Trial Reports Research Articles

Clinical Trial Reporting and Representation—An Opportunity to Advance Health Equity

Clinical Trial Reporting and Representation—An Opportunity to Advance Health Equity

Comparative risk of acute kidney injury among cancer patients treated with immune checkpoint inhibitors

With the development and introduction of immune checkpoint inhibitors (ICIs) in cancer patients, immune-related side effects have increasingly attracted attention. However, the risks of immune-related renal toxicity are poorly characterized. In this study, we performed a network meta-analysis (NMA) of ICI-related randomized clinical trials (RCTs) to elucidate the comparative risk of acute kidney injury (AKI) in cancer patients receiving different ICIs. We also sought to identify other factors potentially affecting the risk of AKI. PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021. Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data. We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups. We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis. Once significant heterogeneity was detected in a traditional direct meta-analysis, multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI. A total of 85 RCTs were included in this study. In the NMA for the risk of grade 1-5 and 3-5 AKI, ipilimumab showed a significantly higher risk than avelumab and durvalumab, whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (N1I3) showed a significantly higher risk than other groups. In terms of treatment ranking, durvalumab ± low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI, whereas N1I3, ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI. Compared with other cancers, renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI. The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy. In this NMA involving large-scale up-to-date ICI trials, we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI. Based on data from the ICI arms of these trials, we also revealed several potential risk factors for immune-related AKI, including tumor type and treatment paradigm.

El orden de los descreídos. Un juicio de corrupción a los burócratas

In this paper we study a very complete trial for embezzlement by appropriation in an intermediate city in Colombia. We review not only the sentence and the entire trial report, but also evidence provided by the Prosecutor's Office and its investigators. This case allows an exploration of the objective and subjective barriers of the bureaucrats and the custom in the face of corruption that allows us to analyze what was definitive for there to be a sanction. It is important to advance that what was definitive in this trial was not the discovery and what we normally understand as an absent civil society, here the crime was alerted and began to be corrected from the internal part of the mayor's office (the municipal government); the crime was committed by officials of the mayor's office and also accused, which makes the municipal government the victim, but also that the criminal enterprise arises from the entrails of the same institution. The trial offers a correlate of responsibility and astonishment in the formal voice of the mayor's office (the municipal government), which may be sincere and well-intentioned, and a self-regulation of an excess in an informal voice of a treasury secretary that ends up recorded by judicial investigators.

Key Characteristics and Development of Psychoceuticals: A Review

Psychoceuticals have brought benefits to the pharmacotherapeutic management of central nervous system (CNS) illnesses since the 19th century. However, these drugs have potential side effects or lack high response rates. This review covers twenty drugs' biochemical mechanisms, benefits, risks, and clinical trial reports. For this study, medications from seven psychoceutical organizations were reviewed and evaluated. Nineteen drugs were chosen from the organizations, and one was selected from the literature. The databases used for the search were Pubmed, Google Scholar, and NIH clinical trials. In addition, information from the organizations' websites and other sources, such as news reports, were also used. From the list of drugs, the most common targets were serotonergic, opioid, and N-methyl-D-aspartate (NMDA) receptors. These drugs have shown promise in psychiatric illnesses such as substance abuse, post-traumatic stress disorder (PTSD), anxiety, depression, and neurological conditions, such as Parkinson's disease, traumatic brain injury, and neuroinflammation. Some of these drugs, however, are still early in development, so their therapeutic significance cannot be determined. These twenty drugs have promising benefits, but their clinical usage and efficacy must still be explored.

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer

BackgroundHere we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC). Materials and MethodsRetrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC. ResultsUpdated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months). ConclusionAdding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases

It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. ClinicalTrials.gov Identifier: NCT02614794.

Reporting of and explanations for under-recruitment and over-recruitment in pragmatic trials: a secondary analysis of a database of primary trial reports published from 2014 to 2019

ObjectivesTo describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated with under-recruitment and over-recruitment.Study design and settingSecondary analysis of...

