Better Survival in Patients with Esophageal Cancer After Surgical Treatment in University Hospitals: A Plea for Performance by Surgical Oncologists

Background: In primary esophageal cancer, studies have frequently focused on surgical patients in an effort to link outcome to hospital- or surgeon-related experience, with operative mortality used as the main outcome measure. Many studies have found an inverse relationship between operative mortality and hospital volume and surgical expertise. This study aims to assess the influence of surgeon-related expertise and hospital volume on the relative survival of operated esophageal cancer patients. Methods: From January 1994 to January 2002, a total of 1149 consecutive patients with primary esophageal cancer were diagnosed in the region of the Comprehensive Cancer Center North-Netherlands. As a proxy for surgeon-related expertise, hospitals in this region were categorized into three types: university, teaching nonuniversity, and nonteaching hospitals. The influence of hospital type on the relative survival of operated patients was studied by a multivariate Poisson regression model. Results: Of the 1149 patients, 18.5% underwent surgery. There was no evidence of selective referral for surgery between the three hospital types with regard to age, tumor stage, and location. For operated patients, the 5-year relative survival was 49.2% for the university hospital versus 32.6% and 27.3% for teaching nonuniversity and nonteaching hospitals, respectively (P = .0039). When adjusted for age, tumor stage, hospital volume and referral frequency, the relative excess risk of death for the university hospital was considerably lower at .57 (95% confidence interval, .29-1.12) compared with nonteaching hospitals and .43 (95% confidence interval, .24-.76) compared with teaching nonuniversity hospitals (P = .0126). Conclusions: In our region, patients with esophageal cancer who underwent esophagectomy in the university hospital had a markedly better relative survival compared with those who underwent surgery at teaching nonuniversity and nonteaching hospitals, emphasizing the need for referral of esophageal surgery to centers with a greater experience

Surgical Complications and Referral Patterns in 567 Patients with Differentiated Thyroid Cancer in the Northern Region of the Netherlands:A Population-Based Study Towards Clinical Management Implementation

Background In the Netherlands, differentiated thyroid cancer (DTC) is treated surgically in three different hospital types, including university, teaching, and non- teaching peripheral hospitals. This study evaluates postoperative complications and referral patterns in patients with DTC in the northern region of the Netherlands to gain an understanding on how to improve management implementation. Methods Data from 567 patients diagnosed between 1989 and 2009 were obtained from the Netherlands Cancer Registry and were supplemented with information from hospital digital information systems and patient records from 15 hospitals: 1 university, 3 teaching, and 11 peripheral hospitals. Surgically treated patients with a histologically proven DTC derived from the original pathology reports were included. Results Surgical treatment could be performed in a single procedure in 234 patients (41.3%), but several surgeries were needed in the remaining 333 patients (58.7%). Recurrent laryngeal nerve (RLN) palsy occurred after all types of thyroid surgical procedures, but mostly after initial (hemi)thyroidectomy and reoperations. RLN was temporary in 3.2% of the nerves at risk and persistent in 1.8%. Temporary hypocalcemia developed in 13.7% of patients, and persistent hypocalcemia occurred in 4.8%. Patients were mainly referred to the university hospital from a non-teaching (40.7%, 48/118) or teaching hospital (11.1%, 16/144); however, 80% of patients were not referred. Conclusions The complication rate and number of multiple surgeries support the efforts in optimizing clinical management in thyroid cancer. Careful considerations prior to initial surgical treatment by early discussion in telemedicine-based regional tumor boards could possibly prevent reoperations and potentially diminish complications

A Critical Appraisal of Circumferential Resection Margins in Esophageal Carcinoma

