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Background Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e’ mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8–60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2–48.8). Between the first and second evaluation, the e’ mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e’ mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e’ mean (β coefficient: −0.169, 95% CI: −0.292; −0.047, P = 0.008 and β coefficient: −0.177, 95% CI: −0.240; −0.113, P < 0.001, respectively). Conclusions and relevance In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

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.

Background and purposeWhen treating patients for esophageal cancer (EC) with photon or proton radiotherapy (RT), breathing motion of the target and neighboring organs may result in deviations from the planned dose distribution. The aim of this study was to evaluate the magnitude and dosimetric impact of breathing motion. Results were based on comparing weekly 4D computed tomography (4D CT) scans with the planning CT, using the diaphragm as an anatomical landmark for EC.Material and methodsA total of 20 EC patients were included in this study. Diaphragm breathing amplitudes and off-sets (changes in position with respect to the planning CT) were determined from delineated left diaphragm structures in weekly 4D CT-scans. The potential dosimetric impact of respiratory motion was shown in several example patients for photon and proton radiotherapy.ResultsVariation in diaphragm amplitudes were relatively small and ranged from 0 to 0.8 cm. However, the measured off-sets were larger, ranging from -2.1 to 1.9 cm. Of the 70 repeat CT-scans, the off-set exceeded the ITV-PTV margin of 0.8 cm during expiration in 4 CT-scans (5.7%) and during inspiration in 13 CT-scans (18.6%). The dosimetric validation revealed under- and overdosages in the VMAT and IMPT plans.ConclusionsDespite relatively constant breathing amplitudes, the variation in the diaphragm position (off-set), and consequently tumor position, was clinically relevant. These motion effects may result in either treatments that miss the target volume, or dose deviations in the form of highly localized over- or underdosed regions.

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.

Contains fulltext : 225882.pdf (Publisher’s version ) (Closed access) Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged

Background Lymph node metastasis (LNM) is possible after endoscopic resection of early esophageal adenocarcinoma (EAC). This study aimed to develop and internally validate a prediction model that estimates the individual risk of metastases in patients with pT1b EAC. Methods A nationwide, retrospective, multicenter cohort study was conducted in patients with pT1b EAC treated with endoscopic resection and/or surgery between 1989 and 2016. The primary end point was presence of LNM in surgical resection specimens or detection of metastases during follow-up. All resection specimens were histologically reassessed by specialist gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop the prediction model. The discriminative ability of this model was assessed using the c-statistic. Results 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9 % (95 % confidence interval [CI] 25.1 %–36.8 %). The risk of metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95 %CI 1.02–1.14, for every increase of 500 μm), lymphovascular invasion (SHR 2.95, 95 %CI 1.95–4.45), and for larger tumors (SHR 1.23, 95 %CI 1.10–1.37, for every increase of 10 mm). The model demonstrated good discriminative ability (c-statistic 0.81, 95 %CI 0.75–0.86). Conclusions A third of patients with pT1b EAC experienced metastases within 5 years. The probability of developing post-resection metastases was estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size, and lymphovascular invasion. This model requires external validation before implementation into clinical practice.

Background The role of postoperative external beam radiotherapy (EBRT) in patients with residual iodine refractory-differentiated thyroid cancer (IR-DTC) is still inconclusive. The aim of this retrospective study was to evaluate locoregional control (LRC) and overall survival (OS), and potential side effects after postoperative EBRT for both microscopic and macroscopic non-radically resected, locally advanced IR-DTC. Methods Between 1990 and 2016, 49 patients with locally advanced IR-DTC received EBRT for microscopic (R1; n = 28) or macroscopic (R2; n = 21) locoregional residual disease. For more insight into the added effect of EBRT, we performed an intrapatient sub-analysis in 32 patients who had undergone more than 1 surgical intervention, comparing LRC after primary, curative-intended surgery with LRC after repeated surgery plus EBRT. To estimate LRC and OS, we used Kaplan–Meier curves. From 2007 onward, we prospectively recorded toxicity data in our head and neck cancer database (n = 10). Results LRC rates 5 years after EBRT were higher for R1 (84.3%) than for R2 (44.9%) residual disease (P = 0.016). The 5-year OS rate after EBRT was 72.1% for R1 and 33.1% for R2 disease (P = 0.003). In the intrapatient analysis (n = 32), LRC rates were 6.3% 5 years after only initial surgery and 77.9% after repeated surgery with EBRT (P < 0.001). Acute toxicity was limited to grade I and II xerostomia, mucositis, and hoarseness; only one patient developed late grade III dysphagia. Conclusions Postoperative EBRT is associated with long-lasting LRC and OS with acceptable toxicity in patients with locally advanced IR-DTC, especially in microscopic residual disease.

