Optimizing GRID and Lattice Spatially Fractionated Radiation Therapy: Innovative Strategies for Radioresistant and Bulky Tumor Management.

Treating radioresistant and bulky tumors is challenging due to their inherent resistance to standard therapies and their large size. GRID and lattice spatially fractionated radiation therapy (simply referred to GRID RT and LRT) offer promising techniques to tackle these issues. Both approaches deliver radiation in a grid-like or lattice pattern, creating high-dose peaks surrounded by low-dose valleys. This pattern enables the destruction of significant portions of the tumor while sparing healthy tissue. GRID RT uses a 2-dimensional pattern of high-dose peaks (15-20 Gy), while LRT delivers a three-dimensional array of high-dose vertices (10-20 Gy) spaced 2-5 cm apart. These techniques are beneficial for treating a variety of cancers, including soft tissue sarcomas, osteosarcomas, renal cell carcinoma, melanoma, gastrointestinal stromal tumors (GISTs), pancreatic cancer, glioblastoma, and hepatocellular carcinoma. The specific grid and lattice patterns must be carefully tailored for each cancer type to maximize the peak-to-valley dose ratio while protecting critical organs and minimizing collateral damage. For gynecologic cancers, the treatment plan should align with the international consensus guidelines, incorporating concurrent chemotherapy for optimal outcomes. Despite the challenges of precise dosimetry and patient selection, GRID RT and LRT can be cost-effective using existing radiation equipment, including particle therapy systems, to deliver targeted high-dose radiation peaks. This phased approach of partial high-dose induction radiation therapy with standard fractionated radiation therapy maximizes immune modulation and tumor control while reducing toxicity. Comprehensive treatment plans using these advanced techniques offer a valuable framework for radiation oncologists, ensuring safe and effective delivery of therapy for radioresistant and bulky tumors. Further clinical trials data and standardized guidelines will refine these strategies, helping expand access to innovative cancer treatments.

Prevalence of postoperative pain after hospital discharge: systematic review and meta-analysis.

Assessment and management of postoperative pain after hospital discharge is very challenging. We conducted a systematic review to synthesize available evidence on the prevalence of moderate-to-severe postoperative pain within the first 1 to 14 days after hospital discharge. The previously published protocol for this review was registered in PROSPERO. MEDLINE and EMBASE databases were searched until November 2020. We included observational postsurgical pain studies in the posthospital discharge setting. The primary outcome for the review was the proportion of study participants with moderate-to-severe postoperative pain (eg, pain score of 4 or more on a 10-point Numerical Rating Scale) within the first 1 to 14 days after hospital discharge. This review included 27 eligible studies involving a total of 22,108 participants having undergone a wide variety of surgical procedures. The 27 studies included ambulatory surgeries (n = 19), inpatient surgeries (n = 1), both ambulatory and inpatient surgeries (n = 4), or was not specified (n = 3). Meta-analyses of combinable studies provided estimates of pooled prevalence rates of moderate-to-severe postoperative pain ranging from 31% 1 day after discharge to 58% 1 to 2 weeks after discharge. These findings suggest that moderate-to-severe postoperative pain is a common occurrence after hospital discharge and highlight the importance of future efforts to more effectively evaluate, prevent, and treat postsurgical pain in patients discharged from the hospital.

Genetic Analysis of the Single-Nucleotide Polymorphisms rs880810, rs545793, rs80094639, and rs13251901 in Nonsyndromic Oral Clefts: A Case-Parent Trio Study.

Oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are the most common types of congenital anomalies of the human face. Various genetic and environmental factors play a role in developing oral clefts. Several studies have shown the association of the PAX7 gene and the 8q24 region with these oral clefts in different populations worldwide. However, there are no reported studies on the possible connection between the PAX7 gene and the 8q24 region nucleotide variants and the risk of developing nonsyndromic oral clefts (NSOC) in the Indian population. Hence, this study aimed to test the possible association between PAX7 gene single-nucleotide polymorphisms (SNPs) rs880810, rs545793,rs80094639, and rs13251901 of the 8q24 region using a case-parent trio design. Forty case-parent trios were selected from the CLP center. Genomic DNA was isolated from the cases and their parents. The rs880810, rs545793, rs80094639, and rs13251901 were genotyped by the MassARRAY technique. PLINK software was used for statistical analysis. All the SNPs were tested for Hardy-Weinberg equilibrium. No statistical significance was found with any SNPs, as none of the genotyped SNPs showed a p -value of less than 0.05. Hence, the rs880810, rs545793, and rs80094639 of the PAX7 gene, and rs13251901 of the 8q24 region are not associated with NSOC in the Indian population.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer.

Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy.

PURPOSE: Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials. METHODS AND MATERIALS: Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development. RESULTS: Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed. CONCLUSIONS: This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

Neoadjuvant concurrent chemoradiotherapy using infusional gemcitabine in locally advanced rectal cancer: A phase II trial.

INTRODUCTION: Gemcitabine is a well-known radiosensitizer. Herein, we tested the efficacy and toxicity of preoperative concurrent infusional gemcitabine and radiotherapy in locally advanced rectal cancer. PATIENTS AND METHODS: This was a phase II, single-arm trial. Eligible patients had a diagnosis of rectal adenocarcinoma with clinical stage T3-T4 and/or nodal involvement, age ≥18 years, and no prior chemotherapy or radiotherapy. Patients received preoperative radiation at a dose of 50.4-54 Gy over 28 days with concurrent infusional gemcitabine administered at a dose of 100 mg/m2 over the course of 24 h weekly for 6 weeks. The primary endpoint was pathological complete response (pCR). RESULTS: Forty patients were recruited. Only one patient did not complete therapy due to death. Eight patients did not undergo surgery, one died, two progressed to nonresectable disease, and five withdrew consent. Five patients progressed prior to surgery, with two having unresectable metastases and three having resectable liver metastases. One was found to have peritoneal metastasis during surgery. Out of the 32 patients who underwent surgery, seven achieved pCR at a rate of 20%. With a median follow-up of 30 months, four additional patients had a distant relapse (one had a subsequent local relapse). The 3-year event-free and overall survival rates were 70% and 85%, respectively. The commonest preoperative grade 3-4 toxicity included lymphopenia (50%), neutropenia (41%), anemia (15%), diarrhea (12%), abdominal pain (12%), and proctitis (8%). CONCLUSION: Concurrent preoperative chemoradiotherapy using infusional gemcitabine for locally advanced rectal cancer achieved an encouraging degree of local control with manageable toxicity.

Streeter's Syndrome of Lower Limb Associated with CTEV.

Introduction: The term Streeter's syndrome is a term used to describe rare congenital malformations that includes a variety of clinical presentations usually consisting of a constriction band around a part of the body which can be as superficial as involving just the skin which can be only cosmetic and asymptomatic or can be as deep as causing restricted circulation distally which may be in incompatible with life. Such conditions are remarkably rare accounting for an incidence range from 1:1.2 k to 1: 15 k live births and 178:10 k spontaneous abortions [1]. Males and females are uniformly affected. Almost all cases are sporadic; extremely rare evidence of familial transmission. The entity has been described in the literature in 34 different terms, (such as amniotic rupture sequence, ADAM complex, constriction band syndrome, Streeter's dysplasia, etc.) due to its extremely variable clinical features and lack of understanding of the etiology. This results in a lack of understanding and creates unnecessary stress for the surgeon/physician as well as the parents. Case Report: We discuss case reports of two such cases with their simple nature of treatment with their outcomes. Conclusion: There is a significant deficit in the education of cases with low incidence, such is the case with pediatric patients presenting with amniotic bands, which usually present and are associated with Congenital Talipes Equino Varus deformity. In such cases, improper or incorrect treatment and/or neglect of the constriction may lead to the vascular deficit and eventually auto-amputation of the segment distal to the amniotic band.

The association of age with acute toxicities in NRG oncology combined modality lower GI cancer trials.

