Group Trial Research Articles

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Durvalumab plus tremelimumab or best supportive care. Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl. The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C). The active and placebo vaccines were administered by intramuscular electroporation. There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4 + and/or CD8 + T cells in arm A compared with arm C ( P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) ( P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements. A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55 Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial

The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

A Pro-Inflammatory Gene Signature Characterizes a Better Risk Aged AML Patient Group in ECOG-ACRIN Cancer Research Group's Clinical Trial E3999

Background: Acute myeloid leukemia in patients over the age of 60 (aAML) is associated with poor prognosis. aAML patients are the majority diagnosed but are underrepresented in large molecular studies. We have identified two clinical subgroups of aAML patients with distinct survival outcomes (low-risk and high-risk) in ECOG-ACRIN Cancer Research Group's clinical trial E3999 (NCT00046930). We hypothesize that these two groups are characterized by distinct biological mechanisms that contribute to leukemogenesis. We also hypothesize that the low-risk group harbor molecular and phenotypic signatures characteristic of known better-risk AMLs. Methods: Diagnostic specimens were obtained from patients enrolled in NCT00046930. Disease enriched cells were isolated by negative selection of lymphocytes (magnetic beads). Flow cytometry was used to characterize the blast population. Bulk RNA-sequencing was performed on 220 blast enriched samples and 10 age matched normal controls (CD34+ bone marrow cells). Transcriptional differences were determined using DESeq2. Differentially expressed genes (DEGs) were identified as those with an absolute log2 fold change greater than 1 and q less than 0.05. Gene set enrichment analysis (GSEA) was performed against the MSigDB databases. Upstream regulators associated with gene expression changes were identified using Ingenuity Pathway Analysis (IPA). DESeq2 was used to identify genes that were differentially associated with overall survival times between the risk groups. Enrichment for transcription factor gene targets was calculated using EnrichR based on the CHEA Transcription Factor Target Dataset. Cytokines were quantified in a subset of patient serum samples using a Luminex assay. Results: We identified 2314 DEGs between the low-risk and high-risk aAMLs with high-risk as the baseline. The upregulated genes in the low-risk aAMLs were positively enriched for gene signatures derived from: 1. Favorable risk AML ( NPM1 mutated), 2. M4 and M5 AML patients, 3. Differentiated hematopoietic cells and 4. Inflammatory response pathways. On the contrary, upregulated genes in the high-risk aAMLs were enriched for gene signatures identified in hematopoietic and leukemic stem cells and known poor-risk AMLs (for example: EVI1 fusion). Accordingly, immunophenotypic data from flow cytometry results gated on the blast populations validated differences in the surface expression of hematopoietic cell markers between the two groups. Next, we sought to determine upstream regulators associated with the DEGs using IPA. We identified 107 potential upstream regulators that associated with the changes in gene expression observed between the low- and high-risk groups (87 activated and 20 inhibited). The results suggested that several pro-inflammatory cytokines (ex. tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ)) were predicted activators in the low-risk aAML group. Accordingly, we detected significantly higher levels of TNFα and IFNγ in the serum levels of a subset of low-risk aAML patients. Finally, we assessed for genes whose expression significantly associated with overall survival. Interestingly, in agreement with a previously proposed inflammation score (iScore), we identified higher iScore associated with the high-risk group. Of note, the upstream regulators identified do not overlap with those contributing to the calculation of iScore. Additionally, longer overall survival times were associated with higher levels of expression of genes associated with heme metabolism and erythroblast differentiation in the low-risk aAML patient group. Conclusions: Our results suggest that the low-risk aAML patients were characterized by a more mature hematopoietic cell gene expression signature and cell surface markers as well as a pro-inflammatory state. Our study supports the possibility that pro-inflammatory cytokines and/or signaling could mediate AML cell survival in the low-risk aAML patient group. The high-risk aAML patients were characterized by a more primitive hematopoietic and leukemic stem cell gene expression signature. Collectively, we propose that differences in the underlying molecular and/or immune-based mechanisms could contribute to leukemogenesis in the two risk groups. These findings suggest that distinct therapeutic approaches may need to be considered to improve clinical outcomes in the two aAML risk groups.

