBRT such as a higher prescribed dose to the prostate gland while avoiding unnecessary irradiation of organs at risk, a precipitous dose gradient, a brief treatment time, and a short hospital stay. Previous reports revealed that the long-term oncologic outcomes of LDR brachytherapy are superior to those of EBRT. The oncologic outcomes of low- to intermediate-risk patients are equivalent to those of RP using the recurrence definition of surgery of prostate specific antigen (PSA) >0.2 ng/mL, while the oncologic outcomes of LDR brachytherapy as tri-modality (combined EBRT and androgen deprivation therapy) for high-risk patients is superior to that of RP using the recurrence definition of surgery. In respect of toxicity, urinary disorders such as urgency and frequency are often observed after the acute phase of treatment, but these events usually resolve, while the quality of life of urinary continence is well preserved for a long time. Erectile function decreases yearly, but is relatively preserved compared to RP. In conclusion, the most noteworthy strength of LDR brachytherapy for low- to intermediate-risk patients is the "brief treatment time" that provides long recurrence-free survival, while that for high-risk patients who received LDR brachytherapy (tri-modality) is "excellent disease control."
PubMed: 37745911
DOI: 10.1016/j.prnil.2023.01.004 -
Journal of Cardiothoracic and Vascular... Sep 2022The clinical efficacy of corticosteroids remains unclear. The primary aim of this systematic review and meta-analysis was to evaluate the use of high-dose versus low-... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The clinical efficacy of corticosteroids remains unclear. The primary aim of this systematic review and meta-analysis was to evaluate the use of high-dose versus low- dose corticosteroids on the mortality rate of COVID-19 patients.
DESIGN
Systematic review and meta-analysis.
SETTING
Electronic search for randomized controlled trials and observational studies (MEDLINE, EMBASE, CENTRAL).
PARTICIPANTS
Hospitalized adults ≥ 18 years old who were SARS-CoV-2 PCR positive.
INTERVENTIONS
High-dose and low-dose corticosteroids.
MEASUREMENTS AND MAIN RESULTS
A total of twelve studies (n=2759 patients) were included in this review. The pooled analysis demonstrated no significant difference in mortality rate between the high-dose and low-dose corticosteroids groups (n=2632; OR: 1.07 [95%CI 0.67, 1.72], p=0.77, I=76%, trial sequential analysis=inconclusive). No significant differences were observed in the incidence of intensive care unit (ICU) admission rate (n=1544; OR: 0.77[95%CI 0.43, 1.37], p=0.37, I= 72%), duration of hospital stay (n=1615; MD: 0.53[95%CI -1.36, 2.41], p=0.58, I=87%), respiratory support (n=1694; OR: 1.51[95%CI 0.77, 2.96], p=0.23, I=84%), duration of mechanical ventilation (n=419; MD: -1.44[95%CI -4.27, 1.40], p=0.32, I=93%), incidence of hyperglycemia (n=516, OR: 0.91[95%CI 0.58, 1.43], p=0.68, I=0%) and infection rate (n=1485, OR: 0.86[95%CI 0.64, 1.16], p=0.33, I=29%).
CONCLUSION
The meta-analysis demonstrated high-dose corticosteroids did not reduce mortality rate. However, high-dose corticosteroids did not pose higher risk of hyperglycemia and infection rate for COVID-19 patients. Due to the inconclusive trial sequential analysis, substantial heterogeneity and low level of evidence, future large-scale randomized clinical trials are warranted to improve the certainty of evidence for the use of high-dose compared to low-dose corticosteroids in COVID-19 patients.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; COVID-19; Humans; Hyperglycemia; Respiration, Artificial; SARS-CoV-2
PubMed: 35715291
DOI: 10.1053/j.jvca.2022.05.011