PURPOSE: Expected toxicity from chemoradiation (CRT) is an important factor in treatment decisions but is poorly understood in older adults with lower gastrointestinal (GI) malignancies. Our objective was to compare acute adverse events (AAEs) of older and younger adults with lower GI malignancies treated on NRG studies. METHODS: Data from 6 NRG trials, testing combined modality therapy in patients with anal or rectal cancer, were used to test the hypothesis that older age was associated with increased AAEs. AAEs and compliance with protocol-directed therapy were compared between patients aged ≥70 and < 70. Categorical variables were compared across age groups using the chi-square test. The association of age on AAEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value <0.01 was considered statistically significant. RESULTS: There were 2525 patients, including 380 patients ≥70 years old (15%) evaluable. Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p = 0.001), but otherwise baseline characteristics were similar. Older patients were less likely to complete their chemotherapy (78% vs. 87%, p < 0.001), but had similar RT duration. On univariate analysis, older patients were more likely to experience grade ≥ 3 GI AAEs (36% vs. 23%, p < 0.001), and less likely to experience grade ≥ 3 skin AAEs (8% vs. 14%, p = 0.002). On multivariable analysis, older age was associated with grade ≥ 3 GI AAE (OR 1.93, 95% CI: 1.52, 2.47, p < 0.001) after adjusting for sex, race, PS, and disease site. CONCLUSIONS: Older patients with lower GI cancers who underwent CRT were less likely to complete chemotherapy and had higher rates of grade 3+ GI AAEs. These results can be used to counsel older adults prior to treatment and manage expected toxicities throughout pelvic CRT.

International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.

ABSTRACT: The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

Efficacy and Safety of Drug Combinations for Chronic Pelvic Pain: Protocol for a Systematic Review.

BACKGROUND: Chronic pelvic pain with various etiologies and mechanisms affects men and women and is a major challenge. Monotherapy is often unsuccessful for chronic pelvic pain, and combinations of different classes of medications are frequently prescribed, with the expectation of improved outcomes. Although a number of combination trials for chronic pelvic pain have been reported, we are not aware of any systematic reviews of the available evidence on combination drug therapy for chronic pelvic pain. OBJECTIVE: We have developed a protocol for a systematic review to evaluate available evidence of the efficacy and safety of drug combinations for chronic pelvic pain. METHODS: This systematic review will involve a detailed search of randomized controlled trials investigating drug combinations to treat chronic pelvic pain in adults. The databases searched will include the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant studies. The primary outcome will be pain relief measured using validated scoring tools. Secondary outcomes, where reported, will include the following: adverse events, serious adverse events, sexual function, quality of life, and depression and anxiety. Methodological quality of each included study will be assessed using the Cochrane Risk of Bias Tool. RESULTS: The systematic review defined by this protocol is expected to synthesize available good quality evidence on combination drug therapy in chronic pelvic pain, which may help guide future research and treatment choices for patients and their health care providers. CONCLUSIONS: This review will provide a clearer understanding of the efficacy and safety of combination pharmacological therapy for chronic pelvic pain. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020192231; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=192231. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21909.

Effects of tree species diversity and stand structure on carbon stocks of homestead forests in Maheshkhali Island, Southern Bangladesh.

BACKGROUND: The homestead forests of Bangladesh occupy 0.27 million hectares (10% of the total forested area) and have potential to store carbon (C) and conserve biodiversity. Small scale forestry practices, however, are lacking reliable estimation of C stocks and tree species diversity. This may hinder successful implementation of REDD + and similar mechanisms as they concentrate on large-scale forests. This study aimed to estimate the above- and below-ground carbon stocks in homestead forests of Maheshkhali Island in Bangladesh and how tree species diversity and stand structural variation affect these C stocks. We randomly surveyed a total of 239 homestead forests in the hillside, beachside, and inland in 2019. RESULTS: Tree biomass C stocks were 48-67% greater in the inland and hillside forests than in the beachside due to significantly greater stand density, basal area, tree diameter. In total we found 52 tree species, but most abundant species in the inland and hillside forests, Mangifera indica, Samanea saman, and Artocarpus heterophyllus stored the most C in tree biomass. Greater tree species richness and diversity index in the inland and hillside forests indicated greater above- and below-ground tree biomass C stocks. An increase in tree species richness and diversity index by one unit was found to increase the tree biomass C stock by 22 and 30 Mg C ha-1, respectively. The total soil C stock was also affected by tree species diversity, stand density, and their interaction with soil properties. Total soil C stocks were greatest (51 Mg ha-1) in the inland forests, having also the greatest stand density and tree species richness. C stock in soil surface was greatest in the hillside forests due to the greatest litterfall, but the average share of litterfall from the total biomass C was only 0.1%. CONCLUSIONS: Homestead forest ecosystems could store 96 Mg C ha-1 in total, which can contribute to climate change mitigation by generating C credits for small-scale homestead forests owners. Above- and below-ground tree biomass C stocks were found to correlate with tree species diversity, which may also contribute to biodiversity conservation in the REDD + in Bangladesh and countries alike.

Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain. METHODS: A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults ≥ 18 years old. Risk of bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis. RESULTS: Nine studies (n = 863) were included (five randomized controlled trials [RCTs], two open-label non-comparative studies and two comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of three RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% confidence interval [CI]: -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI: -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain. CONCLUSIONS: While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine.

General risks of harm with cannabinoids, cannabis, and cannabis-based medicine possibly relevant to patients receiving these for pain management: an overview of systematic reviews.

ABSTRACT: The growing demand for improved pain treatments together with expanding legalization of, and access to, cannabinoids, cannabis, and cannabis-based medicines has intensified the focus on risk-benefit considerations in pain management. Given limited harms data from analgesic clinical trials, we conducted an overview of systematic reviews focused on all harms possibly relevant to patients receiving cannabinoids for pain management. This PROSPERO-registered, PRISMA-compliant systematic overview identified 79 reviews, encompassing over 2200 individual reports about psychiatric and psychosocial harms, cognitive/behavioral effects, motor vehicle accidents, cardiovascular, respiratory, cancer-related, maternal/fetal, and general harms. Reviews, and their included studies, were of variable quality. Available evidence suggests variable associations between cannabis exposure (ranging from monthly to daily use based largely on self-report) and psychosis, motor vehicle accidents, respiratory problems, and other harms. Most evidence comes from settings other than that of pain management (eg, nonmedicinal and experimental) but does signal a need for caution and more robust harms evaluation in future studies. Given partial overlap between patients receiving cannabinoids for pain management and individuals using cannabinoids for other reasons, lessons from the crisis of oversupply and overuse of opioids in some parts of the world emphasize the need to broadly consider harms evidence from real-world settings. The advancement of research on cannabinoid harms will serve to guide optimal approaches to the use of cannabinoids for pain management. In the meantime, this evidence should be carefully examined when making risk-benefit considerations about the use of cannabinoids, cannabis, and cannabis-based medicine for chronic pain.

Prevalence of Postoperative Pain Following Hospital Discharge: Protocol for a Systematic Review.

BACKGROUND: Pain is one of the most common, feared, and unpleasant symptoms associated with surgery. However, there is a clear gap in patient care after surgical patients are discharged from hospital, resulting in poorly controlled postoperative pain. Inadequate pain management after discharge can have detrimental effects on quality of life and lead to the development of chronic postsurgical pain. The severity of postoperative pain before discharge is well described, but less emphasis has been placed on assessing pain at home after hospital discharge. OBJECTIVE: The objective of this review is to summarize the prevalence of moderate-to-severe postoperative pain within the first 1 to 14 days after hospital discharge. METHODS: A detailed search of epidemiological studies investigating postoperative pain will be conducted on MEDLINE and EMBASE from their inception until the date the searches are run. The primary outcome will be the proportion of patients reporting moderate-to-severe postoperative pain at rest and with movement within the first 1 to 14 days after hospital discharge. The secondary outcomes will include a comparison of postoperative pain after discharge between patients who underwent ambulatory and inpatient surgery, and adverse outcomes attributable to poor pain control after hospital discharge (eg, readmission to hospital, emergency room or other unplanned medical visits, or a decrease in quality of life). RESULTS: The protocol has been registered in PROSPERO (registration number CRD42020194346). The search strategies for MEDLINE and EMBASE have been completed. The final results are expected to be published in May 2021. CONCLUSIONS: This systematic review is expected to synthesize evidence describing the prevalence of postoperative pain after hospital discharge. Available epidemiological evidence may help inform the magnitude of the problem of postoperative pain at home after hospital discharge. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020194346; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=194346. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/22437.

Systematic scoping review of interactions between analgesic drug therapy and mindfulness-based interventions for chronic pain in adults: current evidence and future directions.

