De-escalation Approach Research Articles

Monitoring of circulating tumor DNA and indication of de-escalation adjuvant targeted therapy for EGFR-mutated non-small cell lung cancer after complete resection

IntroductionEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard adjuvant treatment for patients with stage IB-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). However, adapting this approach to include a molecular residual disease (MRD)-guided de-escalation strategy warrants further investigation. MethodsFrom January 2019 to December 2022, 71 patients with stage I–III NSCLC and EGFR (exon 19 del or L858R) mutations were enrolled in this observational study. A total of 375 blood samples were analyzed using the MRD_Navigator assay. Among them, 27 patients suspended EGFR-TKI treatment based on undetectable MRD and were thus included in the adaptive, de-escalation group. ResultsOverall, the sensitivity of longitudinal MRD was 86.2%. Only four patients (11.8%) recurred with longitudinal undetectable MRD, indicating a negative predictive value of 88.2%. Of the patients who had detectable MRD after surgery, nine subsequently received EGFR-TKI treatment, with only one (11.1%) achieving persistent ctDNA clearance post-EGFR-TKI. Twenty-two patients with stage IB-III disease who had previously suspended their TKI treatment based on undetectable MRD were included in the adaptive group, with an average duration of TKI 3.9 (range, 0–35.0) months. The 2-year disease-free survival rate of these 22 patients was 80.2%, and the median was not reached. Five patients (n=5/22, 22.7%) showed disease recurrence during the period of drug cessation, but were stable under EGFR-TKI treatment until the latest follow-up. Two patients remained in complete remission. ConclusionsOur initial findings underscore the potential of an adaptive, de-escalation approach to adjuvant EGFR-TKIs based on ctDNA-MRD monitoring.

A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma (cSCC) with the use of neoadjuvant pembrolizumab: De-Squamate.

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in resectable cSCC pts of all sites receiving neoadjuvant pembrolizumab. Methods: This multi-centre, open-labelled, non-randomised, single-arm phase 2 study evaluated the response of neoadjuvant Pembrolizumab for 4 cycles administered IV 200mg Q3W in immunocompetent pts with Stage II-IV (M0) resectable cSCC. Pts underwent CT/MRI and 18F-FDG-PET imaging at baseline and following completion of neoadjuvant pembrolizumab. In those with a complete metabolic response, mapping biopsies of target site(s) were performed and if negative for residual SCC (clinical complete response [CCR]), surgery and post operative radiation therapy (PORT) were omitted. Patients with clinical or radiological residual disease/ positive mapping biopsy underwent surgical resection. PORT was de-escalated if there was a pathological complete response (PCR - no residual tumour cells) or major pathological response (MPR - less than or equal to 10% viable tumour cells). Pts proceeded to 13 cycles of maintenance Pembrolizumab. The primary endpoint was the combined rate of PCR, MPR and CCR following neoadjuvant Pembrolizumab and secondary endpoint includes treatment de-escalation and safety. Results: All 27 patients were enrolled and received a minimum of 2 cycles of neoadjuvant Pembrolizumab. The primary endpoint was observed in 17 patients (63%, 95% CI: 42-80), comprised of PCR (15%), MPR (0%) and CCR (48%). De-escalation of both surgery and PORT was achieved in 48% and a further 15% avoided PORT alone. With a minimum follow up of 6 months, no pts with PCR/MPR/CCR recurred. Investigator assessed treatment-related adverse events ≥ grade 3 was seen in 2 patients (7%). Conclusions: Pembrolizumab led to a high rate of PCR and CCR in resectable cSCC. The de-squamate study design effectively selected pts for surgical and PORT de-escalation and demonstrated a sustained response in this cohort. Clinical trial information: NCT05025813 .

Should Children Be Included in Human Challenge Studies?

