De-escalation Strategies Research Articles

The Civil Society-Military Interface in the Protection of Civilians: the Bangsamoro Case

Abstract The peace process between the Philippine government and the separatist Moro Islamic Liberation Front provided breathing space for many communities and opportunities for calibrated civilian protection practices by the military and non-governmental organisations (ngo s). While the principle of non-intervention largely kept the imprint of the Association of Southeast Asian Nations (asean) to a minimum, Indonesian and Malaysian brokering enabled the establishment of bridging mechanisms such as ceasefire monitoring committees to moderate the armed violence. A more permissive environment allowed ngo s to deliver humanitarian aid and acquire improved capacities for risk mitigation in the Bangsamoro region, aided in part by a shift in the Philippine military’s approach toward putting a premium on civilian consultation and dialogue. Despite these normative gains, the uptick in horizontal violence among rival clans and the military’s preference for the use of artillery fire as a conflict de-escalation strategy create enduring challenges for civilian protection on the ground.

Impact of Human Papillomavirus-Negative Dominance in Oropharyngeal Cancer on Overall Survival: A Population-Based Analysis in Germany from 2018 to 2020.

The impact of the relation of human papillomavirus (HPV) and smoking status of oropharyngeal squamous cell carcinoma (OPSCC) on overall survival (OS) was investigated in a retrospective population-based study in Thuringia, Germany. A total of 498 patients with OPSCC (76.9% men; mean age 62.5 years) from 2018 to 2020 were included. OPSCC cases were 37.3% HPV-positive (+) (31.2% smokers; mean incidence: 2.91/100,000 population) and 57.8% HPV-negative (63.5% smokers; mean incidence: 4.50/100,000 population). Median follow-up was 20 months. HPV+ patients had significantly better OS than HPV-negative (-) patients (HPV+: 2-year OS: 90.9%; HPV-: 2-year OS: 73.6%; p < 0.001). In multivariable analysis, HPV- patients (hazard ratio (HR) = 4.5; 95% confidence interval (CI): 2.4-8.6), patients with higher N classification (N2: HR = 3.3; 95% CI: 1.71-6.20; N3: HR = 3.6; 95% CI: 1.75-7.31) and with a higher cancer staging (III: HR = 5.7; 95% CI: 1.8-17.6; IV: HR = 19.3; 95% CI: 6.3-57.3) had an increased hazard of death. HPV- smokers formed the majority in Thuringia. Nicotine and alcohol habits had no impact on OS. Optimizing OPSCC therapeutic strategies due to the dominance of HPV- is more important than discussing de-escalation strategies for HPV+ patients.

De-escalation of Biologic Treatment in Inflammatory Bowel Disease: A Comprehensive Review.

Biologic therapy is an effective treatment for inflammatory bowel disease [IBD]. However due to cost and safety concerns, dose de-escalation strategies after achieving remission have been suggested. To critically review available data on dose de-escalation of biologics [or other advanced therapies] in IBD. We will focus on studies evaluating de-escalation to standard dosing in patients initially optimised, and also on studies assessing de-escalation from standard dosing. A systematic bibliographic search was performed. The mean frequency of de-escalation after previous dose intensification [12 studies, 1,474 patients] was 34%. The corresponding frequency of de-escalation from standard dosing [five studies, 3,842 patients] was 4.2%. The relapse rate of IBD following anti-tumour necrosis factor [TNF] de-escalation to standard dosing in patients initially dose-escalated [10 studies, 301 patients] was 30%. The corresponding relapse rate following anti-TNF de-escalation from standard dosing [nine studies, 494 patients] was 38%. The risk of relapse was lower for patients in clinical, biologic, and endoscopic/radiological remission at the time of de-escalation. A role of anti-TNF therapeutic drug monitoring in the decision to dose de-escalate has been demonstrated. In patients relapsing after de-escalation, re-escalation is generally effective. De-escalation is not consistently associated with a better safety profile. The cost-effectiveness of the de-escalation strategy remains uncertain. Finally, there is not enough evidence to recommend dose de-escalation of biologics different from anti-TNFs or small molecules. Any consideration for de-escalation of biologic therapy in IBD must be tailored, taking into account the risks and consequences of a flare and patients' preferences.

Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement.

Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST. We conducted a single-institution, retrospective study of 521 patients with cN2-3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan-Meier analyses were performed. The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor-positive (HR+)/HER2-negative tumors (HER2-; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008). In a high-risk cohort of patients with cN2-3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2-3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.

Dosimetric and radiobiological analyses of a de-escalation strategy for elective nodal regions in human papillomavirus-associated oropharyngeal cancer

IntroductionIn this simulation study, we examined the effects of a de-escalation strategy with a reduced dose to subclinical nodal regions in patients with human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC). MethodsWe created two patterns of intensity-modulated radiotherapy for 16 patients with HPV-associated OPC. In the standard and de-escalation plans, the initial field including elective nodal regions received 46 and 30 Gy, followed by 20 and 36 Gy to the cutdown field, respectively. Comparison metrics were set for each organ at risk (OAR). We compared these metric values and the probability of adverse effects based on the normal tissue complication probability (NTCP) model between the two plans. ResultsBoth plans generally met the dose constraints for the targets and all OAR. Among the comparison metrics, the mean doses to the brain, pharyngeal constrictor muscle, thyroid, and skin and the dose to a 1 % volume of the skin were higher in the standard plan than in the de-escalation plan (P = 0.031, 0.007, < 0.001, < 0.001, and 0.006, respectively). NTCP analyses revealed that the probability of adverse effects in the ipsilateral parotid gland and thyroid was higher in the standard plan than in the de-escalation plan (standard vs. de-escalation plans: ipsilateral parotid gland, 6.4 % vs. 5.0 %, P = 0.016; thyroid, 3.3 % vs. 0.5 %, P < 0.001). ConclusionsA de-escalation strategy with elective nodal regions is a promising treatment to prevent a decline in the quality of life in patients with HPV-associated OPC, particularly xerostomia, dysphagia, and hypothyroidism.

Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

Antithrombotic Treatment in Coronary Artery Disease.

Coronary artery disease exhibits growing mortality and morbidity worldwide despite the advances in pharmacotherapy and coronary intervention. Coronary artery disease is classified in the acute coronary syndromes and chronic coronary syndromes according to the most recent guidelines of the European Society of Cardiology. Antithrombotic treatment is the cornerstone of therapy in coronary artery disease due to the involvement of atherothrombosis in the pathophysiology of the disease. Administration of antiplatelet agents, anticoagulants and fibrinolytics reduce ischemic risk, which is amplified early post-acute coronary syndromes or post percutaneous coronary intervention; though, antithrombotic treatment increases the risk for bleeding. The balance between ischemic and bleeding risk is difficult to achieve and is affected by patient characteristics, procedural parameters, concomitant medications and pharmacologic characteristics of the antithrombotic agents. Several pharmacological strategies have been evaluated in patients with coronary artery disease, such as the effectiveness and safety of antithrombotic agents, optimal dual antiplatelet treatment schemes and duration, aspirin de-escalation strategies of dual antiplatelet regimens, dual inhibition pathway strategies as well as triple antithrombotic therapy. Future studies are needed in order to investigate the gaps in our knowledge, including special populations.