Summary Total thyroidectomy as part of thyroid cancer treatment results in hypothyroidism requiring lifelong daily thyroid hormone replacement. Unbalanced hormone levels result in persistent complaints such as fatigue, constipation, and weight increase. Therefore, we aimed to investigate a patient-derived thyroid organoid model with the potential to regenerate the thyroid gland. Murine and human thyroid-derived cells were cultured as organoids capable of self-renewal and which expressed proliferation and putative stem cell and thyroid characteristics, without a change in the expression of thyroid tumor-related genes. These organoids formed thyroid-tissue-resembling structures in culture. (Xeno-)transplantation of 600,000 dispersed organoid cells underneath the kidney capsule of a hypothyroid mouse model resulted in the generation of hormone-producing thyroid-resembling follicles. This study provides evidence that thyroid-lineage-specific cells can form organoids that are able to self-renew and differentiate into functional thyroid tissue. Subsequent (xeno-)transplantation of these thyroid organoids demonstrates a proof of principle for functional miniature gland formation., Graphical abstract, Highlights • Thyroid-organoid-derived cells can self-renew and form all tissue lineages • Thyroid organoids express putative stem cell markers and no tumor gene expression • Maturation of these organoids leads to formation of tissue-resembling mini-glands • (Xeno-)transplantation into hypothyroid mice regenerates thyroid-resembling tissue, In this article, Ogundipe and colleagues demonstrate that thyroid gland-derived cells can be cultured as organoids for a prolonged time and differentiate in vitro to form hormone-producing mini-glands. (Xeno-)transplantation of dissociated organoids into hypothyroid mice allows generation of hormone-producing tissue-resembling follicles. These findings indicate that thyroid-lineage-specific cells contain proliferative potential to form thyroid-derived organoids capable of generating functional tissue.

PURPOSE: This study was designed to assess the impact of age and comorbidity on choice and outcome of definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy plus surgery.METHODS: In this population-based study, all patients with potentially curable EC (cT1N+/cT2-3, TX, any cN, cM0) diagnosed in the South East of the Netherlands between 2004 and 2014 were included. Kaplan-Meier method with log-rank tests and multivariable Cox regression analysis were used to compare overall survival (OS).RESULTS: A total of 702 patients was included. Age ≥ 75 years and multiple comorbidities were associated with a higher probability for dCRT (odds ratio [OR] 8.58; 95% confidence interval [CI] 4.72-15.58; and OR 3.09; 95% CI 1.93-4.93). The strongest associations were found for the combination of hypertension plus diabetes (OR 3.80; 95% CI 1.97-7.32) and the combination of cardiovascular with pulmonary comorbidity (OR 3.18; 95% CI 1.57-6.46). Patients with EC who underwent dCRT had a poorer prognosis than those who underwent nCRT plus surgery, irrespective of age, number, and type of comorbidities. In contrast, for patients with squamous cell carcinoma with ≥ 2 comorbidities or age ≥ 75 years, OS was comparable between both groups (hazard ratio [HR] 1.52; 95% CI 0.78-2.97; and HR 0.73; 95% CI 0.13-4.14).CONCLUSIONS: Histological tumor type should be acknowledged in treatment choices for patients with esophageal cancer. Neoadjuvant chemoradiotherapy plus surgery should basically be advised as treatment of choice for operable esophageal adenocarcinoma patients. For patients with esophageal squamous cell carcinoma with ≥ 2 comorbidities or age ≥ 75 years, dCRT may be the preferred strategy.

