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BackgroundPORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis.Methods427 women with HIR endometrial cancer were randomised between 2002–2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.ResultsMedian follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.ConclusionLong-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. National Institute for Health Research Health Technology Assessment Programme.

P. aeruginosa is classified as a priority one pathogen by the World Health Organisation, and new drugs are urgently needed, due to the emergence of multidrug-resistant (MDR) strains. Antimicrobial-resistant nosocomial pathogens such as P. aeruginosa pose unwavering and increasing threats. Antimicrobial stewardship has been a challenge during the COVID-19 pandemic, with a majority of those hospitalized with SARS-CoV2 infection given antibiotics as a safeguard against secondary bacterial infection. This increased usage, along with increased handling of sanitizers and disinfectants globally, may further accelerate the development and spread of cross-resistance to antibiotics. In addition, P. aeruginosa is the primary causative agent of morbidity and mortality in people with the life-shortening genetic disease cystic fibrosis (CF). Prolonged periods of selective pressure, associated with extended antibiotic treatment and the actions of host immune effectors, results in widespread adaptive and acquired resistance in P. aeruginosa found colonizing the lungs of people with CF. This review discusses the arsenal of resistance mechanisms utilized by P. aeruginosa , how these operate under high-stress environments such as the CF lung and how their interconnectedness can result in resistance to multiple antibiotic classes. Intrinsic, adaptive and acquired resistance mechanisms will be described, with a focus on how each layer of resistance can serve as a building block, contributing to multi-tiered resistance to antimicrobial activity. Recent progress in the development of anti-resistance adjuvant therapies, targeting one or more of these building blocks, should lead to novel strategies for combatting multidrug resistant P. aeruginosa. Anti-resistance adjuvant therapy holds great promise, not least because resistance against such therapeutics is predicted to be rare. The non-bactericidal nature of anti-resistance adjuvants reduce the selective pressures that drive resistance. Anti-resistance adjuvant therapy may also be advantageous in facilitating efficacious use of traditional antimicrobials, through enhanced penetration of the antibiotic into the bacterial cell. Promising anti-resistance adjuvant therapeutics and targets will be described, and key remaining challenges highlighted. As antimicrobial stewardship becomes more challenging in an era of emerging and re-emerging infectious diseases and global conflict, innovation in antibiotic adjuvant therapy can play an important role in extending the shelf-life of our existing antimicrobial therapeutic agents.

Background Microvascular invasion (MVI) is considered to be one of the important prognostic factors that affect postoperative recurrence in patients with hepatocellular carcinoma (HCC) with variable results across their treatment options. This study was carried out to investigate efficacy of postoperative adjuvant RT in HCC patients with MVI. Methods This was single center, prospective study carried out in HCC patients with MVI, aged 35–72 years. All patients were non-randomly allocated to receive standard postoperative treatment of HBV/HCV and nutritional therapy or RT in addition to standard postoperative treatment (1:1). The primary endpoints assessed were relapse-free survival and overall survival. The prognostic factors associated with survival outcomes were also analyzed. The safety events were graded according to NCI-CTCAE v4.03 criteria. Results Of the 115 patients eligible for study, 59 patients were included in analysis. Univariate analysis revealed that MVI classification ( P  = 0.009), post-operative treatment strategies ( P  = 0.009) were prognostic factors for worst RFS; tumor size ( P  = 0.011), MVI classification ( P  = 0.005) and post-operative treatment ( P  = 0.015) were associated for OS. The 1-, 2-, 3-year RFS rates were 86.2, 70.5 and 63.4% for patients in RT group, and 46.4, 36.1, and 36.1% in control group. For OS, corresponding rates were 96.6, 80.7, and 80.7% for patients in RT group and 79.7, 58.3, and 50.0% in control group. Subgroup classification of HCC patients according to low risk MVI showed significantly longer RFS ( P  = 0.035) and OS ( P  = 0.004) in RT group than control group, while for high risk MVI, RT depicted longer OS than control group with no significance ( P  = 0.106). Toxicities were usually observed in acute stage with no grade 4 toxicities. Conclusion Postoperative adjuvant RT following hepatectomy offers better RFS for HCC patients with MVI than with standard postoperative therapy. Also, it will be useful to control microscopic lesions in both M1 (low risk) and M2 (high risk) subgroups of HCC patients with MVI. Trial registration Trial Registration number: ChiCTR1800017371 . Date of Registration: 2018-07-26. Registration Status: Retrospectively registered.