Disparities in the Inclusion of Racial and Ethnic Minority Groups and Older Adults in Prostate Cancer Clinical Trials

Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity. To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials. MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively. All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses. This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model. Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades. Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002). The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

This is the third update of the review first published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. To determine if lower blood pressure targets (systolic/diastolic 135/85 mmHg or less) are associated with reduction in mortality and morbidity compared with standard blood pressure targets (140 mmHg to 160mmHg/90 mmHg to 100 mmHg or less) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). For this updated review, we used standard, extensive Cochrane search methods. The latest search date was January 2022. We applied no language restrictions. We included randomized controlled trials (RCTs) with more than 50 participants per group that provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (135/85 mmHg or less) compared with standard targets for blood pressure (140 mmHg to 160 mmHg/90 mmHg to 100 mmHg or less). Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. We used standard Cochrane methods. We used GRADE to assess the certainty of the evidence. We included seven RCTs that involved 9595 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). Six of seven RCTs provided individual participant data. None of the included studies was blinded to participants or clinicians because of the need to titrate antihypertensive drugs to reach a specific blood pressure goal. However, an independent committee blinded to group allocation assessed clinical events in all trials. Hence, we assessed all trials at high risk of performance bias and low risk of detection bias. We also considered other issues, such as early termination of studies and subgroups of participants not predefined, to downgrade the certainty of the evidence. We found there is probably little to no difference in total mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.91 to 1.23; 7 studies, 9595 participants; moderate-certainty evidence) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; 6 studies, 9484 participants; moderate-certainty evidence). Similarly, we found there may be little to no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; 7 studies, 9595 participants; low-certainty evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure (CHF)) (RR 0.89, 95% CI 0.80 to 1.00; 7 studies, 9595 participants; low-certainty evidence). The evidence was very uncertain about withdrawals due to adverse effects. However, studies suggest more participants may withdraw due to adverse effects in the lower target group (RR 8.16, 95% CI 2.06 to 32.28; 3 studies, 801 participants; very low-certainty evidence). Systolic and diastolic blood pressure readings were lower in the lower target group (systolic: mean difference (MD) -8.77 mmHg, 95% CI -12.82 to -4.73; 7 studies, 8657 participants; diastolic: MD -4.50 mmHg, 95% CI -6.35 to -2.65; 6 studies, 8546 participants). More drugs were needed in the lower target group (MD 0.56, 95% CI 0.16 to 0.96; 5 studies, 7910 participants), but blood pressure targets at one year were achieved more frequently in the standard target group (RR 1.20, 95% CI 1.17 to 1.23; 7 studies, 8699 participants). We found there is probably little to no difference in total mortality and cardiovascular mortality between people with hypertension and cardiovascular disease treated to a lower compared to a standard blood pressure target. There may also be little to no difference in serious adverse events or total cardiovascular events. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on withdrawals due to adverse effects, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (135/85 mmHg or less) in people with hypertension and established cardiovascular disease. Several trials are still ongoing, which may provide an important input to this topic in the near future.

Effects of Eligibility Criteria on Patient Selection and Treatment Implications from 10 Multidomain Dementia Prevention Trials: A Population-Based Study

