Long-Term Mortality and Morbidity after Carotid Endarterectomy for Symptomatic and Asymptomatic Carotid Stenosis.

To investigate whether the occurrence of ischemic stroke due to carotid stenosis is a marker of the severity of atherosclerotic disease and of an excess risk of cardiovascular morbidity and mortality, and of all-cause mortality, after carotid endarterectomy (CEA). Patients who had undergone a CEA from June 2015 to august 2016 were included. Patients were classified into 2 groups, namely symptomatic and asymptomatic. Neurological event, myocardial infarction, and death during early follow up were monitored. Major adverse cardiovascular events, major limb eventss, and all-cause mortality were compared for patients with a CEA for an asymptomatic carotid stenosis versus those with a symptomatic stenosis. Among the 190 patients included, 86 (51%) had a CEA for an asymptomatic stenosis and 84 (49%) for a symptomatic stenosis. During the first 30 days, the rate of all-cause death or ischemic stroke was similar in both groups (1%, P = 0.986). After 30 days, there were a total of 35 major adverse cardiovascular events (21.3%) and 15 major limb events (9.1%) during mean follow up of 53 (22.6) months. Overall cardiovascular morbidity and mortality was 30.4% and did not differ between groups (P = 0.565). New ischemic stroke occurred in 11 patients (9.1%) and was significantly more frequent in the asymptomatic group (9 (14.8%) versus 2 (3.6%) in the symptomatic group, (odds ratio: 4.96; confidence interval 95% [1.04-23.77]; P = 0.013)). Overall all-cause mortality was 24% in both groups (P = 0.93) CONCLUSIONS: The occurrence of ischemic stroke of carotid origin before revascularization does not appear to be associated with an excess risk of cardiovascular morbidity or mortality or all-cause mortality after surgery.

Tresson P ，Lo S ，Rivoire E ，Cho TH ，Millon A ，Long A ... -  《-》

Retrospective Analysis of a Novel Grading System for Evaluating the Long-Term Benefit of Revascularization on Carotid Artery Stenosis.

To estimate revascularization benefit for carotid artery stenosis, with a novel grading system containing symptoms, stenosis, plaque, and collateral compensation (SSPC grading system). A retrospective multicenter study examined 945 consecutive patients diagnosed with carotid stenosis from January 2013 to December 2017. The cohort was classified into 2 groups: the revascularization group and the best medical therapy (BMT) group. Demographic, clinical, and lesion characteristics of all patients were recorded and 5-year nonprocedural stroke survival was calculated using Kaplan-Meier curve analyses. Of the 945 patients, 514 underwent carotid revascularization (483 for carotid endarterectomy and 31 for transfemoral-carotid artery stenting) and 431 patients were treated with BMT. Patients in the revascularization group had a significantly higher proportion of preprocedural stroke/transient ischemic attack (TIA) and grades of stenosis. Of the patients in the revascularization group, 3.1% were classified as SSPC I, 10.3% as SSPC II, 41.4% as SSPC III, and 45.1% as SSPC IV. Meanwhile, 17.9% were classified as SSPC I, 19.7% as SSPC II, 49.2% as class III, and 13.2% had class IV in the BMT group. Procedural stroke developed in 13 patients (2.5%) following revascularization (10 of them were non-disabling). The overall rate of freedom from any nonprocedural stroke was 94.1 ± 1.1% in the revascularization group and 89.5 ± 1.6% in the BMT group (P = 0.01). Subgroup analysis was conducted for asymptomatic carotid stenosis (ACS) and carotid near-occlusion (CNO) patients. Nonsignificance was noted in the rate of freedom from any nonprocedural stroke between revascularization and BMT in both ACS and CNO subgroups (P = 0.09 and 0.12, respectively). Of note, in ACS patients graded as SSPC III, a significant difference in stroke survival was found between the revascularization and BMT group (96.0 ± 2.0% vs. 89.1 ± 2.4%, P = 0.04). Meanwhile, in symptomatic CNO patients, similar results were found regarding SSPC classification (94.8 ± 3.6% vs. 63.8 ± 14.9%, P = 0.01). The SSPC grading system stratifies the patients with carotid artery stenosis and predicts the long-term benefits of revascularization. Meanwhile, potential revascularization benefits could be better attained via SSPC classes in specific patients with ACS and CNO.

Fan W ，Tan J ，Wang J ，Deng Y ，Liang K ，Tong J ，Tang J ，Shi W ，Yu B ... -  《-》

Impact of diabetes on carotid artery revascularization.

Diabetes has been suggested as a marker of higher operative risk during carotid artery revascularization. The aim of this study was to summarize the current evidence comparing the effectiveness of carotid revascularization in diabetic vs nondiabetic patients. We conducted a systematic search of MEDLINE, Embase, and the Cochrane Library databases (1946 to January 2015) for all studies comparing the clinical outcomes of diabetic vs nondiabetic patients who underwent carotid endarterectomy (CEA) or carotid artery stenting (CAS) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two authors independently reviewed the studies for inclusion and quality and extracted the data. A third author validated study selection and data extraction. We calculated treatment effects as odds ratios (ORs) and 95% confidence intervals (CIs). We quantified heterogeneity using the I(2) statistic. All pooled analyses were based on random-effects models. The predefined review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO 2015:CRD42015015873). Of the 1241 abstracts screened, we included 14 observational studies involving 16,264 patients. There was excellent agreement in study selection between the two reviewers (κ statistic, 0.83; 95% CI, 0.72-0.94). CEA was used in 10 studies, CAS was used in 3 studies, and both CEA and CAS were used in 1 study. All included studies were published after 1984, and 93% were published after 1997. Carotid revascularization in diabetic patients was associated with a higher risk of the following outcomes: perioperative stroke (OR, 1.38; 95% CI, 1.02-1.88; P = .04; I(2) =13%), death (OR, 1.94; 95% CI, 1.36-2.75; P = .0002; I(2) = 0%), composite risk of stroke or death (OR, 1.80; 95% CI, 1.32-2.47; P = .0002; I(2) = 26%), and long-term risk of death (OR, 1.57; 95% CI, 1.22-2.03; P = .0005; I(2) = 0%). No association was found between diabetes and perioperative risk of myocardial infarction (MI); composite risk of MI, stroke, or death; and long-term risk of stroke. Study quality was limited by selection bias, minimal control for confounders, and single-center retrospective design. Sensitivity analyses excluding low-quality studies did not change the effect of diabetes on the risk of stroke, death, or MI. Diabetic patients are at an increased risk of perioperative stroke, death, and long-term mortality compared with nondiabetic patients who undergo carotid artery revascularization. This knowledge can help further risk stratify patients with carotid artery stenosis before treatment. Future studies should focus on evaluating which mode of revascularization (CEA or CAS) is more effective in diabetic patients with carotid artery stenosis.

Hussain MA ，Bin-Ayeed SA ，Saeed OQ ，Verma S ，Al-Omran M ... -  《-》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.

Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Bryant A ，Hiu S ，Kunonga PT ，Gajjar K ，Craig D ，Vale L ，Winter-Roach BA ，Elattar A ，Naik R ... -  《Cochrane Database of Systematic Reviews》