Prognostic Value of Lymph Node Yield on Overall Survival in Esophageal Cancer Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: This meta-analysis determines whether increased lymph node yield improves survival in patients with esophageal cancer undergoing esophagectomy with or without neoadjuvant therapy. BACKGROUND: Esophagectomy involves resection of the esophagus and surrounding lymph nodes, which are commonly the first stations of cancer spread. The extent of lymphadenectomy during esophagectomy remains controversial, with several studies publishing conflicting results, especially in the era of neoadjuvant therapy. METHODS: An electronic literature search was undertaken using Embase, Medline, and the Cochrane library databases (2000 to 2017). Articles with esophageal cancer patients undergoing esophagectomy with lymphadenectomy and investigating the effects of low and high lymph node yield on overall survival and disease-free survival were included. Meta-analysis of data was conducted using a random effects model. If the study divided the cohort into multiple groups based on lymph node yield, survival was compared between the lowest and highest lymph node yield groups. In addition to analysis of the entire cohort, subset analysis of only those patients receiving neoadjuvant therapy was also performed. RESULTS: A total of 26 studies were included in this meta-analysis with a follow-up ranging from 15 to 94 months. For the analysis of overall survival, 23 studies were included. A meta-analysis showed that overall survival significantly improved in the high lymph node yield group [hazard ratio (HR) = 0.81; 95% confidence interval (95% CI) = 0.74-0.87; P < 0.01]. In the 10 studies describing disease-free survival, this was significantly improved in the high lymph node yield group (HR = 0.72; 95% CI = 0.62-0.84; P < 0.01). Subset analysis of neoadjuvant-treated patients demonstrated a survival benefit of high lymph node yield on overall survival (HR = 0.82; 95% CI = 0.73-0.92; P < 0.01). CONCLUSION: This meta-analysis demonstrates the benefit of an increased lymph node yield from esophagectomy on overall and disease-free survival. In addition, a survival benefit of a high lymph node yield was demonstrated in patients receiving neoadjuvant therapy followed by esophagectomy.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Role of neoadjuvant chemoradiotherapy in clinical T2N0M0 esophageal cancer: A population-based cohort study.

BACKGROUND: The aim of this population-based cohort study was to determine whether the addition of neoadjuvant chemoradiotherapy (nCRT) to surgery is associated with improved pathologic outcomes and survival in patients with cT2N0M0 esophageal cancer. METHODS: Patients who underwent nCRT followed by surgery or surgery alone for cT2N0M0 esophageal cancer were identified from The Netherlands Cancer Registry database (2005-2014). Accuracy of clinical staging was assessed using the resection specimen as gold standard. After propensity score matching, influences of both treatment strategies on radical resection (R0) rates and overall survival were compared. RESULTS: In total 533 patients were included; 353 underwent nCRT followed by surgery and 180 underwent surgery alone. In the nCRT group 32% of patients achieved a pathologic complete response. Clinical understaging was observed in 62% of the patients in the surgery alone group based on pT-stage (n = 30, 27%), pN-stage (n = 26, 23%), or both (n = 55, 50%). Propensity score matching resulted in 78 patients who underwent nCRT plus surgery versus 78 who underwent surgery alone. In the nCRT group radical resections were more frequently observed (99% vs. 89% p = 0.031) and resulted in improved 5-year overall survival (46% vs. 33%, p = 0.017). CONCLUSION: In this population-based study, clinical staging of cT2N0M0 esophageal cancer was highly inaccurate. Compared to surgery alone, neoadjuvant chemoradiotherapy was associated with higher radical resection rates and improved overall survival.

Impact of Lymph Node Yield on Overall Survival in Patients Treated With Neoadjuvant Chemoradiotherapy Followed by Esophagectomy for Cancer: A Population-based Cohort Study in the Netherlands.