Introduction: Dementia prevention trials have so far shown little benefit of multidomain interventions against cognitive decline. Recruitment strategies in these trials often centre around dementia risk or cardiovascular risk profile, but it is uncertain whether this leads to inclusion of individuals who may benefit most from the intervention. We determined the effects of eligibility criteria on the recruitment of potential trial participants in the general population. Methods: In a systematic search until January 1, 2022, we identified all published and ongoing large (≥500 participants), phase-3 multidomain trials for the prevention of cognitive decline or dementia. We applied trial eligibility criteria to 5,381 participants of the population-based Rotterdam Study (mean age: 72 years, 58% women), to compare participant characteristics, predicted risk of cardiovascular disease, and dementia risk, between trial eligible and ineligible persons. Results: We identified 10 trials, of which 5 had been published (DR’s EXTRA, FINGER, preDIVA, MAPT, and HATICE) and 5 are ongoing (US-POINTER, MIND-CHINA, MYB, AgeWell.de, and J-Mint). Among all Rotterdam Study participants, eligibility across published trials ranged from 48% for MAPT to 87% for preDIVA, in line with original trial reports. Variability in eligibility was wider for ongoing trials, from 1% for US-POINTER to over 94% for MYB trial. Over 70% of trial eligible individuals are recommended preventive intervention in routine care based on their cardiovascular risk, similar for lipid-lowering (71%) and blood pressure-lowering treatment (73%). Ten-year risks of dementia were similar for eligible compared to ineligible individuals (12 vs. 11%). Conclusion: Multidomain dementia prevention trials fail to preferentially include those at the highest risk of dementia and mostly include individuals who qualify for interventions already on the basis of cardiovascular prevention guidelines. These findings call for better targeted enrolment of individuals for whom trial results can improve clinical decision-making.

Cross-cultural adaptation of the spa therapy checklist (SPAC) in Greek.

The importance of spa therapy is growing worldwide, with care practitioners paying more attention to how this intervention can alleviate various health issues. Multiple studies have been performed and reported on the efficiency of balneotherapy, creating a need to understand the quality of the information in the existing studies and how they can inform practitioners in promoting evidence-based practice. The SPAC assessment tool describes and assesses the quality of reports of interventional trials in balneotherapy. The present study had two goals. The first goal was the translation and cross-cultural adaptation of the SPAC assessment tool in Greek language following an internationally accepted methodology. The second goal was to assess the reliability of the tool employing test-retest and interrater reliability studies in a sample of 15 relative RCT papers and to assess the criterion validity of the Greek version by comparing its results with the original English version when assessing the same 15 papers. The results revealed that the SPAC checklist was translated and adapted in Greek without difficulties between the translators. Reliability of the SPAC was found excellent in both test-retest (ICC = .98) and interrater (ICC = .95) indexes. The criterion validity assessment for Greek version of SPAC checklist was also almost perfect (ICC = .98). In the present study, the Greek version of the SPAC checklist was found to be a comprehensible, reliable, and valid tool to assess the quality of interventional trial reports on the efficacy of spa therapy for cure and health enhancement.

Long-Term Outcomes of High-Risk Stage 1/2 Classic Hodgkin Lymphoma Managed with an Advanced Stage Treatment Approach