Human challenge studies, in which human research subjects are intentionally exposed to pathogens to contribute to scientific knowledge, raise many ethical complexities. One controversial question is whether it is ethically permissible to include children as participants. Commentary of the past decades endorses the exclusion of children, while new guidance suggests that pediatric human challenge studies can be ethically permissible. This paper argues that neither children's exclusion nor their inclusion are well justified. I examine and reject three arguments for exclusion, but suggest that these arguments establish pediatric human challenge studies as a complex ethical category of research that requires caution. I then argue for a strong presumption against children's inclusion, by drawing on an analogy to children's inclusion in phase I trials, emphasizing a requirement of necessity, and suggesting that accommodating children's vulnerability promotes an age de-escalation approach for pediatric human challenge studies research. In the final section, I suggest a procedure for ethics review.

Adjuvant Hypofractionated Whole Breast Irradiation (WBI) vs. Accelerated Partial Breast Irradiation (APBI) in Postmenopausal Women with Early Stage Breast Cancer: 5Years Update of the HYPAB Trial

Therapeutical strategies in breast cancer are continuously updating. Recent researches assessed the possibility of irradiating only the surgical bed in selected patients (Partial Breast Irradiation, PBI). In 2014 we designed a study to evaluate toxicity and cosmesis of APBI using Volumetric Modulated Arc Therapy-Rapid Arc compared with hypofractionated whole breast irradiation (WBI). We present here the 5-years updated data. HYPAB was a single-institution randomized trial that recruited 172 patients from 2015 to 2018. Patients underwent conserving surgery and were randomized to either adjuvant WBI (40.5Gy/15 fractions with simultaneous boost to 48 Gy to tumoral bed) or APBI (30Gy/5 fractions), both delivered with VMAT-RA technique. Clinical evaluation was performed during the first visit, once a week during radiotherapy and during follow up. Cosmesis was assessed using the Harvard Scale for Breast Cosmesis. At the time of the analysis 161 patients were eligible, 53% in the WBI and 47% in the APBI group, with a median follow-up of 67 months. Most common late skin toxicities were G1 fibrosis (32%) and oedema (28%) and were higher in the WBI group; no G3 toxicities were observed. Cosmesis was rated poor in only 6 cases. 147 patients had no evidence of disease at the last follow-up, and no patients died of the disease. Mature results confirm the safety and efficacy of APBI in selected early stage breast cancer patients. Late toxicity is improved in the APBI arm at the cost of a slight increase in local relapse. Further studies are ongoing to better elucidate the use of APBI as a de-escalation approach.

Micrometastases in the sentinel node after neoadjuvant therapy. Is axillary dissection still required?

The present review intends to discuss the controversies and strengths in clinically node-positive patients with axillary nodal status ypNi+/mi after neoadjuvant chemotherapy. Over the past 20 years, a de-escalation approach toward axillary surgery has been observed in patients with breast cancer. The worldwide use of sentinel node biopsy in the upfront setting and after primary systemic therapy substantially reduced surgical complications or late sequelae and eventually improving quality of life of patients. However, the role of axillary dissection is still unclear in patients with low residual disease post-chemotherapy, namely those with micrometastases in the sentinel node, and its prognostic role is still not very clear. The aim of the present narrative review is to report the available evidence on this topic, discussing the pros and cons of performing axillary lymph node dissection in the infrequent finding of micrometastases in the sentinel node after neoadjuvant chemotherapy. We will also describe the ongoing prospective studies which are expected to shed light and guide future decisions.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P=.018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P=.037) compared with patients receiving standard CRT. Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Long term effects of de-escalation antimicrobial strategy in the burn unit

