Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
, this has not been comprehensively evaluated in large randomized studies. Here we ...analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
The aim of the study was to compare 6-month efficacy and safety for treatment of vaginal dryness/genitourinary syndrome of menopause in women undergoing fractionated CO2 vaginal laser therapy to ...women using estrogen vaginal cream.
This multicenter, randomized trial compared fractionated CO2 laser to estrogen cream at 6 institutions. We included menopausal women with significant vaginal atrophy symptoms and we excluded women with prolapse below stage 2, recent pelvic surgery, prior mesh surgery, active genital infection, history of estrogen sensitive malignancy, and other autoimmune conditions. The primary outcome was the visual analog scale vaginal dryness score. Secondary outcomes included evaluation of vaginal atrophy, quality of life symptoms, assessment of sexual function, and urinary symptoms. Adverse events (AEs) and patient global impression of improvement (PGI-I) and satisfaction were also assessed.
Sixty-nine women were enrolled in this trial before enrollment was closed due to the Federal Drug Administration requiring the sponsor to obtain and maintain an Investigational Device Exemption. Of the 69 participants enrolled, 62 completed the 6-month protocol; 30 women were randomized to the laser and 32 to estrogen cream from June 2016 to September 2017. Demographics did not differ between groups except the laser group was less parous (0 range 0-4 vs 2 0-6, P = 0.04). On patient global impression, 85.8% of laser participants rated their improvement as "better or much better" and 78.5% reported being either "satisfied or very satisfied" compared to 70% and 73.3% in the estrogen group; this was not statistically different between groups. On linear regression, mean difference in female sexual function index scores was no longer statistically significant; and, vaginal maturation index scores remained higher in the estrogen group (adj P value 0.02); although, baseline and 6-month follow-up vaginal maturation index data were only available for 34 participants (16 laser, 18 estrogen).
At 6 months, fractionated CO2 vaginal laser and vaginal estrogen treatment resulted in similar improvement in genitourinary syndrome of menopause symptoms as well as urinary and sexual function. Overall, 70% to 80% of participants were satisfied or very satisfied with either treatment and there were no serious adverse events. : Video Summary:http://links.lww.com/MENO/A470.
Recent developments in CBT emphasize the promotion of psychological flexibility to improve daily functioning for people with a wide range of health conditions. In particular, one of these approaches, ...Acceptance and Commitment Therapy (ACT), has been studied for treatment of chronic pain. While trials have provided good support for treatment effectiveness through follow-ups of as long as seven months, the longer-term impact is not known. The present study of 108 participants with chronic pain examined outcomes three years after treatment completion and included analyses of two key treatment processes, acceptance of pain and values-based action. Overall, results indicated significant improvements in emotional and physical functioning relative to the start of treatment, as well as good maintenance of treatment gains relative to an earlier follow-up assessment. Effect size statistics were generally medium or large. At the three-year follow-up, 64.8% of patients had reliably improved in at least one key domain. Improvements in acceptance of pain and values-based action were associated with improvements in outcome measures. A “treatment responder” analysis, using variables collected at pre-treatment and shorter term follow-up, failed to identify any salient predictors of response. This study adds to the growing literature supporting the effectiveness of ACT for chronic pain and yields evidence for both statistical and clinical significance of improvements over a three-year period.
► Long-term outcomes of Acceptance and Commitment Therapy for chronic pain were assessed. ► Improvement across measures of outcome was indicated at a three-year follow-up. ► There was evidence of maintenance of treatment gains relative to earlier follow-up. ► Changes in treatment processes were associated with these improvements. ► Most patients had reliably changed on at least 1 key outcome 3 years after treatment.
Abstract Background Desmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing ...patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib. Patients and methods We initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years range: 19–80; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR6mo ) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013. Results The final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate. Conclusions Imatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib.
Background
Cancer stem cells are associated with metastatic potential, treatment resistance, and poor patient prognosis. Distant recurrence remains the major cause of mortality in rectal cancer ...patients with preoperative chemoradiotherapy (CRT). We investigated the role of three stem cell markers (
CD133
,
OCT4
, and
SOX2
) in rectal cancer and evaluated the association between these gene levels and clinical outcome in rectal cancer patients with preoperative CRT.
Methods
Thirty-three patients with rectal cancer underwent preoperative CRT. Total RNAs of rectal cancer cells before and after CRT were isolated. Residual cancer cells after CRT were obtained from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. The expression levels of three stem cell genes were measured using real-time reverse-transcription polymerase chain reaction (RT-PCR). The association between these gene levels and radiation was evaluated using colon cancer cell lines. Immunohistochemical staining of these markers after CRT was also investigated.
Results
There were significant positive correlations among the three genes after CRT. Patients who developed distant recurrence had higher levels of the three genes compared with those without recurrence in residual cancer after CRT. These elevated gene levels were significantly associated with poor disease-free survival. The radiation caused upregulation of these gene levels in LoVo and SW480 in vitro. Immunohistochemically, CD133 staining was observed in not only luminal surface but also cytoplasm.
Conclusions
Expression of CD133, OCT4, and SOX2 may predict distant recurrence and poor prognosis of rectal cancer patients treated with preoperative CRT. Correlations among these genes may be associated with tumor regrowth and metastatic relapse after CRT.
Please see Appendix 4 for a glossary of terms.The outcome of patients with esophageal cancer is generally poor. Although multimodal therapy is standard, there is conflicting evidence regarding the ...addition of esophagectomy to chemoradiotherapy.
To compare the effectiveness and safety of chemoradiotherapy plus surgery with that of chemoradiotherapy alone in people with nonmetastatic esophageal carcinoma.