Background: The definition of advanced stage classic Hodgkin lymphoma (cHL) may vary, with bulky stage 2A (> 10cm or > 33% of transthoracic diameter otherwise described as 'large mediastinal adenopathy’ (LMA)) and/or stage 2B with risk factors, included in some studies and clinical guidelines. The ECHELON 1 study recently demonstrated improved overall survival (OS) using AVD-brentuximab vedotin (BV) compared with ABVD in stage 3/4 cHL (Ansell et al. NEJM 2022). Similarly, the pediatric combination BV-AVE-PC demonstrated improved event free survival (EFS) over ABVE-PC in a phase 3 trial of 'high risk patients (pts)’ age 2-21 years (y) (AHOD1331), a definition that included stage 2B bulky (LMA) pts, with a significant benefit shown in this subgroup (HR 0.09 (0.01-0.69)) (Castellino et al. ASCO 2022). Thus, re-evaluation of 'advanced stage’ definitions is warranted, especially in the adult population. Herein, we evaluated the long-term outcomes of pts with stages 1/2 bulky and 2B, a group that has been uniformly included in our advanced stage management approach. Methods: The BC Cancer Lymphoid Cancer Database was screened to identify all pts 16-70 y with 1/2A bulky (≥ 10 cm) and 2B (± bulky) disease treated with ABVD chemotherapy. Since 2005, advanced stage cHL pts in BC have been managed with 6 cycles of ABVD and PET-guided consolidative RT, whereby those with an EOT PET positive (pos) scan received RT. Following report of the RATHL trial in 2015, those pts with an interim PET2 negative (neg) scan had bleomycin omitted from the latter 4 cycles. For the current study, PET scans assessed by the IHP criteria were re-reviewed to assign a Deauville (D) score (PET-neg=D1-3, DX; PET-pos=D4-5). Freedom from treatment failure (FFTF) was measured from diagnosis to relapse/ progression of HL, or death due to HL or treatment toxicity. Results: From 2005-2020, 295 pts (148 M, 147 F) were identified. By stage: 1A bulky n=2, 2A bulky n=71 (henceforth called 'bulky only’ n=73); 2B n=133; 1B bulky n=3, 2B bulky n=86 (henceforth called stage 1/2B bulky n=89). Median age was 30 y (range 17- 69 y), median mass size 10 cm overall and 11 cm in bulky cases (range 10-20 cm). Of those with bulky disease (n=162), 147 (91%) had a bulky mediastinal mass. Using the reverse Kaplan-Meier method, median follow-up was 9.3 y (0.9 -17.3 y). The 5 y FFTF and OS for all pts were 84% and 94%. By stage groups, 5 y FFTF estimates were: 90% for bulky only, 82% in 2B, and 81% in 1/2B bulky pts (p=0.29) (Figure 1a), while corresponding 5 y OS estimates were 95%, 93%, and 94%, respectively (p=0.52) (Figure 1b). An EOT PET was performed in 250 pts and an additional 11 patients were included who only had a PET2-neg scan which was not repeated (total PET scan n= 261). The main reason for not having a PET scan was absence of residual mass on CT scan (21/34); 2 patients had progressive disease (PD) while on treatment (both stage 2B). In total 208/261(80%) had a PET-neg scan (2 pts received RT), and 53/261 (20%) had an EOT PET-pos scan of which, 32 (63%) received RT (mediastinal RT, 30/32). Stage 1/2B bulky cases were more likely to have a PET-pos scan (1/2B 32% vs 2B 18% vs bulky only 10%, p=0.002), and as a result, were more likely to receive RT (1/2B bulky 23% vs 2B 9% vs bulky only 6%, p=0.003). Overall, the 5 y FFTF was superior in PET-neg cases (93% vs 49%, p<0.001 (and 62.5% in PET-pos pts who received RT)), and 5 y OS was 96% vs 88% (p=0.17). For the 259 cases in which the D score was available, 5 y FFTF was similar across PET-neg D categories: DX 95%; D1 92%; D2 94%; D3 93%. For all DX-3, 5y FFTF was 94%, and superior to both D4 70% and D5 17% (p<0.001). Corresponding 5 y OS estimates for DX-D3, D4, and D5, were 96%, 95%, and 77%, respectively, with only the latter demonstrating an inferior prognosis (p=0.005). An EOT D5 PET scan was more common in pts with B symptoms: stage 1/2B bulky cases 12/83, 14.5%; 2B 10/106, 9%; bulky only 2/70, 3% (p=0.048). Conclusion: Applying an advanced stage management approach yields excellent outcomes, particularly in the 80% of patients with a PET-neg scan. Further, use of a PET-scan limited RT use to only 6% of pts with stage 1/2A bulky disease. However, those with stage 1/2B bulky disease have a higher likelihood of an EOT PET-pos scan and subsequent RT. Further, an EOT PET D5 score was more common in those with B symptoms overall, especially when coupled with bulky disease. This data provides further rationale for consideration of BV with upfront therapy in other advanced stage subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

INNV-16. SPINAL POST-TREATMENT SURVEILLANCE IN MEDULLOBLASTOMA – A SYSTEMATIC REVIEW OF THE LITERATURE AND CLINICAL TRIALS