In esophageal cancer, circumferential resection margins (CRMs) are considered to be of relevant prognostic value, but a reliable definition of tumor-free CRM is still unclear. The aim of this study was to appraise the clinical prognostic value of microscopic CRM involvement and to determine the optimal limit of CRM.To define the optimal tumor-free CRM we included 98 consecutive patients who underwent extended esophagectomy with microscopic tumor-free resection margins (R0) between 1997 and 2006. CRMs were measured in tenths of millimeters with inked lateral margins. Outcome of patients with CRM involvement was compared with a statistically comparable control group of 21 patients with microscopic positive resection margins (R1).A cutoff point of CRM at a parts per thousand currency sign1.0 mm and &gt; 1.0 mm appeared to be an adequate marker for survival and prognosis (both P &lt;0.001). The outcome in patients with CRMs a parts per thousand currency sign1.0 and &gt; 0 mm was equal to that in patients with CRM of 0 mm (P = 0.43). CRM involvement was an independent prognostic factor for both recurrent disease (P = 0.001) and survival (P &lt;0.001). Survival of patients with positive CRMs (a parts per thousand currency sign1 mm) did not significantly differ from patients with an R1 resection (P = 0.12).Involvement of the circumferential resection margins is an independent prognostic factor for recurrent disease and survival in esophageal cancer. The optimal limit for a positive CRM is a parts per thousand currency sign1 mm and for a free CRM is &gt; 1.0 mm. Patients with unfavorable CRM should be approached as patients with R1 resection with corresponding outcome.</p

Role of mTOR through Autophagy in Esophageal Cancer Stemness

SIMPLE SUMMARY: Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis, which seems related to esophageal cancer stem-like cells (CSCs), which reside in a hypoxic niche. We demonstrated, using EC cell lines and patient-derived organoids, that the hypoxia-responding mammalian target of rapamycin (mTOR) can suppress autophagy and stemness of esophageal CSCs. In addition, mTOR inhibitor Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Collectively, our data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. The mTOR pathway could be a novel therapeutic target for putative esophageal CSCs. ABSTRACT: Esophageal cancer (EC) is a highly aggressive disease with a poor prognosis. Therapy resistance and early recurrences are major obstacles in reaching a better outcome. Esophageal cancer stem-like cells (CSCs) seem tightly related with chemoradiation resistance, initiating new tumors and metastases. Several oncogenic pathways seem to be involved in the regulation of esophageal CSCs and might harbor novel therapeutic targets to eliminate CSCs. Previously, we identified a subpopulation of EC cells that express high levels of CD44 and low levels of CD24 (CD44(+)/CD24(−)), show CSC characteristics and reside in hypoxic niches. Here, we aim to clarify the role of the hypoxia-responding mammalian target of the rapamycin (mTOR) pathway in esophageal CSCs. We showed that under a low-oxygen culture condition and nutrient deprivation, the CD44(+)/CD24(−) population is enriched. Since both low oxygen and nutrient deprivation may inhibit the mTOR pathway, we next chemically inhibited the mTOR pathway using Torin-1. Torin-1 upregulated SOX2 resulted in an enrichment of the CD44(+)/CD24(−) population and increased sphere formation potential. In contrast, stimulation of the mTOR pathway using MHY1485 induced the opposite effects. In addition, Torin-1 increased autophagic activity, while MHY1485 suppressed autophagy. Torin-1-mediated CSCs upregulation was significantly reduced in cells treated with autophagy inhibitor, hydroxychloroquine (HCQ). Finally, a clearly defined CD44(+)/CD24(−) CSC population was detected in EC patients-derived organoids (ec-PDOs) and here, MHY1485 also reduced this population. These data suggest that autophagy may play a crucial role in mTOR-mediated CSCs repression. Stimulation of the mTOR pathway might aid in the elimination of putative esophageal CSCs

Effect of Extending the Original CROSS Criteria on Tumor Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer Patients:A National Multicenter Cohort Analysis