BACKGROUND: De-escalation strategy of antimicrobial therapy demonstrates favorable short-term results: it lowers the mortality and reduces the cost of treatment. The long-term results of applying this strategy in the burn unit had not been studied previously.&#x0D; AIM: To compare the long-term results of the de-escalation approach to antimicrobial therapy on the microbial spectrum, resistance of the hospital microflora and consumption of antimicrobials in the burn unit.&#x0D; MATERIALS AND METHODS: The study comprises the data from the burn unit of the Severstal hospital for 2006, 2012 and 2021: statistical data on mortality and the average duration of hospital stay; microbiological data on spectrum and resistance of bacteria to antimicrobials.&#x0D; RESULTS: The use of the de-escalation strategy of antimicrobial therapy in the burn unit of the Healthcare Institution Severstal for 10 years has reduced mortality, length of stay, consumption of antimicrobials. De-escalation strategy has not significantly affect the spectrum of nosocomial microflora but has lowered the resistance of gram-positive microorganisms to antibiotics. There was a decrease in the drug resistance index for the main pathogens of infectious complications as a result of implementing the de-escalation strategy.&#x0D; CONCLUSIONS: The implementation a de-escalation strategy of antimicrobial therapy requires conducting periodic microbiological monitoring for early correction of starting antimicrobial regimens.

Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity.

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P < 0.05). A neutropenic rabbit pneumonia model demonstrated that aztreonam plus ceftazidime-avibactam with or without polymyxin B resulted in similar bacterial killing, and these combination therapies were statistically significantly better than monotherapies (P < 0.05). However, only the polymyxin B-containing combination therapy produced a statistically significant decrease in lung weights (P < 0.05), indicating a decreased inflammatory process. Altogether, adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM- and CTX-M-producing K. pneumoniae improved bacterial killing effects, reduced lung inflammation, suppressed resistance amplification, and limited virulence changes.

Characterizing Lymph Node Burden With Elective Unilateral Neck Irradiation in Human Papillomavirus-Positive Tonsil Squamous Cell Carcinoma: Defining the Upper Limits.

ObjectivesElective unilateral neck irradiation in well-lateralized tonsil carcinoma for N2b disease is controversial. Metrics regarding nodal burden beyond the N-stage to define the upper limit of this de-escalation approach remain limited. We investigated the role of nodal number, level, and volume on outcomes in patients with well-lateralized tonsil carcinoma treated with this approach.MethodsA total of 37 patients received radiotherapy (RT) with unilateral neck coverage for well-lateralized tonsil cancer. Of patients, 95% had p16+ disease, and 81% were staged with positron emission tomography/computed tomography. The majority of patients received definitive chemoradiation on prospective de-escalation trials. Ten patients had ipsilateral neck dissections and were treated adjuvantly. The median RT dose to the ipsilateral neck (generally II-IV) was 45 Gy. The effects of nodal number, max dimension, volume, and level on recurrence-free survival (RFS) and overall survival (OS) were to be analyzed via Cox proportional hazards (Cox-PH).ResultsAfter a median follow-up of 3.9 years, two-year RFS and two-year OS were 100% and 97%, respectively. Given the 0% contralateral recurrence rate, Cox-PH analysis was not performed. Of patients, 70% were American Joint Committee on Cancer (AJCC) 7th edition N2b, with a median number of nodes, number of nodal levels, max dimension, and volume of two, one, 3.4 cm, and 15.6 cc, respectively. There were several patients with low-lying nodes; aggregate nodal volume measured was up to 85.4 cc.ConclusionUnilateral neck irradiation in well-lateralized tonsil carcinoma resulted in no contralateral recurrence. Nodal volume, level, and number do not seem to have a significant impact on outcomes.

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

BackgroundStrategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation.ObjectiveTo provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients.MethodsWe reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation.ResultsYounger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity.ConclusionIn a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Adjuvant treatment with paclitaxel plus trastuzumab for node-negative breast cancer: real-life experience.

Background: In node-negative HER2-overexpressedbreast cancers, adjuvant paclitaxel plus trastuzumab treatment is a successful de-escalation approach with excellent survival outcomes. Methods: All patients with HER2+ breast cancer treated in our centers were retrospectively reviewed. Results: We analyzed 173 patients who were treated with adjuvant paclitaxel plus trastuzumab. The mean tumor size was 2.2cm. There were eight invasive disease events or death: four distant recurrences (2.3%), three locoregional recurrences (1.7%)and one death without documented recurrence after a52monthfollow-up. The 3-year disease-free survival and recurrence-free interval rate was 96.6%. Conclusion: This real-life experience with adjuvant paclitaxel plus trastuzumab demonstrated few distant recurrences and iscompatible with theAPT trial findings.