Abstract BACKGROUND Monitoring for dissemination in medulloblastoma involves spinal MRIs (sMRIs) and lumbar punctures (LPs). The frequency and duration of these studies vary depending on risk of dissemination; general practice varies between and within institutions. Our goal is to review the current practice in post-treatment monitoring via examination of published data, clinical trial standards, and expert practice. METHODS We reviewed the available literature and accessible clinical trial protocols. Using PRISMA guidelines, we conducted searches of Ovid MEDLINE, Embase, and PubMed to identify studies which detailed relapse rates and patterns, and recommended practice for patients with medulloblastoma aged 3-21 years. Eligible studies from 1990 to present were included. RESULTS Thirteen multi-institutional clinical trials from North America and Europe were analyzed for frequency of post-therapy surveillance with LPs/sMRIs. Several studies (n=8) recommend LPs/sMRIs every 3-6 months in standard risk and every 3 months in high risk disease for two years when initially completing therapy, and then often diverge in frequency after 2 years. Some studies (n=5) did not include post-treatment recommendations. Cumulative data on relapse from available clinical trial reports and single institution studies (n=673 relapses) demonstrated local failure rate of 18.4%, distant failure of 49.1%, and combined distant and local failure of 32.5%. Spine-only relapses were reported to occur in approximately 13-20%, with one small study reporting spine-only relapse rate of 37.5%. DISCUSSION Patterns of recurrence in medulloblastoma have shifted over time as therapeutic approaches have evolved, including more spinal-only recurrences. Standardized guidance regarding surveillance could have significant impact on clinical detection and streamline management to minimize unnecessary examinations. Early detection of recurrent disease could optimize treatment options for providers and families, whether focusing on curative approaches or quality of life.

Crime in the nineteenth-century Irish home

ABSTRACT This article interrogates the Irish home as the scene of a crime. Using a sample of nineteenth-century textual records, namely coroners’ inquest documents, police and witness statements, judges’ reports of trials, and newspapers, it showcases how the home could become a focus of attention in court. Police (and sometimes the general public) infiltrated these domestic spaces in their search for clues; they often interfered with domestic materiality, or confiscated objects or fragments therefrom. In court, maps, plans and models illustrated the physical space and layout of the home for those who had not crossed the threshold. Witness testimonies accounting for the crime inadvertently reveal how the homes looked, some of their contents, and the nature of relationships between occupants and neighbours. These Irish homes were typically ordinary domestic spaces but as this article shows, the crime brought the intimate space to a more public arena. It also demonstrates how the home could both protect or expose a suspect.

2 Oral - Randomised controlled trial of breast conserving therapy: 30 year analysis of the Scottish breast conservation trial

Background: The standard of care for most early breast cancer patients is breast conserving surgery (BCS), adjuvant radiotherapy (RT) and systemic therapy. Several trials have confirmed that RT reduces local recurrence, but there are few reports of trials with longterm follow up assessing the impact of omission of RT on overall survival. The Scottish Conservation trial of BCS & systemic therapy appropriate to ER status ± postoperative whole breast RT (Forrest et al. Lancet 1996;348:708–13) showed ipsilateral breast tumour recurrence (IBTR) of 24.5% in the no RT arm and 5.8% in the RT arm but no difference in overall survival at 6 years after randomisation.

Early rehabilitation of cancer patients after endoprosthetic reconstruction following resection of the lower extremity long bones

Aim of the study: to conduct a systematic analysis of the data available in the modern literature, prognostic factors, and modern methods of rehabilitation of cancer patients after endoprosthetic reconstruction following resection of the lower extremity long bones. Material and methods. We assessed reports of clinical trials published over the past 10 years, which evaluated prognostic factors, rehabilitation programs for cancer patients who underwent endoprosthetic reconstruction following resection of the lower extremity long bones, depending on the location and size of the implant and the age of the patient. The review also evaluated various prognostic factors that affected functional recovery following resection of the lower extremity long bones. Results. Findings that helped in choosing the best option for surgical treatment, thus providing the best quality of life in the postoperative period, were published. Conclusion. Further studies are needed to optimize rehabilitation techniques and develop new algorithms for the treatment of cancer patients who underwent endoprosthetic reconstruction following resection of the lower extremity long bones.