Is 80 the New 70? Octogenarians with Oropharyngeal Squamous Cell Carcinoma

As the human papilloma virus (HPV) pandemic evolves and life expectancy increases, the number of older adults with oropharyngeal squamous cell carcinoma (OPSCC) continues to increase. However, there is a paucity of data regarding the fastest growing subset of this population: octogenarians (OGs). We sought to understand differences in treatment tolerability and clinical outcomes between septuagenarians (SGs) and OGs with OPSCC. We identified SGs (age 70-79) and OGs (age 80-89) with OPSCC from a cohort of older adults with nonrecurrent, nonmetastatic head and neck squamous cell carcinoma (HNSCC) treated curatively from 2007-2020. We compared demographics, treatment characteristics and toxicities using Fischer's exact test. Time-to-event outcomes, overall survival (OS), locoregional control (LRC), and disease-specific survival (DSS), were evaluated using the Kaplan-Meier method. Of 293 patients (age 70-89) with HNSCC, 39% (n = 114) had OPSCC: 93 SGs (median age: 73; interquartile range [IQR]: 71-76), and 21 OGs (median age: 81, IQR: 80-84). The median follow-up for included patients was 2.4 years; 82% were male, 64% white, 48% > 20 pack year smoking history, 37% ECOG 1. Patients had AJCC 8th edition Stage: I (27%); II (33%); III (18%); IV (22%) OPSCC. Treatment consisted of adjuvant radiation (RT) (19%), adjuvant chemoradiation (CRT) (8%), surgery alone (6%), induction/concurrent CRT (27%), concurrent CRT (28%), or RT (12%), with no significant differences in stage or treatment modalities noted between SGs and OGs. Of note, 69% of SGs and 76% of OGs were HPV+. Among 107 patients who received any RT, 24% experienced a treatment interruption (19% of SGs vs. 48% of OGs, p = 0.001) and 2 patients (both HPV- SGs) died on treatment due to unrelated health conditions. Percutaneous endoscopic gastrostomy (PEG) tubes were placed prior to or during treatment in 43% of SGs and 62% of OGs, with OGs more likely to have a PEG placed during treatment (p = 0.025). There was no difference in the prevalence of late (> 6 months) CTCAE grade 2+ dysphagia (36%) or xerostomia (31%) between SGs and OGs. Estimated 3-year LRC, DSS, and OS were not significantly different between SGs (LRC:85%; DSS:87%; OS:76%) and OGs (LRC: 81%; DSS:94%; OS: 55%, p-values: 0.98, 0.42, 0.052, respectively). However, HPV+ disease significantly increased estimated 3-year OS for both SGs (HPV+: 84%; HPV-: 56%, p = 0.0006) and OGs (HPV+: 68%; HPV-: 20%, p = 0.008). In our cohort, OGs had a higher proportion of HPV+ OPSCC, which was associated with improved OS. This finding may provide insight into the latency of the virus. While there were similar amounts of toxicities among SGs and OGs, OGs more frequently underwent PEG tube placement and experienced more treatment interruptions. Given high rates of HPV+ OPSCC in OGs, our findings suggest that de-escalation strategies should be further investigated to improve tolerability and maximize outcomes for this neglected population.

Radiomics Based Assessment of Tumor Infiltrating CD8 T-Cells Predicts Induction Systemic Therapy Response in HPV+ Oropharyngeal Cancer: Exploratory Analysis of Prospective Trials

The adaptive immune system is increasingly recognized to be important for tumor control in HPV+ oropharyngeal cancer (HPV+OPC), and pre-clinical models suggest tumor specific T-cell priming occurs in draining lymph nodes. De-escalation strategies incorporating T-cell infiltration present a novel prognostic biomarker. The purpose of this study was to examine the utility of a validated radiomics model of CD8 T-cell infiltration within the framework of 2 prospective HPV+OPC response-adaptive de-escalation trials. We hypothesized that nodal radiomics scores (RS) would be correlated with response to induction systemic therapy. Patients enrolled on 2 prospective phase II response adapted de-escalation trials for low- and high-risk HPV+OPC were included in the analysis. Patients received induction chemotherapy and chemoimmunotherapy in trials 1 and 2, respectively. Primary tumors and nodes were retrospectively delineated on diagnostic CT scans before and after induction therapy to ascertain volumetric tumor burden & response. RS were generated on pre-induction scans for both primary tumors and nodes. RS and tumor response were dichotomized using a 50% threshold (high vs low, responder vs non-responder, respectively). Linear regression was used to evaluate the correlation between % volume change in tumor burden and RS. Fisher's exact test was used to evaluate concordance between RS and tumor response. A total of 87 patients (N = 47 Trial 1, N = 40 Trial 2) were evaluable. The mean post-induction therapy reduction in primary and nodal volumetry was 80.7% and 67% respectively. Primary and nodal RS were not associated with primary (T1/T2 vs T3/T4) or nodal stage (N1-N2b vs N2c-N, p > 0.10 both). Both primary and nodal RS were correlated with % volume change, r = 0.24 (p = 0.034) and r = 0.37 (p = 0.002), respectively. The mean difference in % volume change in primary and node, using the RS, was 11.13% (p = 0.015) and 17. 69% (p = 0.004). There was no association between primary tumor RS and total lesion responder status (p = 0.312). However, there was an association between high vs low nodal RS and total lesion responder status (p = 0.005). This is the first report of a validated radiomics score of CD8-T cell infiltration in HPV+OPC to predict response to systemic therapy. While radiomics scores in both the primary and nodes were associated with percent volume response, this association was stronger in nodes. Higher nodal radiomics scores were associated with improved volume reduction in total lesion burden. This effect however was not observed in the primary tumor. CD8-T cell infiltration in nodes, but not in the primary tumor, was associated with overall tumor response after systemic induction therapy in HPV+ oropharyngeal cancer.