Canadian Cancer Trials Group SC.26 - Emotion and Symptom-Focused Engagement (EASE): A Multi-Site Randomized Controlled Trial of an Intervention for Individuals with Acute Leukemia

Background: Despite the rapid onset and life-threatening nature of acute leukemia (AL) and its treatment, there is a lack of research on its psychological and physical consequences and even less on interventions to alleviate them [Bryant 2016]. A longitudinal study of individuals with newly diagnosed or recently relapsed AL showed substantial physical and psychological distress in this population [Rodin 2013; Zimmermann 2013]. Based on these findings, an integrated psychosocial and early palliative care intervention, Emotion And Symptom-focused Engagement (EASE), was developed for patients with AL [Rodin 2015]. A phase II randomized pilot trial of EASE vs. usual care demonstrated feasibility and showed promising positive effects on traumatic stress symptoms (primary outcome) and other secondary outcomes, including depressive symptoms, number and severity of physical symptoms and related distress, pain, quality of life (QOL), satisfaction with care, and attachment security [Rodin 2020]. Study design and methods:The Canadian Cancer Trials Group SC.26 (NCT04224974) randomized phase III trial is underway to test the effectiveness and cost-effectiveness of the EASE intervention in AL. EASE is a novel manualized intervention that combines psychological support with routine symptom screening plus triggered referral to palliative care for symptom control. The goal is to reduce psychological distress and symptom burden, and enhance QOL and satisfaction with care in individuals with newly diagnosed AL undergoing induction therapy. Participants are randomized in a 1:1 unblinded ratio to usual care (UC) or UC and EASE (EASE). EASE consists of two components: the psychotherapy intervention (EASE-psy) and triggered early palliative care (EASE-phys). EASE-psy involves tailored supportive psychotherapy delivered by trained therapists over the initial 8 weeks following hospital admission for treatment of AL. It combines elements of relational support, affect regulation, and trauma-informed cognitive behavioural therapy. All patients randomized to EASE receive weekly symptom screening during the initial inpatient treatment period with triggered referral to early palliative care (EASE-phys). Subjects are stratified by centre, age (≤60 vs. >60) and type of acute leukemia (acute myeloid leukemia vs. acute lymphoblastic leukemia). For patients diagnosed with a mixed phenotype acute leukemia, the dominant sub-type is used for stratification purposes. Patients are ≥18 years, newly diagnosed and recruited within 2 weeks of hospital admission, and receiving or expected to receive induction therapy with curative intent. Current exclusion criteria include major communication difficulties at the time of recruitment; receipt of on-site psychological/psychiatric counselling or palliative care services at the time of recruitment; a diagnosis of acute promyelocytic leukemia or acute leukemia of ambiguous lineage. The two primary outcomes reflect the dual nature of the physical and psychosocial components of the EASE intervention: Mean severity of traumatic stress symptoms at 4 weeks using the 30-item Stanford Acute Stress Reaction Questionnaire (SASRQ) [Cardeña 1996] updated to be DSM-5-concordant [American Psychiatric Association 2013] and mean physical symptom severity at 4 weeks using the Memorial Symptom Assessment Scale (MSAS) [Portenoy 1994]. Hypotheses will be tested using multilevel modeling with maximum likelihood estimation, conducted as intention-to-treat analyses. Economic analysis will be conducted to measure the cost-effectiveness of the EASE intervention. Utilities will be derived from the EQ-5D-5L [Herdman 2011] and FACIT-Sp [Webster 2003] questionnaires. The planned sample size of this study is 266. Since January 2022, 53 patients at 4 Canadian centres have undergone randomization. Conclusion: The information obtained from this study will inform clinicians and decision makers of the value of implementing the EASE intervention in adults with AL.

Tuberculosis incidence in foreign-born people residing in European countries in 2020.

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

The oesophageal adenocarcinoma tumour immune microenvironment dictates outcomes with different modalities of neoadjuvant therapy - results from the AGITG DOCTOR trial and the cancer evolution biobank.

A plateau in treatment effect can be seen for the current 'one-size-fits-all' approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multi-modality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8+ cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8+ cells, and low infiltration with CD163+ cells was associated with improved survival. High tumour core CD8+ T cell infiltration, and a low tumour margin infiltration of CD163+ cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8+, or high CD163+ cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163+ cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease.