BACKGROUND: Extending the original criteria of the Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) in daily practice may increase the treatment outcome of esophageal cancer (EC) patients. This retrospective national cohort study assessed the impact on the pathologic complete response (pCR) rate and surgical outcome. PATIENTS AND METHODS: Data from EC patients treated between 2009 and 2017 were collected from the national Dutch Upper Gastrointestinal Cancer Audit database. Patients had locally advanced EC (cT1/N+ or cT2-4a/N0-3/M0) and were treated according to the CROSS regimen. CROSS (n = 1942) and the extended CROSS (e-CROSS; n = 1359) represent patients fulfilling the original or extended CROSS criteria, respectively. The primary outcome was total pCR (ypT0N0), while secondary outcomes were local esophageal pCR (ypT0), surgical radicality, and postoperative morbidity and mortality. RESULTS: Overall, CROSS and e-CROSS did not differ in total or local pCR rate, although a trend was observed (23.2% vs. 20.4%, p = 0.052; and 26.7% vs. 23.8%, p = 0.061). When stratifying by histology, the pCR rate was higher in the CROSS group compared with e-CROSS in squamous cell carcinomas (48.2% vs. 33.3%, p = 0.000) but not in adenocarcinomas (16.8% vs. 16.9%, p = 0.908). Surgical radicality did not differ between groups. Postoperative mortality (3.2% vs. 4.6%, p = 0.037) and morbidity (58.3% vs. 61.8%, p = 0.048) were higher in e-CROSS. CONCLUSION: Extending the CROSS inclusion criteria for neoadjuvant chemoradiotherapy in routine clinical practice of EC patients had no impact on the pCR rate and on radicality, but was associated with increased postoperative mortality and morbidity. Importantly, effects differed between histological subtypes. Hence, in future studies, we should carefully reconsider who will benefit most in the real-world setting

Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer

Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy resistance, as well as in cancer stemness. This article focusses on the HH pathway as a putative target in the treatment of EC. Immunohistochemistry on HH members was applied to EC patient material followed by modulation of 3D-EC cell cultures, fluorescence-activated cell sorting (FACS), and gene expression analysis after HH pathway modulation. Sonic Hedgehog (SHH) and its receptor Patched1 (PTCH1) were significantly enriched in EC resection material of patients with microresidual disease (mRD) after receiving nCRT, compared to the control group. Stimulation with SHH resulted in an up-regulation of cancer stemness in EC sphere cultures, as indicated by increased sphere formation after sorting for CD44+/CD24- EC cancer stem-like cell (CSC) population. On the contrary, inhibiting this pathway with vismodegib led to a decrease in cancer stemness and both radiation and carboplatin resistance. Our results strengthen the role of the HH pathway in chemoradiotherapy resistance. These findings suggest that targeting the HH pathway could be an attractive approach to control CSCs.</p

Impact of Endoscopic Ultrasonography on (18)F-FDG-PET/CT Upfront Towards Patient Specific Esophageal Cancer Treatment

INTRODUCTION: In patients with potentially resectable esophageal cancer (EC), the value of endoscopic ultrasonography (EUS) after fluorine-18 labeled fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG-PET/CT) is questionable. Retrospectively, we assessed the impact of EUS after PET/CT on the given treatment in EC patients. METHODS: During the period 2009-2015, 318 EC patients were staged as T1-4aN0-3M0 with hybrid (18)F-FDG-PET/CT or (18)F-FDG-PET with CT and EUS if applicable in a nonspecific order. We determined the impact of EUS on the given treatment in 279 patients who also were staged with EUS. EUS had clinical consequences if it changed curability, extent of radiation fields or lymph node resection (AJCC stations 2-5), and when the performed fine-needle aspiration (FNA) provided conclusive information of suspicious lymph node. RESULTS: EUS had an impact in 80 (28.7%) patients; it changed the radiation field in 63 (22.6%), curability in 5 (1.8%), lymphadenectomy in 48 (17.2%), and FNA was additional in 21 (7.5%). In patients treated with nCRT (n = 194), EUS influenced treatment in 53 (27.3%) patients; in 38 (19.6%) the radiation field changed, in 3 (1.5%) the curability, in 35 (18.0%) the lymphadenectomy, and in 17 (8.8%) FNA was additional. EUS influenced both the extent of radiation field and nodal resection in 31 (16.0%) nCRT patients. CONCLUSIONS: EUS had an impact on the given treatment in approximately 29%. In most patients, the magnitude of EUS found expression in the extent of radiotherapy target volume delineation to upper/high mediastinal lymph nodes

Outcomes of surgery and postoperative radiation therapy in managing medullary thyroid carcinoma