Tailoring Radiation to the Contralateral Neck for Midline HPV-Mediated Oropharyngeal Squamous Cell Carcinoma (p16+ OPSCC)

De-intensification strategies for locally advanced p16+ OPSCC are under active investigation, including omission of contralateral neck radiation (RT) for well-lateralized T1-2N0-2a. This study evaluates the outcomes of omitting contralateral neck nodal levels for p16+ OPSCC that are not well-lateralized. A retrospective review was done of 134 consecutive patients with non-metastatic p16+ OPSCC that were not well-lateralized (< 1 cm from midline or ≥ 1 cm extension to soft palate or base of tongue) who were treated with definitive chemoradiation from 2013 to 2019. IMRT to an EQD2 6364-6735 cGy (200-220 cGy per fraction) was used to treat the primary tumor and ipsilateral or bilateral neck, with tailored nodal level coverage and dose, and with concurrent paclitaxel and carboplatin. Contralateral neck RT was tailored in 121 patients: omitted in 11, limited to level II in 9, and limited to level II and III in 101 (contralateral lower neck omitted); the remaining 13 had bilateral level II-IV neck RT. Local and regional recurrences were evaluated. Median follow up was 45.34 months. Local and/or regional recurrence was noted in 9/134 (6.7%). 3 (2%) recurred in the contralateral neck in unirradiated tissue (out-of-field). All three were salvaged. The remaining 6 recurrences (4%) were in-field; one was at the primary site and 5 were nodal (all ipsilateral). 4 of the 5 regional recurrences were in a location that was treated to EQD2 7000 cGy (all had PET avid nodal disease upfront that was included in the high dose level); the other region of recurrence was treated to an EQD2 6353 cGy (the only recurrence in a never smoker). 4 of the 5 neck recurrences underwent neck dissection; one further underwent adjuvant RT to 5940 cGy in 33 fractions and remains disease-free. 2 of those who underwent salvage neck dissection alone subsequently developed distant metastases. The majority of first recurrences were distant, 19.4% (26/134). 3-year progression free survival (PFS) was 74.41% (95% CI, 65.63-81.26). Taken together, regional recurrence rate in the contralateral, unirradiated neck was 2.5% (3/121) and ultimate locoregional control was 99% (132/134). Our tailored approach demonstrates a contralateral neck local control of 97.5% (118/121) regardless of tumor lateralization; those who recurred in unirradiated cervical lymph nodes were successfully salvaged. Limiting this analysis is moderate sample size and retrospective nature, but it raises important alternative de-escalation strategies (RT volume reduction) for p16+ OPSCC aside from dose reduction, which is under active investigation in phase II/III trials. Improved systemic therapies are needed to combat distant metastases. Prospective randomized clinical trials are needed for further evaluation of nodal omission for definitive chemoradiation of non-well-lateralized p16+ OPSCC.

CtDNA-guided adjuvant treatment after radical-intent treatment of metastatic spread from colorectal cancer—the first interim results from the OPTIMISE study