An Update of Stereotactic Body Radiotherapy (SBRT) for the Palliation of Unirradiated Mucosal Head and Neck Squamous Cell Carcinoma (SCC)

We report the treatment outcomes of palliative Stereotactic Body Radiation Therapy (SBRT) in patients with primary mucosal head and neck cancer (HNC) who were not eligible to receive conventional radiation therapy (RT). This is a retrospective study that reviewed the medical records of patients with primary SCC mucosal HNC who were treated with SBRT between 2011 and 2022. Patients with other histologies, skin cancer, parotid tumors, or recurrent previously irradiated tumors were excluded from the study. A total of 74 patients and 77 tumors were treated with SBRT in this cohort. The median age in the study was 81 (52-97) years and the median follow-up was 7.2 months. The most common site of HNC was the oral cavity (62%), followed by the oropharynx (18%), hypopharynx (8%), larynx (5%), nasal cavity/sinonasal cancer (3%), and unknown primary (1%). T3-4 lesions were found in most patients (76%). SBRT doses ranged from 35-50 Gy in 5 fractions, and the most common prescription dose was ≥45 Gy in 5 fractions (60%) for the GTV prescription. An elective nodal volume of 25 Gy in 5 fractions was infrequently (17%) used. Most patients (81%) who were treated twice a week completed in ≤14 days. The predominant symptoms at presentation were: pain (41%), mass effect (39%), dysphagia/odynophagia (14%), headache/nasal obstruction (1.4%), bleeding (1.4%), stridor (1.4%), asymptomatic (1.4%), and unknown (1.4%). 84% of patients had symptomatic response to treatment with 24% of them having complete symptom response. Cumulative incidence of local failure (LF) was 6.7% and at 6 months and 17.9% at 12 months, respectively. Cumulative incidence of distant metastasis was 7.3% and 10.5% at 6 and 12 months. Cancer was the most common cause of death in 29 patients (51%). The median overall survival (OS) was 8 months with 6 and 12-month OS rates of 67% and 36%, respectively. 39% of patients developed acute G3 toxicity, including 30% with G3 mucositis, 5% with G3 dysphagia, and 4% with G3 dermatitis. A crude rate of late G ≥3 toxicity was observed in 11% of patients including (5%, n = 4) with osteoradionecrosis, and a single case of dysphagia, soft tissue necrosis, supraglottic ulceration, and mucosal necrosis. This study highlights the feasibility of SBRT as a treatment option for primary mucosal head and neck cancer patients who are not eligible for conventional radiation therapy. The results indicate that SBRT was effective in achieving local control and symptom relief, but larger prospective studies are needed to confirm the findings. The Canadian Cancer Trials Group has endorsed HN-13, a randomized control trial comparing HN SBRT to palliative RT.

TROG 15.03/ANZUP International Multicenter Phase II Trial of Focal Ablative STereotactic RAdiotherapy for Cancers of the Kidney (FASTRACK II)

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive alternative for primary renal cell cancer (RCC) in patients unsuitable for surgery. The objective of the FASTRACK II clinical trial was to investigate the efficacy of SBRT for primary RCC. This non-randomized, intergroup multi-institutional phase II study was activated in 7 Australian centers and 1 Dutch center, through the Trans Tasman Radiation Oncology Group (TROG) and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Eligible patients had biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, ECOG performance ≤2 and were medically inoperable, high risk or declined surgery. For tumors ≤4 cm a single fraction of 26 Gy was prescribed, for tumors > 4 cm, 42 Gy in three fractions was prescribed. The primary outcome of the study was to estimate the efficacy of SBRT for primary RCC, defined as local control based on RECIST criteria. The study was powered assuming that 1-year local control would be 90%, with the null hypothesis of ≤80% considered undesirable and not worthy of proceeding to a future randomized controlled trial. Between July 2016 and February 2020, 70 patients were enrolled with a median follow-up of 42 months. Median age was 77 years. Forty-nine patients were male (70%), median BMI was 32 and median Charlson comorbidity score was 7. The median [IQR] RENAL complexity score was 8 [7-10]. Biopsy confirmation was 100%. Twenty-three patients (33%) had T1a disease. The median (interquartile range [IQR]) tumor size was 4.6cm [3.7-5.5]; it was 3.3cm [3.0-3.6] in those receiving single fraction (n = 23), and 5.3cm [4.6-6.0] in those receiving 3-fraction SBRT (n = 47). During real-time pre-treatment quality assurance review, 10 cases (14.3%) required resubmission for protocol deviation, 2119 variables were assessed at final review, and final protocol compliance was 99.3%. Seven (10%) patients experienced grade 3 treatment-related adverse events, with no grade 4 or 5 events observed. Eleven (16%) patients reported no adverse events. Local control was 100% throughout the lifetime of the trial (p<0.001). Cancer-specific survival was also 100% throughout the lifetime of the trial. Freedom from distant failure (95% CIs) at 1 and 3 years was 99% (90-100%). Overall survival (95% CIs) at 1 and 3 years was 99% (90-100%) and 82% (70-89%), respectively. Baseline mean eGFR (95% CI) was 61.1 mLs/min (56.6; 65.6) and reduced by -10.8 mLs/min (-13.0; -8.6) by 1-year, by -14.6 mLs/min (-17.0; -12.2) by 2-years and plateaued thereafter. In the first multicenter prospective trial of a non-surgical primary RCC cohort, enrolling mostly T1b+ disease, SBRT was an effective treatment strategy with no observed local failures. We observed an acceptable side effect profile and renal function after SBRT. These outcomes support the design of a future randomized clinical trial of SBRT versus surgery for primary RCC. The trial was registered with ID: NCT02613819.