Dose and Volume De-Escalation for Elective Nodal Regions in Patients With Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer (OPC) Undergoing Curative-Intent Concurrent Chemoradiation (CCRT)

Several de-escalation strategies for HPV-associated OPC have focused on treatment de-intensification to the gross disease. We propose that by systematically reducing the volume and dose to the elective regions, toxicity can be decreased without compromising tumor control. Here we report our long-term results.Since 2010, we started our systemic de-escalation approach by first reducing the treatment volumes for the node-negative neck. Retropharyngeal, level IB, high level II, and levels IV-V nodal basins were not included in the subclinical target volume. For the node-positive neck, levels IB and V were not covered unless involved. Using this approach, we have observed high control rates. Starting March 2017, we subsequently reduced the dose to all elective regions to 30 Gy in 15 fractions for all patients with HPV-positive OPC undergoing curative CCRT. This is followed by a cone-down to the gross disease with a 3-5 mm margin delivering 40 Gy in 20 fractions. Patients were required to receive concurrent cisplatin or other chemotherapy.From March 2017 to July 2019, 276 consecutive HPV-positive OPC patients underwent CCRT. Median age was 61 (range: 34-87), 90% were male, and 26% had ≥ 15 pack-year of smoking history. Overall, 35% had cT3-4 and 24% had cN2-3 per AJCC 8th Edition. The majority (77%) received high-dose cisplatin and 81% of them had a cumulative dose of 300mg/m2. With a median follow-up of 23 months (range: 1-42), 7 patients (2.5%) developed locoregional recurrence - 6 had disease recurrence in the primary site and/or gross nodes that received 70 Gy and 1 patient had a gross nodal recurrence in the 30 Gy region due to mistargeting. All patients with gross nodal recurrence in the neck were successfully salvaged with surgery. There was no disease recurrence in the subclinical fields receiving 30 Gy or in the omitted radiation fields. Seventeen (6.2%) patients developed distant metastasis. The 2-year locoregional recurrence-free survival was 92.5%, distant metastasis-free survival 90.0%, and overall survival 94.6%. Fifty-six of the 276 patients were also enrolled on an adaptive radiotherapy protocol (NCT03096808) to study modification of the radiation treatment plan during treatment course to account for temporal variations in anatomy, with toxicities and quality-of-life (QoL) metrics evaluated at baseline and follow-up visits. Of the 56 patients on adaptive protocol, 5.8% had feeding tube placement during treatment. No patient had feeding tube dependence at 6 months after radiotherapy. At 2-year follow-up, most of the QoL metrics (pain, social contact, social eating, speech, and swallow) were comparable or superior to baseline measures except for taste and xerostomia.The systematic de-escalation strategy of volume and dose resulted in favorable locoregional control and acute toxicities profile. This regimen can be adapted for treating a wide range of HPV-associated OPC patients undergoing primary CCRT.

Stem-Like Cell Populations, p53-Pathway Activation and Mechanisms of Recurrence in Sonic Hedgehog Medulloblastoma.

While most Sonic Hedgehog-associated medulloblastomas (SHH-MBs) respond to therapeutic intervention, radiation therapy often causes deleterious long-term neurocognitive defects, especially in infants and young children. To limit neurological comorbidities, the development of a reduction-of-therapy treatment or de-escalation approach was investigated. Although retrospective analysis of MBs indicated low-dose therapy was potentially effective, clinical de-escalation trials showed poor outcomes in infant SHH-MBs and was prematurely terminated. Recent studies suggest the existence of cancer-stem-cell (CSC)-like cell populations that are more resistant to therapies and drive tumor recurrence. This review will discuss the mechanism of these CSC-like cells in SHH-MBs in resisting to p53-pathway activation, which may contribute to the disappointing outcomes of the recent de-escalation trials.