PURPOSE Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Contains fulltext : 245204.pdf (Publisher’s version ) (Open Access) AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow-up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2-3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy-eight patients had metastases. The risk of metastases was increased for tumors with 2-3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10-5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37-6.10). The prediction model demonstrated a good discriminative ability (c-statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice.

Objectives To assess the complementary value of human epidermal growth factor receptor 2 (HER2)-related biological tumor markers to clinico-radiomic models in predicting complete response to neoadjuvant chemoradiotherapy (NCRT) in esophageal cancer patients. Methods Expression of HER2 was assessed by immunohistochemistry in pre-treatment tumor biopsies of 96 patients with locally advanced esophageal cancer. Five other potentially active HER2-related biological tumor markers in esophageal cancer were examined in a sub-analysis on 43 patients. Patients received at least four of the five cycles of chemotherapy and full radiotherapy regimen followed by esophagectomy. Three reference clinico-radiomic models based on 18F-FDG PET were constructed to predict pathologic response, which was categorized into complete versus incomplete (Mandard tumor regression grade 1 vs. 2–5). The complementary value of the biological tumor markers was evaluated by internal validation through bootstrapping. Results Pathologic examination revealed 21 (22%) complete and 75 (78%) incomplete responders. HER2 and cluster of differentiation 44 (CD44), analyzed in the sub-analysis, were univariably associated with pathologic response. Incorporation of HER2 and CD44 into the reference models improved the overall performance (R2s of 0.221, 0.270, and 0.225) and discrimination AUCs of 0.759, 0.857, and 0.816. All models exhibited moderate to good calibration. The remaining studied biological tumor markers did not yield model improvement. Conclusions Incorporation of HER2 and CD44 into clinico-radiomic prediction models improved NCRT response prediction in esophageal cancer. These biological tumor markers are promising in initial response evaluation. Key Points • A multimodality approach, integrating independent genomic and radiomic information, is promising to improve prediction of γpCR in patients with esophageal cancer. • HER2 and CD44 are potential biological tumor markers in the initial work-up of patients with esophageal cancer. • Prediction models combining 18F-FDG PET radiomic features with HER2 and CD44 may be useful in the decision to omit surgery after neoadjuvant chemoradiotherapy in patients with esophageal cancer.

Contains fulltext : 245660.pdf (Publisher’s version ) (Closed access) Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [β-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Objective Neoadjuvant chemoradiotherapy followed by surgery establishes a considerable pathologic complete response (pCR) in EC. The aim was to determine site of residual tumor and its prognostic impact. Summary background data High rates of residual tumor in the adventitial region even inside the radiation fields will influence current decision-making. Methods We evaluated resection specimens with marked target fields from 151 consecutive EC patients treated with carboplatin/paclitaxel and 41.4Gy between 2009 and 2018. Results In radically resected (R0) specimens 19.8% (27/136) had a pCR (ypT0N0) and 14% nearly no response (tumor regression grade: tumor regression grade 4-5). Residual tumor commonly extended in or restricted to the adventitia (43.1%; 47/109), whereas 7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymph nodes (ypT0N+). Macroscopic residues in R0-specimens of partial responders (tumor regression grade 2-3: N = 90) were found in- and outside the gross tumor volume (GTV) in 33.3% and 8.9%, and only microscopic in- and outside the clinical target volume in 58.9% and 1.1%, respectively. Residual nodal disease was observed proximally and distally to the clinical target volume in 2 and 5 patients, respectively. Disease Free Survival decreased significantly if macroscopic tumor was outside the GTV and in ypT2-4aN+. Conclusions After neoadjuvant chemoradiotherapy, pCR and ypT1aN0 were seen in a limited number of R0 resected specimens (19.8% and 7.3%, respectively), whereas 6.4% had only nodal disease (yT0N+). Disease Free Survival decreased significantly if macroscopic residue was outside the GTV and in responders with only nodal disease. Therefore, we should be cautious in applying wait and see strategies.