Muscle Blood Flow and Vasodilation are Blunted at the Onset of Exercise Following an Acute Bout of Ischemia-Reperfusion.

Ischemia-reperfusion injury (I/R) can inhibit endothelial function and impair nitric oxide bioavailability. We tested the hypothesis that I/R also blunts the rapid and steady-state hyperemic and vasodilatory response to handgrip exercise. Ten subjects (8M/2F; 24±4yr) performed handgrip exercises before and after I/R (20 min of ischemia/20 min of reperfusion) and time control (40 min supine rest) trials. Forearm blood flow (FBF) and vascular conductance (FVC) were assessed with Doppler ultrasound during single forearm contractions and 3 min of rhythmic handgrip exercise. Venous blood samples were drawn at rest and during exercise to assess plasma [nitrite]. Peak ΔFBF (from baseline) and ΔFVC following single contractions were attenuated following I/R (134±48 vs. 103±42 ml·min-1; 160±55 vs. 118±48 ml·min-1·100 mmHg-1, P<0.05 for both) but not following time control (115±63 vs. 124±57 ml·min-1; 150±80 vs. 148±64 ml·min-1·100 mmHg-1, P=0.16 and P=0.95, respectively). Steady-state ΔFBF and ΔFVC during rhythmic exercise were unchanged in both I/R (192 ± 52 vs. 190±53 ml·min-1; 208±56 vs. 193±60 ml·min-1·100 mmHg-1) and time control (188±54 vs. 196±48 ml·min-1; 206±60 vs. 207±49 ml·min-1·100 mmHg-1) trials (group x time interactions P=0.34 and 0.21, respectively). Plasma [nitrite] under resting conditions and during steady-steady state rhythmic exercise was attenuated following I/R (P<0.05 for both) but not time control (P=0.54 and 0.93). These data indicate I/R blunts hyperemia and vasodilation at the onset of muscle contractions but does not attenuate these responses during steady-state exercise.

More Than a Decade Since the Latest CONSORT Non-inferiority Trials Extension: Do Infectious Diseases Trials Do Enough?

More than a decade after the Consolidated Standards of Reporting Trials group released a reporting items checklist for non-inferiority randomized controlled trials, the infectious diseases literature continues to underreport these items. Trialists, journals, and peer reviewers should redouble their efforts to ensure infectious diseases studies meet these minimum reporting standards.

Weight Gain After Antiretroviral Therapy Initiation and Subsequent Risk of Metabolic and Cardiovascular Disease.

Weight gain following initiation of antiretroviral therapy (ART) is common. We assessed the impact of changes in weight in the year following ART initiation with subsequent cardiometabolic disease among AIDS Clinical Trials Group (ACTG) participants. Linear regression models were fit to examine the association between change in weight/waist circumference (WC) in weeks 0-48 and change in metabolic parameters in weeks 0-48 and 48-96. Cox proportional hazard models were fit to examine the association between changes in weight/WC in weeks 0-48 and diabetes mellitus (DM), metabolic syndrome, or cardiometabolic and cardiovascular events after week 48. Participants (N = 2624) were primarily male (81%) and non-White (60%). Mean weight gain from 0-48 weeks was 3.6 kg (SD 7.3); 130 participants developed DM; 360 metabolic syndrome; 424 any cardiometabolic event; 28 any cardiovascular event, over 480 weeks of follow-up. In adjusted models, total cholesterol increased by 0.63 mg/dL (95% confidence interval [CI] [.38, .089]) and LDL by 0.39 mg/dL (0.19, 0.59) per 1 kg increase in weight from weeks 0 to48. Participants who experienced >10% weight gain (vs -5% to 5%) had an increased risk of DM (hazard ratio [HR] 2.01, 95% CI [1.30, 3.08]), metabolic syndrome (HR 2.24, 95% CI [1.55, 2.62]), and cardiometabolic outcomes (HR 1.54, 95% CI [1.22, 1.95]). Participants who lost more than 5% of their baseline weight had a lower risk of incident metabolic syndrome (HR 0.67, 95% CI [0.42, 1.07]). Trends for WC were similar. Weight and body composition changes in the first year following ART initiation are associated with contemporaneous changes in metabolic parameters and subsequent cardiometabolic disease.