Background Patients with detectable ctDNA after radical-intent treatment of metastatic spread from colorectal cancer (mCRC) have a very high risk of recurrence, which may be prevented with intensified adjuvant chemotherapy (aCTh). In the OPTIMISE study, we investigate ctDNA-guided aCTh after radical-intent treatment of mCRC. Here we present results from the preplanned interim analysis. Material and methods The study is an open-label 1:1 randomized clinical trial comparing ctDNA-guided aCTh against standard of care (SOC), with a run-in phase investigating feasibility measures. Key inclusion criteria; radical-intent treatment for mCRC and clinically eligible for triple-agent chemotherapy. Patients underwent a PET-CT scan before randomization. ctDNA analyses of plasma samples were done by ddPCR, detecting CRC-specific mutations and methylation of the NPY gene. In the ctDNA-guided arm, ctDNA positivity led to an escalation strategy with triple-agent chemotherapy, and conversely ctDNA negativity led to a de-escalation strategy by shared-decision making. Patients randomized to the standard arm were treated according to SOC. Feasibility measures for the run-in phase were; the inclusion of 30 patients over 12 months in two Danish hospitals, compliance with randomization >80%, rate of PET-CT-positive findings <20%, and eligibility for triple-agent chemotherapy >80%. Results Thirty-two patients were included. The rate of PET-CT-positive cases was 22% (n = 7/32). Ninety-seven percent of the patients were randomized. Fourteen patients were randomly assigned to SOC and sixteen to ctDNA-guided adjuvant treatment and follow-up. All analyses of baseline plasma samples in the ctDNA-guided arm passed the quality control, and 19% were ctDNA positive. The median time to result was three working days. All ctDNA-positive patients were eligible for triple-agent chemotherapy. Conclusion The study was proven to be feasible and continues in the planned large-scale phase II trial. Results from the OPTIMISE study will potentially optimize the adjuvant treatment of patients undergoing radical-intent treatment of mCRC, thereby improving survival and reducing chemotherapy-related toxicity.

Optimising antithrombotic therapy after acute coronary syndromes and percutaneous coronary interventions

Dual antiplatelet therapy, combining aspirin with a platelet P2Y12 receptor inhibitor, is the standard treatment for acute coronary syndrome patients undergoing percutaneous coronary intervention. The optimal type and duration of dual antiplatelet therapy depend on the patient's risk for ischemic and hemorrhagic complications. De-escalation strategies, such as switching to a less potent P2Y12 inhibitor, reducing the dose, or discontinuing one of the antiplatelet agents, may be suitable for high-risk bleeding patients with low risk of recurrent ischemic events, and platelet function testing and genetic testing can guide de-escalation. For patients at high ischemic risk, strategies include drug switching, dose escalation, or adding a new drug. Patients at high ischemic and hemorrhagic risk require individualized treatment decisions and trade-off considerations.

Conference Report 33rd European Congress on Clinical Microbiology and Infectious Diseases (ECCMID): New developments in pediatric oncology infectious disease supportive care.

Infections continue to be major causes of morbidity and mortality in immunocompromised children and adolescents with cancer or undergoing allogeneic hematopoietic cell transplantation. This report summarizes new clinical research data presented at the 33rd European Congress on Clinical Microbiology and Infectious Diseases on infections in this vulnerable population, with a focus on the epidemiology, diagnosis, and prevention of invasive fungal diseases and de-escalation strategies in neutropenic patients with fever of unknown origin.

Net clinical benefit of dual antiplatelet therapy in elderly patients with acute coronary syndrome: A systematic review and meta-analysis.

Contemporary dual antiplatelet therapy (DAPT) strategies, such as short-term DAPT or de-escalation of DAPT, have emerged as attractive strategies to treat patients with acute coronary syndrome (ACS). However, it remains uncertain whether they are suitable for elderly patients. PubMed, Embase, and Cochrane CENTRAL databases were searched in September 2022. Randomized controlled trials (RCTs) investigating DAPT strategies, including standard (12 months), short-term, uniform de-escalation, and guided-selection strategies for elderly patients with ACS (age ≥ 65 years) were identified, and a network meta-analysis was conducted. The primary endpoint was the net clinical benefit outcome, a composite of major adverse cardiovascular events (MACEs: cardiovascular death, myocardial infarction, or stroke) and clinically relevant bleeding (equivalent to bleeding of at least type 2 according to the Bleeding Academic Research Consortium). The secondary outcomes were MACE and major bleeding. Sixteen RCTs with a combined total of 47,911 patients were included. The uniform de-escalation strategy was associated with an improved net clinical benefit compared with DAPT using potent P2Y12 inhibitors. The short-term DAPT strategy was associated with reduced risks of the primary outcome and major bleeding compared with DAPT using potent P2Y12 inhibitors, however, it was ranked as the least effective strategy for MACE compared with other DAPT strategies. Uniform de-escalation and short-term DAPT strategies may be advantageous for elderly patients, but need to be tailored based on individual bleeding and ischemic risks. Further RCTs of contemporary DAPT strategies specifically designed for elderly patients are warranted to confirm the findings of the present study.

“If I had a robot.”