OBJECTIVE: To evaluate the impact of lymph node yield (LNY) on survival in patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for cancer. BACKGROUND: The value of an extended lymphadenectomy after nCRT for esophageal cancer is debated. Recent reports demonstrate no association between LNY and survival. This association has not yet been evaluated in larger cohorts. METHODS: All patients who underwent nCRT followed by esophagectomy between 2005 and 2014 were identified from the Netherlands Cancer Registry. The association between LNY and overall survival was analyzed using multivariable Cox regression analyses, adjusting for diagnosis year, referral, hospital volume, age, sex, malignancy history, tumor location, histology, cTN-stage, surgical approach, radicality, and ypTN-stage. Analyses were performed with LNY as categorized predictor (<15 vs ≥15 nodes) and continuous predictor (per 10 additionally nodes). RESULTS: A total of 2698 patients were included with a median overall survival of 34 months (range 4-143). A higher LNY was significantly associated with improved overall survival, both as categorized predictor (hazard ratio 0.77, 95% confidence interval 0.68-0.86) and as continuous predictor (hazard ratio 0.84, 95% confidence interval 0.78-0.90). Furthermore, a higher LNY was associated with favorable hazard ratios across subgroups, including both squamous cell carcinoma and adenocarcinoma, both cN0 and cN+, both transthoracic and transhiatal approaches, and both ypN0 and ypN+. CONCLUSIONS: This large population-based cohort study demonstrates an association between LNY and overall survival, indicating a therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, an extended lymphadenectomy should be the standard of care after nCRT.

Prognostic gene expression profiling in esophageal cancer: a systematic review.

BACKGROUND: Individual variability in prognosis of esophageal cancer highlights the need for advances in personalized therapy. This systematic review aimed at elucidating the prognostic role of gene expression profiles and at identifying gene signatures to predict clinical outcome. METHODS: A systematic search of the Medline, Embase and the Cochrane library databases (2000-2015) was performed. Articles associating gene expression profiles in patients with esophageal adenocarcinoma or squamous cell carcinoma to survival, response to chemo(radio)therapy and/or lymph node metastasis were identified. Differentially expressed genes and gene signatures were extracted from each study and combined to construct a list of prognostic genes per outcome and histological tumor type. RESULTS: This review includes a total of 22 studies. Gene expression profiles were related to survival in 9 studies, to response to chemo(radio)therapy in 7 studies, and to lymph node metastasis in 9 studies. The studies proposed many differentially expressed genes. However, the findings were heterogeneous and only 12 (ALDH1A3, ATR, BIN1, CSPG2, DOK1, IFIT1, IFIT3, MAL, PCP4, PHB, SPP1) of the 1.112 reported genes were identified in more than 1 study. Overall, 16 studies reported a prognostic gene signature, which was externally validated in 10 studies. CONCLUSION: This systematic review shows heterogeneous findings in associating gene expression with clinical outcome in esophageal cancer. Larger validated studies employing RNA next-generation sequencing are required to establish gene expression profiles to predict clinical outcome and to select optimal personalized therapy.

Impact of Weekday of Esophagectomy on Short-term and Long-term Oncological Outcomes: A Nationwide Population-based Cohort Study in the Netherlands.

OBJECTIVE: The aim of this study was to determine whether weekday of esophagectomy impacts 30-day mortality, and short- and long-term oncologic outcomes in esophageal cancer. SUMMARY OF BACKGROUND DATA: Recent literature suggests a relationship between the weekday of esophagectomy and overall survival. This finding could impact clinical practice, but has not yet been validated in other studies. METHODS: The Netherlands Cancer Registry database (2005-2013) identified all patients who underwent esophagectomy for esophageal cancer. The impact of weekday on 30-day mortality, the total number of resected lymph nodes, and R0 resection rates was evaluated with multivariable logistic regression analyses and for overall survival with Cox regression analyses. RESULTS: In total, 3840 patients were included. Weekday was not significantly associated with 30-day mortality (P > 0.05), nor the total number of resected lymph nodes (P > 0.05), nor with R0 resection rates (P > 0.05). Also, weekday did not significantly influence overall survival using weekday as discrete variable [Monday-Friday, hazard ratio (HR) 0.98, P = 0.140), as 2 weekday categories (Wednesday-Friday vs Monday-Tuesday, HR 0.97, P = 0.434), or with separate weekday categories (Tuesday vs Monday, HR 0.99, P = 0.826; Wednesday vs Monday, HR 1.06, P = 0.430; Thursday vs Monday, HR 0.92, P = 0.206; Friday vs Monday, HR 0.91, P = 0.140). CONCLUSIONS: This large population-based cohort study in the Netherlands refutes the finding from a previous report that suggests that the weekday of esophagectomy in patients diagnosed with potentially curable esophageal cancer impacts overall survival. In addition, this study demonstrates that weekday of esophagectomy does not influence other outcomes including the 30-day mortality, total number of resected lymph nodes, and R0 resection rates.

Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty.