Design and analysis considerations for early phase clinical trials in hepatitis B (HBV) cure research: the ACTG A5394 study in persons with both HIV and HBV

With growing interest and efforts to achieve a hepatitis B (HBV) cure, HBV therapeutics have increasingly entered the clinical testing phase. In designing an early phase clinical trial aimed at HBV cure, the heterogeneity in participants and the choice of a biomarker endpoint that signals a cure requires careful consideration. We describe the key elements to consider during the development of HBV clinical trials aimed at a functional cure, and how we have addressed them in the design of a phase II AIDS Clinical Trials Group (ACTG) study, A5394 (NCT05551273). The trial we present is for persons with both HIV and HBV, a unique population that has much to gain from an HBV cure. Our decisions on the design elements are specific to the study agent and the targeted population, but our deliberations may be informative in the emerging field of early phase HBV trials aimed at cure.

Selective outcome reporting in randomised controlled trials including participants with stroke or transient ischaemic attack: A systematic review.

The prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown. We searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group. Of 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB. The prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample. Work is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes.

Power and sample size calculation for incremental net benefit in cost effectiveness analyses with applications to trials conducted by the Canadian Cancer Trials Group

BackgroundHistorically, a priori power and sample size calculations have not been routinely performed cost-effectiveness analyses (CEA), partly because the absence of published cost and effectiveness correlation and variance data, which are essential for power and sample size calculations. Importantly, the empirical correlation between cost and effectiveness has not been examined with respect to the estimation of value-for-money in clinical literature. Therefore, it is not well established if cost-effectiveness studies embedded within randomized-controlled-trials (RCTs) are under- or over-powered to detect changes in value-for-money. However, recently guidelines (such as those from ISPOR) and funding agencies have suggested sample size and power calculations should be considered in CEAs embedded in clinical trials.MethodsWe examined all RCTs conducted by the Canadian Cancer Trials Group with an embedded cost-effectiveness analysis. Variance and correlation of effectiveness and costs were derived from original-trial data. The incremental net benefit method was used to calculate the power of the cost-effectiveness analysis, with exploration of alternative correlation and willingness-to-pay values.ResultsWe identified four trials for inclusion. We observed that a hypothetical scenario of correlation coefficient of zero between cost and effectiveness led to a conservative estimate of sample size. The cost-effectiveness analysis was under-powered to detect changes in value-for-money in two trials, at willingness-to-pay of $100,000. Based on our observations, we present six considerations for future economic evaluations, and an online program to help analysts include a priori sample size and power calculations in future clinical trials.ConclusionThe correlation between cost and effectiveness had a potentially meaningful impact on the power and variance of value-for-money estimates in the examined cost-effectiveness analyses. Therefore, the six considerations and online program, may facilitate a priori power calculations in embedded cost-effectiveness analyses in future clinical trials.

Implications of Contact Days in the Treatment of Relapsed Refractory Diffuse Large B-Cell Lymphoma.

This commentary remarks on a recently published study assessing clinic contact days for patients enrolled in the Canadian Cancer Trials Group LY.12 clinical trial.