Background Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. Methods This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45–50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. Results Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61–0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37–0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44–0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. Conclusion After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

Objective The purpose of the study is to develop a prognosis nomogram for esophageal squamous cell carcinoma (ESCC) patients with radical resection and to identify patients who may benefit from postoperative adjuvant radiotherapy/chemoradiotherapy through survival risk stratification. Methods We retrospectively enrolled patients who underwent esophagectomy in the First Affiliated Hospital of Nanjing Medical University from July 2015 to June 2017. Patients with stage I-III esophageal squamous cell carcinoma who received radical R0 resection with or without postoperative adjuvant radiotherapy/chemoradiotherapy were included. Further, patients were randomly allocated into two groups (training and validation cohorts) with a distribution ratio of 7:3. The prognosis nomogram was constructed based on independent factors determined by univariate and multivariate Cox analyses. The area under the receiver operating characteristic curve (AUC) and calibration curve were adopted to evaluate the discriminative ability and reliability of the nomogram. The accuracy and clinical practicability were respectively assessed by C-index values and decision curve analysis (DCA), and further contrasted the nomogram model and the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system. In addition, survival risk stratification was further performed according to the nomogram, and the effect of postoperative adjuvant therapy on each risk group was appraised by the Kaplan-Meier survival analysis. Results A total of 399 patients with esophageal squamous cell carcinoma were recruited in this study, including the training cohort ( n  = 280) and the validation cohort ( n  = 119). The nomogram-related AUC values ​​for 1, 3, and 5-year OS were 0.900, 0.795, and 0.802, respectively, and 0.800, 0.865, 0.829 in the validation cohort, respectively. The slope of the calibration curve for both cohorts was close to 1, indicating good consistency. The C-index value of the nomogram was 0.769, which was higher than that of the AJCC 8th TNM staging system by 0.061 ( p  < 0.001). Based on the prognosis nomogram, patients were stratified into three risk groups (low, medium, and high), and there were obvious differences in prognosis among the groups ( p  < 0.001). Furthermore, postoperative adjuvant therapy has been shown to enhance the 5-year survival rate by over 15% among patients classified as medium- and high-risk. Conclusion The constructed nomogram as developed resulted in accurate and effective prediction performance in survival outcomes for patients with stage I-III esophageal squamous cell carcinoma who underwent radical R0 resection, which is superior to the AJCC 8th TNM staging system. The survival risk stratification had potential clinical application to guide further personalized adjuvant therapy.

BackgroundThe benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.MethodsSS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.ResultsMedian age of 185 patients was 13.9 years (0.1–56)—with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3–5 cm in 59 (32%), 5–10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.DiscussionOmission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.

There is controversy about the benefit of administering adjuvant therapy to esophageal cancer (EC) patients after preoperative neoadjuvant therapy and surgical treatment. This study aims to investigate the clinical benefit of postoperative adjuvant therapy in EC patients with neoadjuvant therapy and surgery. The study included EC patients diagnosed from 2007 to 2020 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who received neoadjuvant therapy (NCRT) were defined as those who underwent neoadjuvant chemotherapy or neoadjuvant radiotherapy before surgery, while patients who received adjuvant therapy (ACRT) were defined as those who underwent adjuvant chemotherapy or adjuvant radiotherapy after surgery. Propensity score matching (PSM) method was employed to establish matched cohorts, and Kaplan-Meier analysis, COX regression model, and Fine-Gray model were used for survival analysis. The study included a total of 5805 EC patients, with 837 (14.4%) in the ACRT group and 4968 (85.4%) in the no-ACRT group. After PSM, a cohort of 1660 patients who received NCRT was enrolled for analysis, with 830 patients in each group. Kaplan-Meier analysis revealed no significant differences between the two groups in terms of median overall survival (OS) (34.0 vs. 36.0 months, p = 0.89) or cancer-specific survival (CSS) (40.0 vs. 49.0 months, p = 0.16). Multivariate Cox models and Fine-Gray models indicated that ACRT was not a predictive factor for OS or CSS (p > 0.05). Subgroup analysis for CSS suggested a protective effect of ACRT in the N2 (Cox model: HR = 0.640, p = 0.090; Fine-Gray model: HR = 0.636, p = 0.081) and the N3 subgroup (Cox model: HR = 0.302, p = 0.018; Fine-Gray model: HR = 0.306, p = 0.034). Only for esophageal cancer patients with a more advanced N stage, postoperative adjuvant therapy after completing neoadjuvant therapy and curative surgical treatment may be beneficial.