BACKGROUND AND PURPOSE: Aseptic loosening and infection are 2 of the most common causes of revision of hip implants. Antibiotic prophylaxis reduces not only the rate of revision due to infection but also the rate of revision due to aseptic loosening. This suggests under-diagnosis of infections in patients with presumed aseptic loosening and indicates that current diagnostic tools are suboptimal. In a previous multicenter study on 176 patients undergoing revision of a total hip arthroplasty due to presumed aseptic loosening, optimized diagnostics revealed that 4-13% of the patients had a low-grade infection. These infections were not treated as such, and in the current follow-up study the effect on mid- to long-term implant survival was investigated. PATIENTS AND METHODS: Patients were sent a 2-part questionnaire. Part A requested information about possible re-revisions of their total hip arthroplasty. Part B consisted of 3 patient-related outcome measure questionnaires (EQ5D, Oxford hip score, and visual analog scale for pain). Additional information was retrieved from the medical records. The group of patients found to have a low-grade infection was compared to those with aseptic loosening. RESULTS: 173 of 176 patients from the original study were included. In the follow-up time between the revision surgery and the current study (mean 7.5 years), 31 patients had died. No statistically significant difference in the number of re-revisions was found between the infection group (2 out of 21) and the aseptic loosening group (13 out of 152); nor was there any significant difference in the time to re-revision. Quality of life, function, and pain were similar between the groups, but only 99 (57%) of the patients returned part B. INTERPRETATION: Under-diagnosis of low-grade infection in conjunction with presumed aseptic revision of total hip arthroplasty may not affect implant survival.

Active encouragement of older women with urinary incontinence in primary care to undergo diagnosis and treatment: a matched-pair cluster randomized controlled trial.

OBJECTIVES: The URINO trial investigated the effect of offering treatment to older women with urinary incontinence in the general population, who had not sought help on their own initiative. STUDY DESIGN: In a cluster randomized trial, 14 general practitioners were matched into pairs and randomly allocated to an intervention or a control group. Women aged ≥ 55 years registered in the participating practices were asked about urinary incontinence via a postal questionnaire. Patients in the intervention group were assessed and treated whereas patients in the control group received standard care. MAIN OUTCOME MEASURES: Primary outcome was improvement (yes or no) of the severity of symptoms at 12-month follow-up measured with the Incontinence Severity Index. Secondary outcomes were the number of incontinence episodes per day and quality of life. The primary analysis was on an intention-to-treat basis with multiple imputation of missing data. A logistic regression model with correction for cluster randomization was fitted to estimate odds ratios (ORs). RESULTS: At 12 months, the severity of symptoms had improved in more patients in the intervention group (n166) than in the controls (n184) (OR 1.9; 95% CI 1.1-3.3). Also, the number of patients with fewer episodes of incontinence had increased (OR 2.5; 95% CI 1.5-4.1). No between-group differences in changes in quality of life were apparent (p0.14). CONCLUSIONS: It is recommended to encourage women in the general population aged ≥ 55 years with urinary incontinence to undergo diagnosis and treatment.

Impact of urinary incontinence on sexual functioning in community-dwelling older women.

INTRODUCTION: Knowledge on the sexual health of patients with urinary incontinence in primary care is scarce; therefore, the impact of urinary incontinence on sexual functioning was examined in community-dwelling older women. AIM: The aim of this study was to provide primary health care professionals with more information on the sexual health of older women with urinary incontinence, which can be used to discuss this sensitive topic during a consultation. METHOD: A cross-sectional survey among the 350 women aged ≥55 years participating in a primary care trial on urinary incontinence was conducted. MAIN OUTCOME MEASURES: Among patients with a partner, sexual problems of the sexually active patients were described as well as reasons for not being sexually active. A multivariate logistic regression model was performed to identify factors that are predictors of sexual activity, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: Of all participants with a partner, 68% (95% CI: 61-74) were sexually active. Of these, 25% (95% CI: 17-35) felt restricted in (or avoided) sexual activity because of their urinary incontinence. Urine leakage during sexual activity was present in 26% (95% CI: 19-34). The most frequent reason for not being sexually active was a physical problem of their partner (28%, 95% CI: 18-40); only 5% (95%-CI: 2-13) reported that urinary incontinence was a reason for not having sex. Increasing age was the only independent (negative) predictor of sexual activity (OR: 0.95, 95%-CI: 0.90-1.00). CONCLUSIONS: Most of these older women with urinary incontinence were sexually active, if they had a partner. The main reason for not being sexually active was a partner-related problem. Although for only 5% was urinary incontinence the main reason for not having sex, about 25% of the sexually active women reported a negative influence of urine loss on their sex life. This implies that assessing sexual function is relevant in older women with urinary incontinence.