Nivolumab, nabpaclitaxel, and carboplatin followed by risk/response adaptive de-escalated locoregional therapy for HPV-associated oropharyngeal cancer: OPTIMA II trial.

6011 Background: Despite the success of anti-PD-1 in recurrent/metastatic head and neck cancer, incorporation in the curative setting with induction therapy has yet to be investigated. Favorable prognosis of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) has led to interest in treatment de-escalation. OPTIMA 2 evaluated nivolumab (nivo) with nab-paclitaxel and carboplatin followed by risk/response adaptive de-intensified treatment for locoregionally advanced HPV+ OPC. We report the primary analysis and outcomes. Methods: OPTIMA 2 enrolled locoregionally advanced HPV+ OPC. Nivo, nab-paclitaxel, and carboplatin were administered for 3 cycles. High-risk (HR) included any of the following: T4, N2c-N3 (AJCC 7th edition), &gt; 20 pack year smoking history, non-HPV16 subtype; All others were low-risk (LR). Arm A included LR with ≥50% post-induction shrinkage by RECIST received single-modality de-escalation with low-dose radiation (RT) alone (50 Gy) or transoral robotic surgery (TORS). Arm B included HR with ≥50% shrinkage or LR with &lt;50% received intermediate-dose chemoradiation (CRT) to 45-50Gy. Arm C included all others and received regular dose CRT to 70-75Gy. Adjuvant nivo was administered for 6 months. The primary endpoint was deep response rate (DRR) ≥50% shrinkage to induction therapy. Results: From September 2017 until March 2020, 73 patients (pts) were eligible and started treatment. One pt died during induction. The DRR following induction was 70.8% (95% CI 60.3%, 81.3%). Median follow-up 23.1 months. Median age 61 (range 39-85), T4 12.3%, N2c/N3 19.2%, LR 47.9%, and HR 52.1%. De-escalated treatment was administered in 84.9%. Arm A N = 28, Arm B N = 34, and Arm C N = 10. 2-year progression free survival (PFS) for full cohort was 90.4% (95% CI = 79.3%, 95.7%). 2-year PFS for Arms A, B, and C were 96.3%, 85.8%, and 100.0% respectively. 2-year overall survival (OS) for full cohort was 93.3% (95% CI = 82.4%, 97.5%). 2-year OS for Arm A, B, and C were 96.0%, 91.9%, and 100.0% respectively. Among TORS (N = 9), pathologic complete response (pCR) rate was 66.7%. G-tube rates in Arms A, B, and C were 7.1%, 44.1%, and 75.0% respectively (p = 0.0001). Grade 4 toxicity in arms A, B, and C, were observed in 7.1%, 8.8%, and 10.0% of pts respectively. There were 3 local failures and no distant failures. Conclusions: Nivo/nab-paclitaxel/carboplatin followed by risk/response adaptive de-escalated treatment in locoregionally advanced HPV+ OPC demonstrates excellent survival outcomes with reduced toxicity and enteral feeding rates, including high risk disease. Induction chemoimmunotherapy demonstrates a high rate of deep clinical response and represents a promising de-escalation approach that incorporates anti-PD1 in the definitive setting. High pCR rate was observed following nivo/nab-paclitaxel/carboplatin. Clinical trial information: NCT03107182.

Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis

Whether guided selection of antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) is effective in improving outcomes compared with standard antiplatelet therapy remains controversial. We assessed the safety and efficacy of guided versus standard selection of antiplatelet therapy in patients undergoing PCI. For this systematic review and meta-analysis, from Aug 20 to Oct 25, 2020, we searched MEDLINE (via PubMed), Cochrane, Embase, and Web of Science databases for randomised controlled trials and observational studies published in any language that compared guided antiplatelet therapy, by means of platelet function testing or genetic testing, versus standard antiplatelet therapy in patients undergoing PCI. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. Risk ratios (RRs) and 95% CIs were used with random-effects or fixed-effect models according to the estimated heterogeneity among studies assessed by the I2 index. Coprimary endpoints were trial-defined primary major adverse cardiovascular events and any bleeding. Key secondary endpoints were all-cause death, cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and major and minor bleeding. This study is registered with PROSPERO (CRD42021215901). 3656 potentially relevant articles were screened. Our analysis included 11 randomised controlled trials and three observational studies with data for 20 743 patients. Compared with standard therapy, guided selection of antiplatelet therapy was associated with a reduction in major adverse cardiovascular events (RR 0·78, 95% CI 0·63-0·95, p=0·015) and reduced bleeding, although not statistically significant (RR 0·88, 0·77-1·01, p=0·069). Cardiovascular death (RR 0·77, 95% CI 0·59-1·00, p=0·049), myocardial infarction (RR 0·76, 0·60-0·96, p=0·021), stent thrombosis (RR 0·64, 0·46-0·89, p=0·011), stroke (RR 0·66, 0·48-0·91, p=0·010), and minor bleeding (RR 0·78, 0·67-0·92, p=0·0030) were reduced with guided therapy compared with standard therapy. Risks of all-cause death and major bleeding did not differ between guided and standard approaches. Outcomes varied according to the strategy used, with an escalation approach associated with a significant reduction in ischaemic events without any trade-off in safety, and a de-escalation approach associated with a significant reduction in bleeding, without any trade-off in efficacy. Guided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. None.

The Evolving Role of Marked Lymph Node Biopsy (MLNB) and Targeted Axillary Dissection (TAD) after Neoadjuvant Chemotherapy (NACT) for Node-Positive Breast Cancer: Systematic Review and Pooled Analysis.

Simple SummaryThe 5-year survival rate for patients with breast cancer, in whom disease has spread to local lymph nodes, is 85%. However, many live with the complications of surgery to remove the lymph nodes in the armpit thus impacting their quality of life. In recent years, new approaches have been developed to minimise surgery and reduce complications. The aim of this systematic review was to assess the feasibility and accuracy of two minimally invasive surgical procedures, Marked Lymph Node Biopsy and Targeted Axillary Dissection as an alternative to complete removal of the axillary lymph nodes after upfront chemotherapy in patients in whom cancer spread to the regional lymph nodes. Our findings confirm that these procedures can safely replace more radical surgery in women who have responded well to upfront drug treatment. Therefore, although further research to determine long-term outcomes is required, this review concludes that it is reasonable to offer such patients the option of less invasive surgery thus avoiding over treatment and enhancing quality of life.Targeted axillary dissection (TAD) is a new axillary staging technique that consists of the surgical removal of biopsy-proven positive axillary nodes, which are marked (marked lymph node biopsy (MLNB)) prior to neoadjuvant chemotherapy (NACT) in addition to the sentinel lymph node biopsy (SLNB). In a meta-analysis of more than 3000 patients, we previously reported a false-negative rate (FNR) of 13% using the SLNB alone in this setting. The aim of this systematic review and pooled analysis is to determine the FNR of MLNB alone and TAD (MLNB plus SLNB) compared with the gold standard of complete axillary lymph node dissection (cALND). The PubMed, Cochrane and Google Scholar databases were searched using MeSH-relevant terms and free words. A total of 9 studies of 366 patients that met the inclusion criteria evaluating the FNR of MLNB alone were included in the pooled analysis, yielding a pooled FNR of 6.28% (95% CI: 3.98–9.43). In 13 studies spanning 521 patients, the addition of SLNB to MLNB (TAD) was associated with a FNR of 5.18% (95% CI: 3.41–7.54), which was not significantly different from that of MLNB alone (p = 0.48). Data regarding the oncological safety of this approach were lacking. In a separate analysis of all published studies reporting successful identification and surgical retrieval of the MLN, we calculated a pooled success rate of 90.0% (95% CI: 85.1–95.1). The present pooled analysis demonstrates that the FNR associated with MLNB alone or combined with SLNB is acceptably low and both approaches are highly accurate in staging the axilla in patients with node-positive breast cancer after NACT. The SLNB adds minimal new information and therefore can be safely omitted from TAD. Further research to confirm the oncological safety of this de-escalation approach of axillary surgery is required. MLNB alone and TAD are associated with acceptably low FNRs and represent valid alternatives to cALND in patients with node-positive breast cancer after excellent response to NACT.