We performed a computerized search for relevant studies, up to Feburary 2017, on the CENTRAL, MEDLINE, and Embase databases using MeSH headings and keywords. We searched five online databases of clinical trials, handsearched conference proceedings, and screened reference lists of retrieved papers.
We included randomized controlled trials (RCTs) comparing chemoradiotherapy plus esophagectomy with chemoradiotherapy alone for localized esophageal carcinoma. We excluded RCTs comparing chemotherapy or radiotherapy alone with esophagectomy.
Two authors independently selected studies, extracted data, and assessed risk of bias and the quality of the evidence, using standardized Cochrane methodological procedures. The primary outcome was overall survival (OS), estimated with Hazard Ratio (HR). Secondary outcomes, estimated with risk ratio (RR), were local and distant progression-free survival (PFS), quality of life (QoL), treatment-related mortality and morbidity, and use of salvage procedures for dysphagia. Data were analyzed using a random effects model in Review Manager 5.3 software.
From 2667 references, we identified two randomized studies, in six reports, that included 431 participants. All participants were clinically staged to have at least T3 and/or node positive thoracic esophageal carcinoma, 93% of which was squamous cell histology. The risk of methodological bias of the included studies was low to moderate.High-quality evidence found the addition of esophagectomy had little or no difference on overall survival (HR 0.99, 95% CI 0.79 to 1.24; P = 0.92; I² = 0%; two trials). Neither study reported PFS, therefore, freedom from loco-regional relapse was used as a proxy. Moderate-quality evidence suggested that the addition of esophagectomy probably improved freedom from locoregional relapse (HR 0.55, 95% CI 0.39 to 0.76; P = 0.0004; I² = 0%; two trials), but low-quality evidence suggested it may increase the risk of treatment-related mortality (RR 5.11, 95% CI 1.74 to 15.02; P = 0.003; I² = 2%; two trials).The other pre-specified outcomes (quality of life, treatment-related toxicity, and use of salvage procedures for dysphagia) were reported by only one study, which found very low-quality evidence that use of esophagectomy was associated with reduced short-term QoL (MD 0.93, 95% CI 0.24 to 1.62), and low-quality evidence that it reduced use of salvage procedures for dysphagia (HR 0.52, 95% CI 0.36 to 0.75). Neither study compared treatment-related morbidity between treatment groups.
Based on the available evidence, the addition of esophagectomy to chemoradiotherapy in locally advanced esophageal squamous cell carcinoma, provides little or no difference on overall survival, and may be associated with higher treatment-related mortality. The addition of esophagectomy probably delays locoregional relapse, however, this end point was not well defined in the included studies. It is undetermined whether these results can be applied to the treatment of adenocarcinomas, tumors involving the distal esophagus and gastro-esophageal junction, and to people with poor response to chemoradiation.
In virtual reality exposure therapy (VRET), patients are exposed to virtual environments that resemble feared real-life situations. The aim of the current study was to assess the extent to which VRET ...gains can be observed in real-life situations. We conducted a meta-analysis of clinical trials applying VRET to specific phobias and measuring treatment outcome by means of behavioral laboratory tests or recordings of behavioral activities in real-life. Data sources were searches of databases (Medline, PsycInfo, and Cochrane). We included in total 14 clinical trials on specific phobias. Results revealed that patients undergoing VRET did significantly better on behavioral assessments following treatment than before treatment, with an aggregated uncontrolled effect size of g = 1.23. Furthermore, patients undergoing VRET performed better on behavioral assessments at post-treatment than patients on wait-list (g = 1.41). Additionally, results of behavioral assessment at post-treatment and at follow-up revealed no significant differences between VRET and exposure in vivo (g = −0.09 and 0.53, respectively). Finally, behavioral measurement effect sizes were similar to those calculated from self-report measures. The findings demonstrate that VRET can produce significant behavior change in real-life situations and support its application in treating specific phobias.
•Virtual reality interventions can lead to behavioral change in daily life.•Virtual reality interventions for specific phobias are as effective as traditional behavior therapy.•More research is needed using rigorous methodology.
Introduction
Non‐pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological ...rigor and continues to produce mixed results.
Methods
In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System.
Results
Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols.
Discussion
We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area.
Depression is a common, disabling condition for which psychological treatments, in particular cognitive behavioural therapies are recommended. Promising results in recent randomized trials have ...renewed interest in behavioural therapy. This systematic review sought to identify all randomized trials of behavioural therapy for depression, determine the effect of such interventions and examine any moderators of such effect.
Randomized trials of behavioural treatments of depression versus controls or other psychotherapies were identified using electronic database searches, previous reviews and reference lists. Data on symptom-level, recovery/dropout rate and study-level moderators (study quality, number of sessions, severity and level of training) were extracted and analysed using meta-analysis and meta-regression respectively.
Seventeen randomized controlled trials including 1109 subjects were included in this meta-analysis. A random-effects meta-analysis of symptom-level post-treatment showed behavioural therapies were superior to controls standardized mean difference (SMD) -0.70, 95% CI -1.00 to -0.39, k=12, n=459, brief psychotherapy (SMD -0.56, 95% CI -1.0 to -0.12, k=3, n=166), supportive therapy (SMD -0.75, 95% CI -1.37 to -0.14, k=2, n=45) and equal to cognitive behavioural therapy (SMD 0.08, 95% CI -0.14 to 0.30, k=12, n=476).
The results in this study indicate behavioural therapy is an effective treatment for depression with outcomes equal to that of the current recommended psychological intervention. Future research needs to address issues of parsimony of such interventions.
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