Optimal case selection is critical to success in any robotic surgical treatment plan. In the Western world, transoral robotic surgery (TORS) is often employed as a de-escalation strategy in the evolving treatment of HPV-associated oropharyngeal malignancies. Since the orator trials [1,2] endorsed an overall superiority of radiotherapy for treating oropharyngeal cancers, there has been growing skepticism about its rampant and indiscriminate use in head and neck cancers. The current perspective article positions TORS in its evidence base and calibrates it to our routine practice.

Whole Breast Irradiation in Comparison to Endocrine Therapy in Early Stage Breast Cancer-A Direct and Network Meta-Analysis of Published Randomized Trials.

Multiple randomized trials have established adjuvant endocrine therapy (ET) and whole breast irradiation (WBI) as the standard approach after breast-conserving surgery (BCS) in early-stage breast cancer. The omission of WBI has been studied in multiple trials and resulted in reduced local control with maintained survival rates and has therefore been adapted as a treatment option in selected patients in several guidelines. Omitting ET instead of WBI might also be a valuable option as both treatments have distinctly different side effect profiles. However, the clinical outcomes of BCS + ET vs. BCS + WBI have not been formally analyzed. We performed a systematic literature review searching for randomized trials comparing BCS + ET vs. BCS + WBI in low-risk breast cancer patients with publication dates after 2000. We excluded trials using any form of chemotherapy, regional nodal radiation and mastectomy. The meta-analysis was performed using a two-step process. First, we extracted all available published event rates and the effect sizes for overall and breast-cancer-specific survival (OS, BCSS), local (LR) and regional recurrence, disease-free survival, distant metastases-free interval, contralateral breast cancer, second cancer other than breast cancer and mastectomy-free interval as investigated endpoints and compared them in a network meta-analysis. Second, the published individual patient data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) publications were used to allow a comparison of OS and BCSS. We identified three studies, including a direct comparison of BCS + ET vs. BCS + WBI (n = 1059) and nine studies randomizing overall 7207 patients additionally to BCS only and BCS + WBI + ET resulting in a four-arm comparison. In the network analysis, LR was significantly lower in the BCS + WBI group in comparison with the BCS + ET group (HR = 0.62; CI-95%: 0.42-0.92; p = 0.019). We did not find any differences in OS (HR = 0.93; CI-95%: 0.53-1.62; p = 0.785) and BCSS (OR = 1.04; CI-95%: 0.45-2.41; p = 0.928). Further, we found a lower distant metastasis-free interval, a higher rate of contralateral breast cancer and a reduced mastectomy-free interval in the BCS + WBI-arm. Using the EBCTCG data, OS and BCSS were not significantly different between BCS + ET and BCS + WBI after 10 years (OS: OR = 0.85; CI-95%: 0.59-1.22; p = 0.369) (BCSS: OR = 0.72; CI-95%: 0.38-1.36; p = 0.305). Evidence from direct and indirect comparison suggests that BCS + WBI might be an equivalent de-escalation strategy to BCS + ET in low-risk breast cancer. Adverse events and quality of life measures have to be further compared between these approaches.

Transitional justice model implementation’s mechanisms’ characteristics

Way of implementing transitional justice into national contexts is the parallel implementation of four conflict de-escalation strategies consisting of truth-seeking, judicial processes, reparations programs and institutional reforms. In this sense, the objective of this editorial is twofold, on the one hand, to present volume 41, number 78 of Political Questions and, on the other, to practical aspects of the transitional justice model implementation. The author substantiates that the process of transitional justice implementing is endowed with a certain ideological component serving the purpose of transitional justice implementing. The authors concept definition of “transitional justice model implementation” was proposed. It is noted that the mixed implementation mechanism of the studied model, combining domestic and international efforts in the field of peace building is the most acceptable for Ukraine. The author draws attention to the interdependence of the national context and the relevant mechanisms for the transitional justice implementation. The author concludes that implementation mechanisms are determined depending on the exigencies of the post-conflict society.

Short-Term DAPT and DAPT De-Escalation Strategies for Patients With Acute Coronary Syndromes: A Systematic Review and Network Meta-Analysis.