Ensuring Superior Reporting of Non-Inferiority Radiotherapy Clinical Trials: A Systematic Review

<h3>Purpose/Objective(s)</h3> Non-inferiority clinical trials are used to investigate whether a new treatment is not worse than a control by an acceptable amount. These new treatments can be more convenient, cost-effective, or tolerable than the standard of care. Although the frequency of this trial design is increasing, the consistency of reporting and interpretation of these trials can vary. The aim of this systematic review was to assess the methodologic quality of non-inferiority radiotherapy clinical trials. <h3>Materials/Methods</h3> A literature search of PubMed, EMBASE and Cochrane databases of randomized controlled radiotherapy trials with non-inferiority hypotheses published in English between January 2000 and July 2021 was performed by an information scientist. Exclusion criteria included study protocols, and follow-up or interim analyses. Records were screened and full texts were reviewed by two authors with discrepancies settled by a third reviewer or by consensus. Descriptive statistics pertaining to study size, primary cancer type, type of comparison, endpoint, and statistical measures were performed. This review was prospectively registered on PROSPERO: CRD42021270644. <h3>Results</h3> Of 260 records identified on initial search, 44 (17%) trials were included after full-text review. The mean number of participants was 876 (IQR: 216.25–912.5). All were published after 2004, and open label. Four (9%) trials were funded by industry. The most common primary cancer type was breast (n=10, 23%). Most studies (n=37, 84%) had 2 treatment arms. The most common types of interventions included altered radiation fractionation (n=13, 30%) and changes to systemic therapy agents (n=10, 23%). Six (14%) studies compared radiation to another treatment modality (e.g., surgery, radiofrequency ablation), and 3 (7%) studies examined the omission of radiation. The most common primary endpoints were progression-free survival (n=12, 27%) and local/regional control (n=12, 27%). Forty (91%) studies reported the non-inferiority margin, and only 5 (11%) studies provided a statistical rationale for the margin. The median non-inferiority margin was 10% (IQR: 5–10%). Sample size calculation was reported in 42 (95%) studies, and 42 (95%) studies reported confidence intervals of the primary endpoint. Both intention-to-treat and per protocol analyses were reported in the majority (52%) of studies. In 23 (52%) trials, a non-inferiority claim of the primary endpoint was reached. <h3>Conclusion</h3> Clinical trials with a non-inferiority design are relatively uncommon in radiation oncology, and have been used for variable types of comparisons and primary endpoints. Standardization of required data to report and statistical methodology would be helpful to ensure proper interpretation of trial results.

Ginger Constituents and its Effects on Gastrointestinal malignancies: A Review of clinical trials

Abstract The gastrointestinal tract (GI tract) is the tract of the digestive system that contains all the major organs of the digestive system. Disorder in any part of the GI tract results in various disease forms such as malignancies. The occurrence of GI cancer is very high in developed countries including Europe. A wide variety of natural products containing anticancer properties showed significant effects. Ginger, the rhizome of Zingiber officinale, is among one of the natural herbal remedies widely used for its spice and medicinal properties. It is fair sources of vitamins like, β-carotene, vitamin C and minerals. Recently ginger has shown significant attention in clinical studies due to its anti-cancer effects that possesses promising potential for inhibiting the proliferation of multiple cancer cells. The aim of this review is to provide a summarized report of clinical trials on ginger constituents and its effects on gastrointestinal malignancies. A systematic search was conducted by two independent authors on the databases of Scopus, Clinical Trials, PubMed and Science with the search term of the key words. This review article supported that ginger is an important plant with several constituents and gastrointestinal medicinal effects. Ginger constituents suppress the growth and induce apoptosis of variety of cancer types including colon, gastric, pancreatic and other GI cancers. It is mainly the 6-gingerol and 6-shogaol, of the major compounds in ginger rhizomes, among hundreds of molecules. It is reported that antioxidant and anti-inflammatory properties of ginger support its preventive role against the gastrointestinal malignancies. Key messages • This review article provided evidences supporting the effects of ginger on gastrointestinal malignancies and demonstrates the importance of future studies. • Therefore, more extensive and well-controlled clinical trial studies of ginger are required to demonstrate its effect on gastrointestinal malignancies.