Most patients with chronic pain do not find adequate pain relief with a single treatment, and accumulating evidence points to the added benefits of rational combinations of different treatments. Given that psychological therapies, such as mindfulness-based interventions (MBIs), are often delivered in conjunction with concomitant analgesic drug therapies (CADTs), this systematic scoping review examines the evidence for any interactions between MBIs and CADTs. The protocol for this review has been published and registered. MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and PsycINFO databases were searched until July 2019. We included randomized controlled trials that evaluated the efficacy of MBIs for the treatment of chronic pain. A total of 40 randomized controlled trials (2978 participants) were included. Thirty-nine of 40 (97.5%) included mindfulness-based clinical trials allowed the use of CADTs. However, only 6 of these 39 (15.4%) trials provided adequate details of what these CADTs were, and only 4 (10.3%) trials controlled for CADTs. Of great relevance to this review, none of the included trials analyzed the interactions between MBIs and the CADTs to determine whether they have an additive, synergistic, or antagonistic effect on chronic pain. Adverse events were inconsistently reported, and no judgment could be made about safety. Future trials assessing the interactions between MBIs and CADTs, with better harms reporting, are needed to better define the role of MBIs in the management of chronic pain.

Understanding High-Dose, Ultra-High Dose Rate, and Spatially Fractionated Radiation Therapy.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Efficacy and Safety of Magnesium for the Management of Chronic Pain in Adults: A Systematic Review.

Chronic pain is a highly prevalent and complex health problem that is associated with a heavy symptom burden, substantial economic and social impact, and also, very few highly effective treatments. This review examines evidence for the efficacy and safety of magnesium in chronic pain. The previously published protocol for this review was registered in International Prospective Register of Systematic Reviews (PROSPERO), MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched until September 2018. We included randomized controlled trials (RCTs) comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain measures. A total of 9 RCTs containing 418 participants were included. Three studies examined neuropathic pain (62 participants), 3 examined migraines (190 participants), 2 examined complex regional pain syndrome (86 participants), and 1 examined low back pain with a neuropathic component (80 participants). Heterogeneity of included studies precluded any meta-analyses. No judgment could be made about safety because adverse events were inconsistently reported in the included studies. Evidence of analgesic efficacy from included studies was equivocal. However, reported efficacy signals in some of the included trials provide a rationale for more definitive studies. Future, larger-sized trials with good assay sensitivity and better safety assessment and reporting, as well as careful attention to formulations with optimal bioavailability, will serve to better define the role of magnesium in the management of chronic pain.

Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Medical Cannabis and Cannabis-based Medicines for Chronic Noncancer Pain: A Systematic Review.

OBJECTIVE: Current treatments for chronic pain have limited effectiveness and tolerability. With growing interest in the potential of cannabinoids, there is a need to inform risk-benefit considerations. Thus, this focused systematic review assesses the quality of safety assessment and reporting in chronic noncancer pain cannabinoid trials. METHODS: The protocol for this review has been published, and, registered in PROSPERO. We searched MEDLINE, Embase, The Cochrane Library, Scopus, and PsychINFO for double-blind, placebo-controlled, randomized controlled trials of cannabinoids for chronic pain, with a primary outcome related to pain. The primary review outcome is adherence to the 2004 Consolidated Standards of Reporting Trials (CONSORT) Harms extension. Secondary outcomes included type, reporting method, frequency and severity of adverse events (AEs), trial participant withdrawals, and reasons for withdrawals. RESULTS: In total, 43 studies (4436 participants) were included. Type of cannabinoid (number of studies) included nabiximols (12), dronabinol (8), nabilone (7), oral cannabis extract preparations (5), smoked tetrahydrocannabinol (5), vaporized tetrahydrocannabinol (3), novel synthetic cannabinoids (2), sublingual cannabis extract preparations (1). The median CONSORT score was 7. On average, 3 to 4 recommendations of the CONSORT guidelines were not being met in trials. Seventeen trials did not provide their method of AE assessment, 14 trials did not report on serious AEs and, 7 trials provided no quantitative data about AEs. DISCUSSION: Better harms assessment and reporting are needed in chronic pain cannabinoid trials. Improvements may be achieved through: expanded education/knowledge translation increased research regulation by ethics boards, funding agencies and journals, and greater emphasis on safety assessment and reporting throughout research training.

Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Cannabinoids for Chronic Pain: Protocol for a Systematic Review.