Short-term (≤6 months) dual antiplatelet therapy (DAPT) and DAPT de-escalation become attractive for patients with acute coronary syndrome. A systemic search identified randomized controlled trials that included patients with acute coronary syndrome treated using (1) standard DAPT (12 months) with clopidogrel, prasugrel (standard/low dose), or ticagrelor; (2) extended DAPT (≥18 months); (3) short-term DAPT (≤6 months) followed by P2Y12 inhibitor or aspirin; (4) 12-month DAPT with unguided de-escalation from potent P2Y12 inhibitors to low-dose potent P2Y12 inhibitor or clopidogrel at 1 month; and (5) guided selection DAPT with genotype or platelet function tests. The primary efficacy outcome (major adverse cardiovascular events) was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding. This meta-analysis included 32 randomized controlled trials with 103 497 patients. While there were no differences in efficacy between short, unguided de-escalation and guided selection strategies, unguided de-escalation was associated with reduced risk of major adverse cardiovascular events compared with standard DAPT with clopidogrel or ticagrelor (hazard ratio [95% CI], 0.67 [0.49-0.93] and 0.68 [0.50-0.93]). Both short DAPT followed by P2Y12 inhibitor and unguided de-escalation were associated with reduced risks in safety compared with other strategies, including guided selection (hazard ratio [95% CI], 0.66 [0.47-0.93] and 0.48 [0.33-0.71]). Short DAPT followed by a P2Y12 inhibitor was associated with reduced risk of major bleeding and all-cause death compared with standard, extended DAPT (eg, versus DAPT with clopidogrel; hazard ratio [95% CI], 0.64 [0.42-0.97] and 0.60 [0.44-0.82]). By rankogram, unguided de-escalation strategy was the safest and most effective strategy in reducing major adverse cardiovascular events and major or minor bleeding while short DAPT followed by P2Y12 inhibitor was ranked the best for major bleeding and all-cause death. In patients with acute coronary syndrome, unguided de-escalation was associated with the lowest risk of major adverse cardiovascular events and major or minor bleeding outcomes, while short DAPT followed by P2Y12 inhibitor was associated with the lowest risk of major bleeding and all-cause death.

A contrast-enhanced CT radiomics-based model to identify candidates for deintensified chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma patients.

To develop a contrast-enhanced CT (CECT) radiomics-based model to identify locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients who would benefit from deintensified chemoradiotherapy. LA-NPC patients who received low-dose concurrent cisplatin therapy (cumulative: 150mg/m2), were randomly divided into training and validation groups. 107 radiomics features based on the primary nasopharyngeal tumor were extracted from each pre-treatment CECT scan. Through Cox regression analysis, a radiomics model and patients' corresponding radiomics scores were created with predictive independent radiomics features. T stage (T) and radiomics score (R) were compared as predictive factors. Combining the N stage (N), a clinical model (T + N), and a substitution model (R + N) were constructed. Training and validation groups consisted of 66 and 33 patients, respectively. Three significant independent radiomics features (flatness, mean, and gray level non-uniformity in gray level dependence matrix (GLDM-GLN)) were found. The radiomics score showed better predictive ability than the T stage (concordance index (C-index): 0.67 vs. 0.61, AUC: 0.75 vs. 0.60). The R + N model had better predictive performance and more effective risk stratification than the T + N model (C-index: 0.77 vs. 0.68, AUC: 0.80 vs. 0.70). The R + N model identified a low-risk group as deintensified chemoradiotherapy candidates in which no patient developed progression within 3years, with 5-year progression-free survival (PFS) and overall survival (OS) both 90.7% (hazard ratio (HR) = 4.132, p = 0.018). Our radiomics-based model combining radiomics score and N stage can identify specific LA-NPC candidates for whom de-escalation therapy can be performed without compromising therapeutic efficacy. Our study shows that the radiomics-based model (R + N) can accurately stratify patients into different risk groups, with satisfactory prognosis in the low-risk group when treated with low-dose concurrent chemotherapy, providing new options for individualized de-escalation strategies. • A radiomics score, consisting of 3 predictive radiomics features (flatness, mean, and GLDM-GLN) integrated with the N stage, can identify specific LA-NPC populations for deintensified treatment. • In the selection of LA-NPC candidates for de-intensified treatment, radiomics score extracted from primary nasopharyngeal tumors based on CECT can be superior to traditional T stage classification as a predictor.

Early Antibiotic Deescalation and Discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single-Center Prospective Unblinded Randomized Trial

The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n=51) or EDD arm (n=59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P=.016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.