Evaluating the online impact of reporting guidelines for randomised trial reports and protocols: a cross-sectional web-based data analysis of CONSORT and SPIRIT initiatives

Reporting guidelines are tools to help improve the transparency, completeness, and clarity of published articles in health research. Specifically, the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statements provide evidence-based guidance on what to include in randomised trial articles and protocols to guarantee the efficacy of interventions. These guidelines are subsequently described and discussed in journal articles and used to produce checklists. Determining the online impact (i.e., number and type of links received) of these articles can provide insights into the dissemination of reporting guidelines in broader environments (web-at-large) than simply that of the scientific publications that cite them. To address the technical limitations of link analysis, here the Debug-Validate-Access-Find (DVAF) method is designed and implemented to measure different facets of the guidelines’ online impact. A total of 65 articles related to 38 reporting guidelines are taken as a baseline, providing 240,128 URL citations, which are then refined, analysed, and categorised using the DVAF method. A total of 15,582 links to journal articles related to the CONSORT and SPIRIT initiatives were identified. CONSORT 2010 and SPIRIT 2013 were the reporting guidelines that received most links (URL citations) from other online objects (5328 and 2190, respectively). Overall, the online impact obtained is scattered (URL citations are received by different article URL IDs, mainly from link-based DOIs), narrow (limited number of linking domain names, half of articles are linked from fewer than 29 domain names), concentrated (links come from just a few academic publishers, around 60% from publishers), non-reputed (84% of links come from dubious websites and fake domain names) and highly decayed (89% of linking domain names were not accessible at the time of the analysis). In light of these results, it is concluded that the online impact of these guidelines could be improved, and a set of recommendations are proposed to this end.

Long-term follow-up of chronic central serous chorioretinopathy patients after primary treatment of oral eplerenone or half-dose photodynamic therapy and crossover treatment: SPECTRA trial report No. 3

PurposeComparing anatomic and functional efficacy and safety of primary treatment with either half-dose photodynamic therapy (PDT) or oral eplerenone, or crossover treatment in chronic central serous chorioretinopathy patients.MethodsAfter the SPECTRA trial baseline visit, patients were randomized to either half-dose PDT or eplerenone and received crossover treatment if persistent subretinal fluid (SRF) on optical coherence tomography (OCT) was present at first follow-up (at 3 months). Presence of SRF and best-corrected visual acuity (BCVA) was evaluated at 12 months.ResultsOut of the 90 patients evaluated at 12 months, complete SRF resolution was present on OCT in 43/48 (89.6%) of patients who were primarily randomized to half-dose PDT and in 37/42 (88.1%) who were primarily randomized to eplerenone. Out of the 42 patients that were primarily randomized to eplerenone, 35 received crossover treatment with half-dose PDT. The BCVA improved significantly more at 12 months in patients who had received primary half-dose PDT as compared to the primary eplerenone group (p = 0.030).ConclusionsTwelve months after baseline visit, most patients treated with half-dose PDT (either primary or crossover treatment) still had complete SRF resolution. The long-term BCVA in patients who receive primary half-dose PDT is better than in patients in whom PDT is delayed due to initial eplerenone treatment with persistent SRF.