Background Lymph-node (LN) metastasis is an important prognostic factor in resected pancreatic cancer. In this study, the prognostic value of American Joint Committee on Cancer (AJCC) 8th edition N stage, lymph-node ratio (LNR), and log odds of positive lymph nodes (LODDS) in resected pancreatic cancer was investigated. Methods Between January 2005 and December 2017, there were 351 patients with pancreatic cancer treated with R0 resection and adjuvant therapy at Seoul National University Hospital. Relationships between the three LN parameters and overall survival (OS) and recurrence-free survival (RFS) were evaluated using a log-rank test and Cox proportional hazard regression model. Each multivariate-adjusted LN parameter was internally validated by bootstrap-corrected Harrell’s C-index. Results The mean duration from surgery to adjuvant therapy was 47.6 ± 17.4 days. In total, the median OS and RFS was 31.7 (95% CI, 27.2-37.2) and 15.4 (95% CI, 13.5-17.7) months. The three LN classification systems were significantly correlated with OS and RFS in log-rank tests and multivariate-adjusted models (all p  < 0.05). When internally validated, LNR showed the highest discrimination ability in predicting OS and RFS (each C –index = 0.65). LNR also showed the highest C-index in subgroup analysis, classified by adjuvant therapy modality. LNR and the AJCC 8th edition LN classification system were significantly associated with loco-regional recurrence ( p  = 0.026 and p  = 0.027, respectively). Conclusions LNR, which showed the best prognostic performance and significant relationship with loco-regional recurrence, can help further stratify the patients and establish an active treatment plan.

Anaplastic thyroid cancer (ATC) is highly aggressive with a poor prognosis. Adjuvant systemic therapy and radiation post-surgery are endorsed by NCCN and ATA guidelines. Our study aimed to identify those at risk of forgoing postoperative adjuvant treatment and to determine survival predictors. We used the National Cancer Database (NCDB) to identify ATC patients who underwent upfront thyroidectomy from 2010 to 2017, excluding those opting for palliative care. We compared demographics, characteristics, treatments, and outcomes between those who received adjuvant therapy and those who did not. Predictors of receiving adjuvant therapy were identified using logistic regression, while Cox regression identified survival factors. Of 563 patients, 160 received no adjuvant treatment, 82 received radiation only, 16 received systemic therapy only, and 305 received combination therapy. Notably, over 75 ​% of patients who did not receive adjuvant treatment had it excluded from their treatment plan, not due to refusal. Older age (OR 0.92) and non-white race/ethnicity (OR 0.33) were significant predictors of not receiving adjuvant therapy. Undergoing a total thyroidectomy, an R0 or R1 resection, and radiation or combination therapy were associated with better survival, while non-metropolitan location, primary tumor size >7.5 ​cm, and stage IVC disease were negative factors. Total thyroidectomy, R0/R1 resection, and adjuvant therapy reduce mortality in ATC patients. However, older patients and minorities are less likely to receive adjuvant therapy, underscoring disparities in treatment adherence. •Total thyroidectomy, R0 resection, and adjuvant therapy reduce mortality in ATC patients.•Older patients and minorities are less likely to receive adjuvant therapy in ATC.•Most patients that did not receive adjuvant therapy did not cite refusal as the reason for not receiving it, suggesting possible poor provider adherence to guidelines.