The effect of systematic screening of older women for urinary incontinence on treatment uptake: the URINO trial.

BACKGROUND: Female urinary incontinence is a common condition that has a negative influence on quality of life and generates high costs, but spontaneous help-seeking is limited. In the URINO trial the effects and cost-effectiveness of actively encouraging older women to undergo diagnostics and treatment for urinary incontinence were compared with usual care. OBJECTIVES: To describe the design of the URINO trial and to give data on the effect of treatment uptake after screening. In the discussion, the criteria of Wilson and Jungner are applied to discuss whether screening for urinary incontinence is suitable. METHODS: In a cluster randomized trial all registered female patients aged ≥55 years received a screening questionnaire. The intervention consisted of actively encouraging women to undergo diagnostics, after which tailored treatment was offered. In the control group care as usual was offered, but uptake of diagnostics and treatment was not encouraged. Results The response rate was 76%. 31% reported urinary incontinence; of these, 47% was willing to participate. All patients in the intervention group underwent diagnostics and treatment uptake was 80%; in the control group this was 2%. CONCLUSION: To increase treatment uptake, screening must be followed by active encouragement for further diagnostics and treatment. Based on the principles of Wilson and Jungner, female urinary incontinence is a condition suitable for screening. The effect of treatment however needs further evaluation before screening can be recommended. The results of the URINO trial will fill this gap in knowledge.

Severity, not type, is the main predictor of decreased quality of life in elderly women with urinary incontinence: a population-based study as part of a randomized controlled trial in primary care.

BACKGROUND: Urinary incontinence negatively influences the lives of 25-50% of elderly women, mostly due to feelings of shame and being limited in activities and social interactions. This study explores whether differences exist between types of urinary incontinence (stress, urgency or mixed) and severity of the symptoms, with regard to their effects on generic and condition-specific quality of life. METHODS: This is a cross-sectional study among participants of a randomized controlled trial in primary care. A total of 225 women (aged ≥ 55 years) completed a questionnaire (on physical/emotional impact and limitations) and were interviewed for demographic characteristics and co-morbidity. Least squares regression analyses were conducted to estimate differences between types and severity of urinary incontinence with regard to their effect on quality of life. RESULTS: Most patients reported mixed urinary incontinence (50.7%) and a moderate severity of symptoms (48.9%). Stress urinary incontinence had a lower impact on the emotional domain of condition-specific quality of life compared with mixed urinary incontinence (r = -7.81). There were no significant associations between the types of urinary incontinence and generic quality of life. Severe symptoms affected both the generic (r = -0.10) and condition-specific (r = 17.17) quality of life. CONCLUSIONS: The effects on condition-specific quality of life domains differ slightly between the types of incontinence. The level of severity affects both generic and condition-specific quality of life, indicating that it is not the type but rather the severity of urinary incontinence that is the main predictor of decreased quality of life.

Systematic screening for urinary incontinence in older women: who could benefit from it?

OBJECTIVE: To identify women who are suffering from urinary incontinence but do not consult a physician and to identify reasons for this. DESIGN: Survey study as part of a randomized controlled trial that investigates the effects of a standardized assessment and evidence-based treatment on urinary incontinence in older women, the URINO project. SETTING: Female patients from general practices in the Northern part of the Netherlands. PATIENTS: A total of 225 women of 55 years and older suffering from urinary incontinence. MAIN OUTCOME MEASURES: Number of patients with urinary incontinence who are not registered by their GP as suffering from this, factors associated with help-seeking behaviour, and reasons for not seeking help. RESULTS: Of the 225 patients, 143 (64%) were not registered by their GP as suffering from urinary incontinence. These women were more often younger and had lower levels of distress due to their urogynaecological symptoms. The most common reason for not consulting a GP was that patients considered their symptoms not to be serious enough. CONCLUSION: The prevalence of older women with urinary incontinence who do not seek help is high. Help-seeking behaviour is associated with increasing age and higher levels of distress caused by the symptoms. Younger patients more often hesitate to consult their GP if they perceive their symptoms to be relatively mild.