Current temperatures limit the potential impact of a commonly traded predatory gastropod

The pet trade has facilitated the spread of invasive alien species (IAS) globally, with negative consequences for biodiversity. The prediction of impacts is a major goal for invasion ecologists, and is especially crucial in an industry often lacking knowledge about traded species. We focused on the predatory gastropod Anentome helena, a species originating in south-east Asia and traded around the world, but with taxonomic uncertainty. We first set out to determine where our study organism fell within the A. “helena” species complex, known to comprise at least four cryptic species, before assessing the effect of temperature on the number of prey, the pulmonate snail Physella acuta, killed per predator via functional response experiments at two temperatures. We used 22 °C as a recommended temperature for housing the species in captivity, and 18 °C as a representative summer lake temperature in temperate climates of Europe. We also assessed the role of predator group size (1×, 2×, 3×) on predation (total consumption and average per capita consumption) at the experimental temperatures with fixed densities of prey, as well as the effect of these temperatures on prey activity. Our organisms belonged to a cryptic species originating from Thailand (Anentome sp. A), matching the findings of aquarium trade samples in other continents. In the functional response experiments, we found maximum feeding rate to be significantly reduced at the lower temperature. A similar result ensued from group feeding, with total consumption significantly reduced and the reduction in average per capita consumption approaching significance at the lower temperature. There was no significant effect of group size on the average per capita consumption in the group trial, indicating neutral conspecific interactions. No significant effect of temperature on the activity of the prey species was found, suggesting decreased consumption was mainly driven by predator, rather than prey. These results suggest limited A. helena impacts in the short-term, but increasing temperatures with climate change may facilitate greater consequences from releases. We suggest future studies assess other potential predatory impacts and survival across relevant abiotic conditions, and encourage the use of similar methods to assess the impacts of other commonly traded species.

Non-inferiority trial of a shorter (7 days) compared with a longer (14 days) duration of antimicrobial therapy for the treatment of bacteraemic urinary sepsis, measured by microbiological success after the completion of therapy: a substudy protocol for the Bacteraemia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) multicentre randomised controlled trial

IntroductionThe BALANCE study is a randomised clinical trial (3626 participants) designed to assess the non-inferiority of 7 days (short-course) antibiotic therapy compared with 14 days of therapy for bacteraemia using...

DS03 Lentigo maligna: is it time to put down the scalpel?

Abstract Lentigo maligna (LM) is a subtype of melanoma in situ that often proves to be a diagnostic and therapeutic challenge. Treatment aims to prevent progression to an invasive tumour called lentigo maligna melanoma (LMM). In the UK, common treatment modalities include conventional excision, staged re-excisions, slow Mohs surgery or expectant monitoring. Although considered the ‘gold standard’, surgical excision of LM can be disfiguring as it frequently affects cosmetically sensitive areas requiring complex surgical reconstructions. Topical imiquimod 5% presents a pragmatic alternative treatment modality without the need for surgery. In vivo reflectance confocal microscopy (RCM) allows real-time noninvasive delineation of LM. Evidence suggests this is an effective diagnostic tool for pre- and post-treatment evaluation (Brand FL, Jafari SM, Hunger RE. Confocal microscopy and lentigo maligna: an in vivo pilot study for the assessment of response to imiquimod therapy. Dermatology 2019; 235:150–5). We retrospectively analysed 35 cases of histologically confirmed LM that completed treatment with imiquimod between 2018 and 2022. The average patient age at diagnosis was 73.9 years, with a female : male ratio of 18 : 17. Following assessment with RCM, patients were prescribed a protocol of topical imiquimod 5% once a day, 5 days per week for 12 weeks, along with instructions to apply this 10 mm beyond the mapped area or a cosmetic unit (Australia and New Zealand Melanoma Trials Group RADICAL trial). Patients were counselled about expected side-effects; all completed the course and achieved significant inflammation and superficial ulceration. To ensure a response was achieved, the following stepwise interventions were used: application increased to 7 days per week, occlusion with a dressing and addition of a topical retinoid. Repeat RCM was performed 6 months after treatment completion. At this point, 30 of 35 (86%) patients responded with no evidence of residual LM on RCM. Three cases required a second course of treatment. Two of these were shown to be clear on RCM, while the third is clinically clear and awaiting RCM confirmation. A fourth patient was lost to follow-up. A further patient has failed two courses and is about to embark on a third round of treatment. In total, 16 cases completed the 12-month review and maintained clearance. We demonstrate that imiquimod is an effective treatment for LM, potentially avoiding extensive surgery and complex reconstruction. Reflectance confocal microscopy can be used to delineate the extent of the LM and assess the post-treatment response. Our preliminary data suggest a significant proportion of LM cases achieved clearance with no recurrences to date. Follow-up of these patients will help evaluate the long-term efficacy of imiquimod, but our data suggest this treatment protocol provides a promising alternative to surgical intervention.

Management of rectal cancer in the era of total neoadjuvant therapy and watch and wait: A multidisciplinary team discussion at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting 2022.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.