Management of the axilla in breast cancer: outcome analysis in a series of ductal versus lobular invasive cancers

Axillary lymph node dissection (ALND) has been considered essential for the staging of breast cancer (BC). As the impact of tumor biology on clinical outcomes is recognized, a surgical de-escalation approach is being implemented. We performed a retrospective study focused on surgical management of the axilla in invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC). 1151 newly diagnosed BCs, IDCs (79.6%) or ILCs (20.4%), were selected among patients treated at our Breast Cancer Unit from 2012 to 2018. Tumor characteristics and clinical information were collected and predictors of further metastasis after positive sentinel lymph node biopsy (SLNB) analyzed in relation to disease-free survival (DFS) and overall survival (OS). 27.5% of patients with ILC had ≥ 3 metastatic lymph nodes at ALND after positive SLNB versus 11.48% of IDCs (p = 0.04). Risk predictors of further metastasis at ALND were the presence of > 2 positive lymph nodes at SLNB (OR = 4.72, 95% CI 1.15-19.5 p = 0.03), T3-T4 tumors (OR = 4.93, 95% CI 1.10-22.2, p = 0.03) and Non-Luminal BC (OR = 2.74, 95% CI 1.16-6.50, p = 0.02). The lobular histotype was not associated with the risk of further metastasis at ALND (OR = 1.62, 95% CI 0.77-3.41, p = 0.20). ILC histology is not associated with higher risk of further metastasis at ALND in our analysis. However, surgical management decisions should be taken considering tumor histotype, biology and expected sensitivity to adjuvant therapies.

A Rational Approach to a De-Escalation of Double Antithrombotic Therapy: The Possibilities of Clopidogrel

In the review based on existing clinical recommendations and guidelines of the European cardiology society and results of clinical and register trials difficult questions about a antithrombotic therapy in the patients with an acute coronary syndrome and percutaneous coronary interventions were discussed. The perspective strategy of risk management on ischemic and hemorrhagic events were described. Need of the maximum personification of purpose of double antithrombotic therapy at patients with an acute coronary syndrome or after carrying out transdermal coronary interventions is updated. Real requirement on constant assessment of balance in risks of ischemic and hemorrhagic events in this group of patients were defined. The perspective strategy of risk management in ischemic and hemorrhagic events from a position of results of relevant clinical trials were described. Results of clinical trials (TOPIC, TROPICAL-ACS) about transfer the ACS patients from “new” desaggregants on clopidogrel were presented (De-Escalation approach). Examples of the clinical situations suitable for realization of such approach were reviewed. The prospects of use of De-Escalation approach are designated and positions of a clopidogrel and, in particular, the original drug Plavix were provided. At the same time, appointment in patients with ACS within 12 months of double antiaggregant therapy is the proved option of treatment allowing to improve the prognisis. However, in some cases there is a reasonable requirement of the transfer of the patient from the “new” antiaggregants (ticagrelor or prasugrel) to clopidogrel (“de-escalation”). It needs to perfome according to the available evidence base recommendations and it is strict according to clinical indications. In particular, patients can have a perspective de-escalation with high risk of bleedings or with already developed bleeding; in patients with the forced refusal of reception of “new” antiaggregants owing to development of side effects / intolerance / allergic reactions; in the presence of indications for life long intake of anticoagulants in case of the need for purpose of double or triple antithrombotic therapy; in patients with ACS with low risk.