BACKGROUND: Chronic pain affects a significant proportion of the population and presents a major challenge to clinicians and pain specialists. Despite the availability of pharmacologic treatment options such as opioids, many patients continue to experience persistent pain. Cannabinoids present an alternative option with some data on efficacy; however, to date, a systematic review of adverse events (AEs) assessment and reporting in randomized clinical trials (RCTs) involving cannabinoids has not been performed. As a result, it is unclear whether a clear profile of cannabinoid-associated AEs has been accurately detailed in the literature. As cannabinoids are likely to become readily available for patients in the near future, it is important to study how well AEs have been reported in trials so that the safety profile of cannabinoids can be better understood. OBJECTIVE: With a potentially enormous shift toward cannabinoid use for managing chronic pain and spasticity, this study aims to reveal the adequacy of AE reporting and cannabinoid-specific AEs in this setting. Spasticity is a major contributor to chronic pain in patients with multiple sclerosis (MS), with a comorbidity of 75%. Many cannabinoid studies have been performed in MS-related painful spasticity with relevant pain outcomes, and these studies will be included in this review for comprehensiveness. The primary outcome will be the quality of AE assessment and reporting by adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Secondary outcomes will include the type of AE, method of AE reporting, severity of AE, frequency of AEs, patient withdrawals, and reasons for withdrawals. METHODS: We will perform a systematic review by searching for primary reports of double-blind, randomized controlled trials of cannabinoids compared with placebo and any active comparator treatments for chronic pain, with a primary outcome directly related to pain (eg, pain intensity, pain relief, and pain-related interference). We will search the following databases: MEDLINE, Embase, Cochrane Library, and PsycINFO. RevMan software will be used for meta-analysis. RESULTS: The protocol has been registered on the International Prospective Register of Systematic Reviews (CRD42018100401). The project was funded in 2018 and screening has been completed. Data extraction is under way and the first results are expected to be submitted for publication in January or February 2019. CONCLUSIONS: This review will better elucidate the safety of cannabinoids for the treatment of chronic pain and spasticity through identifying gaps in the literature for AE reporting. Like in any new therapy, it is essential that accurate information surrounding the safety and efficacy of cannabinoids be clearly outlined and identified to balance the benefit and harm described for patients. TRIAL REGISTRATION: PROSPERO CRD42018100401; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=100401. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11637.

Magnesium for the Management of Chronic Noncancer Pain in Adults: Protocol for a Systematic Review.

BACKGROUND: Chronic pain is a highly prevalent and complex health problem that is associated with a severe symptom burden, as well as substantial economic and social impact. Many patients with chronic pain still suffer from unrelieved or undertreated pain due to the incomplete efficacy and dose-limiting adverse effects of current therapies. Long-term and high-dose opioid use has considerably increased in the past 20 years despite limited evidence supporting its effectiveness in several chronic pain conditions, and serious concerns have emerged regarding adverse effects and potential misuse. Until recently, the steady increase in opioid prescribing rates has been associated with rising opioid-related mortality and other serious problems, emphasizing the need for better nonopioid therapies. Emerging evidence supports the safe use of magnesium in controlling chronic pain, but its overall efficacy and safety is still unclear. OBJECTIVE: This paper aims to assess the efficacy and safety of magnesium compared with a placebo for the treatment of chronic noncancer pain. METHODS: We will conduct a detailed search on Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant randomized controlled trials. The reference lists of retrieved studies as well as Web-based trial registries will also be searched. We will include randomized double-blind trials comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain assessment. Two reviewers will independently evaluate studies for eligibility, extract data, and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity or pain relief. Dichotomous data will be used to calculate the risk ratio and number needed to treat or harm. The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: This protocol is grant-funded and has undergone a peer-review process through the Queen's University Department of Anesthesiology and Perioperative Medicine Vandewater Endowed Studentship. This project is also supported, in part, by the Chronic Pain Network of the Canadian Institutes of Health Research Strategy for Patient-Oriented Research. The electronic database search strategies are currently being developed and modified. The entire review is expected to be completed by January 1, 2019. CONCLUSIONS: The completion of this review is expected to identify available high-quality evidence describing the efficacy and safety of magnesium for the treatment of chronic noncancer pain. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11654.