Background and Objectives We evaluated the outcomes of surgery with or without postoperative radiation therapy (PORT) in the management of medullary thyroid carcinoma (MTC). Methods From two tertiary cancer centers, 297 consecutive patients with MTC treated with PORT (n = 46) between 1990 and 2016 or surgery alone (n = 251) between 2000 and 2016 were reviewed. Results Ten-year cumulative incidences of locoregional and distant failure were 30.2% and 24.9% in the surgery cohort, and 16.9% and 55.2% in the PORT cohort. In the surgery alone cohort, T4 disease, extrathyroidal extension, N1 disease, extranodal extension (ENE), and residual disease after surgery were associated with local failure. The PORT cohort had significantly higher proportions of patients with T4 disease, N1 disease, ENE, and residual disease. Conclusions High-risk clinical features can help identify patients with MTC at high-risk for local failure after surgery alone. Patients with high-risk clinical features had effective locoregional control after PORT

Timing of Parathyroidectomy Does Not Influence Renal Function After Kidney Transplantation

BACKGROUND: Parathyroidectomy (PTx) is the treatment of choice for end-stage renal disease (ESRD) patients with therapy-resistant hyperparathyroidism (HPT). The optimal timing of PTx for ESRD-related HPT-before or after kidney transplantation (KTx)-is subject of debate.METHODS: Patients with ESRD-related HPT who underwent both PTx and KTx between 1994 and 2015 were included in a multicenter retrospective study in four university hospitals. Two groups were formed according to treatment sequence: PTx before KTx (PTxKTx) and PTx after KTx (KTxPTx). Primary endpoint was renal function (eGFR, CKD-EPI) between both groups at several time points post-transplantation. Correlation between the timing of PTx and KTx and the course of eGFR was assessed using generalized estimating equations (GEE).RESULTS: The PTxKTx group consisted of 102 (55.1%) and the KTxPTx group of 83 (44.9%) patients. Recipient age, donor type, PTx type, and pre-KTx PTH levels were significantly different between groups. At 5 years after transplantation, eGFR was similar in the PTxKTx group (eGFR 44.5 ± 4.0 ml/min/1.73 m2) and KTxPTx group (40.0 ± 6.4 ml/min/1.73 m2, p = 0.43). The unadjusted GEE model showed that timing of PTx was not correlated with graft function over time (mean difference -1.0 ml/min/1.73 m2, 95% confidence interval -8.4 to 6.4, p = 0.79). Adjustment for potential confounders including recipient age and sex, various donor characteristics, PTx type, and PTH levels did not materially influence the results.CONCLUSIONS: In this multicenter cohort study, timing of PTx before or after KTx does not independently impact graft function over time.</p

Adequate debridement and drainage of the mediastinum using open thoracotomy or video-assisted thoracoscopic surgery for Boerhaave’s syndrome

Background Boerhaave's syndrome has a high mortality rate (14-40%). Surgical treatment varies from a minimal approach consisting of adequate debridement with drainage of the mediastinum and pleural cavity to esophageal resection. This study compared the results between a previously preferred open minimal approach and a video-assisted thoracoscopic surgery (VATS) procedure currently considered the method of choice. Methods In this study, 12 consecutive patients treated with a historical nonresectional drainage approach (1985-2001) were compared with 12 consecutive patients treated prospectively after the introduction of VATS during the period 2002-2009. Baseline characteristics were equally distributed between the two groups. Results In the prospective group, 2 of the 12 patients had the VATS procedure converted to an open thoracotomy, and 2 additional patients were treated by open surgery. In the prospective group, 8 patients experienced postoperative complications compared with all 12 patients in the historical control group. Four patients (17%), two in each group, underwent reoperation. Six patients, three in each group, were readmitted to the hospital. The overall in-hospital mortality was 8% (1 patient in each group), which compares favorably with other reports (7-27%) based on drainage alone. Conclusions Adequate surgical debridement with drainage of the mediastinum and pleural cavity resulted in a low mortality rate. The results for VATS in this relatively small series were comparable with those for an open thoracotomy