Prospective Phase I Dose Escalation Study for Neoadjuvant Radiosurgery for Large Brain Metastases

Single session stereotactic radiosurgery (SRS) alone for brain metastases larger than 2cm in maximal dimension results in local control of only 50%. Surgical resection followed by SRS to the resection cavity can result in leptomeningeal failure (LMD). Neoadjuvant SRS followed by resection has been investigated as a dose de-escalation approach with good local control and without LMD. The purpose of this Phase I trial is to determine the maximum tolerated radiosurgery dose (MTD) for neoadjuvant radiosurgery for brain metastases larger than 2cm in maximal dimension. Radiosurgery dose was escalated at 3 Gy increments from currently accepted RTOG dosing; and cohorts of 2-6 patients were treated at each dose. Initially 2 patients were treated at a particular dose and followed for 4 months. If no dose-limiting toxicities (DLT) were observed the dose was escalated and a new cohort of 4 patients were treated. Patients underwent surgical resection of brain metastases within 2 weeks of SRS and were followed with brain MRIs and neurologic evaluations every 3 months. A total of 27 patients have enrolled on the trial. Median and mean follow up are 9.2 and 15.2 months, respectively. For tumor size >2.0 - 3.0 cm, 2 patients completed treatment at 18 Gy and 3 patients at 21Gy. For tumor size >3.0 - 4.0 cm, 4 patients were treated at 15 Gy and 9 patients were treated at 18 Gy and 1 patient at 21 Gy. For tumor size > 4.0 - 5.0 cm, 1 patient was treated at 12 Gy and 7 patients at 15 Gy. No DLT have occurred. MTD has not yet been met. Twenty-six patients were evaluable for acute toxicity. Twenty-two patients (85%) had no adverse events related to protocol treatment. Three patients had grade I fatigue or headaches and 1 patient had grade II fatigue possibly related to treatment. No patients have experienced radiation necrosis. 13 patients have died at time of analysis. The 6 and 12 month local control was 94.7% and 94.7%, respectively. Six and 12 month distant brain control was 71.7% and 49.6% respectively. Overall survival at 6 and 12 months was 81.5% and 54.9%, respectively. One patient developed LMD 5 months following SRS. Only one patient has received whole brain radiotherapy. There are low rates of toxicity for neoadjuvant SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size. MTD has not yet been reached. Early results demonstrate excellent local control with low risk of LMD.

Antimicrobial de-escalation in adult hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin.

The optimal duration of empiric antimicrobial therapy in febrile neutropenia of unknown origin is unclear. This study evaluated outcomes in autologous and allogeneic hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin who received early de-escalation of broad-spectrum antimicrobials prior to hematopoietic recovery versus those who continued broad-spectrum antimicrobials until hematopoietic recovery. A single-center, retrospective study assessed hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin. Patients were categorized into either cohort 1, representing early de-escalation prior to hematopoietic recovery, or cohort 2, representing continuation of broad-spectrum antimicrobials until hematopoietic recovery. A total of 107 patients were included (22.4% in cohort 1 and 77.6% in cohort 2). Most patients (87.5%) in cohort 1 underwent haploidentical hematopoietic cell transplantation, whereas 84.3% of patients in cohort 2 received autologous hematopoietic cell transplantation. There were no significant differences in rates of recurrent fever (4.2% versus 7.2%, in cohorts 1 and 2, respectively, adjusted odds ratio = 0.84, P = 0.85), re-escalation (4.2% versus 4.8%, adjusted odds ratio = 1.57, P = 0.64), and Clostridioides difficile-associated infections (4.2% versus 2.4%, adjusted odds ratio = 2.27, P = 0.43). No patient experienced in-hospital mortality, intensive care unit admission, or bacteremia. Hematopoietic cell transplantation recipients with febrile neutropenia of unknown origin in which broad-spectrum antimicrobials were de-escalated prior to hematopoietic recovery did not experience adverse outcomes. These results concur with recently published studies and the Fourth European Conference on Infections in Leukemia guidelines. An early de-escalation approach in haploidentical hematopoietic cell transplantation recipients specifically appears safe and may result in a reduction in antimicrobial utilization.