Background: Isolated local recurrent or persistent esophageal cancer (EC) after curative intended definitive (dCRT) or neoadjuvant chemoradiotherapy (nCRT) with initially omitted surgery, is a potential indication for salvage surgery. We aimed to evaluate safety and efficacy of salvage surgery in these patients. Material and methods: A systematic literature search following PRISMA guidelines was performed using databases of PubMed/Medline. All included studies were performed in patients with persistent or recurrent EC after initial treatment with dCRT or nCRT, between 2007 and 2017. Survival analysis was performed with an inverse-variance weighting method. Results: Of the 278 identified studies, 28 were eligible, including a total of 1076 patients. Postoperative complications after salvage esophagectomy were significantly more common among patients with isolated persistent than in those with locoregional recurrent EC, including respiratory (36.6% versus 22.7%; difference in proportion 10.9 with 95% confidence interval (CI) [3.1; 18.7]) and cardiovascular complications (10.4% versus 4.5%; difference in proportion 5.9 with 95% CI [1.5; 10.2]). The pooled estimated 30-and 90-day mortality was 2.6% [1.6; 3.6] and 8.0% [6.3; 9.8], respectively. The pooled estimated 3-year and 5-year overall survival (OS) were 39.0% (95% CI: [35.8; 42.2]) and 19.4% [95% CI:16.5; 22.4], respectively. Patients with isolated persistent or recurrent EC after initial CRT had similar 5-year OS (14.0% versus 19.7%, difference in proportion -5.7, 95% CI [-13.7; 2.3]). Conclusions: Salvage surgery is a potentially curative procedure in patients with locally recurrent or persistent esophageal cancer and can be performed safely after definitive or neoadjuvant chemoradiotherapy when surgery was initially omitted. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable. Objectives The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules. Search methods We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018. Selection criteria We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed). Data collection and analysis Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible. Main results In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . Authors' conclusions Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

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.

Cancer treatment, in particular radiotherapy and chemotherapy, is often hindered by an inherent resistance of cancer cells. Cancer stem cells in particular have previously been shown to be more resistant than other cells within a tumor and are thought repopulate the tumour after therapies. Therefore, it is of utmost importance to develop tools and techniques that can be used to study mechanisms of resistance of cancer stem cells as potential treatment targets. Organoids (and cancer-derived organoids), are three-dimensional tissue-resembling cellular clusters derived from tissue or tumor specific stem cells that mimic the in vivo (tumor) characteristics, as well as (tumor) cell heterogeneity. Cancer organoids may further enhance the in vitro and in vivo models that are currently available, improve our understanding of cancer stem cell resistance and can be used to develop novel cancer treatments by improved targeting of cancer stem cells. In this review, we compare organoids with the more traditional laboratory models, such as cell lines and xenografts, and review the literature of the current role of cancer organoids in determining treatment responses.

Purpose: To assess the value of baseline and restaging fluorine 18 (F-18) fluorodeoxyglucose (FDG) positron emission tomography (PET) radiomics in predicting pathologic complete response to neoadjuvant chemotherapy and radiation therapy (NCRT) in patients with locally advanced esophageal cancer.Materials and Methods: In this retrospective study, 73 patients with histologic analysisconfirmed T1/N1-3/M0 or T2-4a/N0-3/M0 esophageal cancer were treated with NCRT followed by surgery (Chemoradiotherapy for Esophageal Cancer followed by Surgery Study regimen) between October 2014 and August 2017. Clinical variables and radiomic features from baseline and restaging F-18-FDG PET were selected by univariable logistic regression and least absolute shrinkage and selection operator. The selected variables were used to fit a multivariable logistic regression model, which was internally validated by using bootstrap resampling with 20 000 replicates. The performance of this model was compared with reference prediction models composed of maximum standardized uptake value metrics, clinical variables, and maximum standardized uptake value at baseline NCRT radiomic features. Outcome was defined as complete versus incomplete pathologic response (tumor regression grade 1 vs 2-5 according to the Mandard classification).Results: Pathologic response was complete in 16 patients (21.9%) and incomplete in 57 patients (78.1%). A prediction model combining clinical T-stage and restaging NCRT (post-NCRT) joint maximum (quantifying image orderliness) yielded an optimism-corrected area under the receiver operating characteristics curve of 0.81. Post-NCRT joint maximum was replaceable with five other redundant post-NCRT radiomic features that provided equal model performance. All reference prediction models exhibited substantially lower discriminatory accuracy.Conclusion: The combination of clinical T-staging and quantitative assessment of post-NCRT F-18-FDG PET orderliness (joint maximum) provided high discriminatory accuracy in predicting pathologic complete response in patients with esophageal cancer.

Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and –Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen’s d: −0.93, P < .001; 0.47, P < .001; −0.84, P < .001; 1.45, P < .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen’s d: −1.00, 0.33, −0.47, −0.34, and 0.33, respectively; all P < .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen’s d: 0.52 and −0.53, respectively; both P < .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study–regimen can be regarded as a standard of care.

113 Background: Knowledge of pathologic complete tumor response (pCR) and the used neoadjuvant chemoradiotherapy (nCRT) schedule on the distribution of recurrent disease is important in the treatment of esophageal cancer (EC) patients. We assessed the effect of both pCR and different nCRT schedules on the pattern of first tumor recurrences in EC. Methods: The study was performed in two different centers in patients with T1N+/T2-4aN0-3/M0 EC. Patients were treated with nCRT according to the CROSS (carboplatin/paclitaxel/41.4Gy : n=134) and Cis/5FU schedule (Cisplatin/5-fluorouracil/45-50.4Gy : n=88) followed by surgery. First we determined the effect of pCR on tumor recurrence distribution (local, distant or combined) and site-specific recurrences in the CROSS group. After propensity matching on clinical T-stage, clinical N-stage and histology (n=63), we determined the effect of both nCRT schedules on the distribution of tumor recurrence and site specific recurrences. Results: The median follow-up after pCR (n=24) was significant longer ( P=0.001) than in non-complete responders (pNCR); 45.5 (IQR 20.3-69.5) and 20.0 months (12.0-42.3), respectively. The pattern of recurrence also differed significantly ( P=0.001), with 0 (0.0%) and 7 (6.4%) locoregional, 5 (20.8%) and 36 (32.7%) distant, and 0 (0.0%) and 21 (19.1%) local and distant recurrence between the pCR and pNCR group, respectively. Patients with a pCR had significant less local and distant recurrences. With equal median time to recurrence, the distribution of metastases in the matched groups differed only in the numbers of lung metastases ( P=0.029), with 15 (23.8%) and 6 (9.5%), respectively. Conclusions: Patients with a pCR have less local and distant recurrences. With equal time to first recurrence, the nCRT schedule itself had only a minor influence on the distribution of recurrences.

Background: Patients with pathologic limited or no response (pNR) to neoadjuvant chemoradiation (nCRT) are subjected to curative intended esophagectomy with subsequent perioperative morbidity and mortality, but potentially only harm from nCRT. The primary aim of this study was to compare the overall survival (OS) of patients with pNR and patients who underwent primary esophagectomy to evaluate potentially benefits of nCRT in these patients. The secondary aim was to identify predictive clinicopathologic factors for pNR and pathologic complete response (pCR) to nCRT with the goal to preselect these patients before the start of treatment.Methods: From the period 2005 to 2016, 206 esophageal cancer (EC) patients treated with Carboplatin/Paclitaxel and radiotherapy with complementary esophagectomy were included in this cohort. OS of patients with pNR was compared with a historical cohort of primary surgically treated patients (n=218) after a propensity score matching resulting in a group of 68 patients with pNR after nCRT versus a group of 68 primary esophagectomy patients.Results: The OS in the pNR group and the primary esophagectomy group was comparable (P=0.986). No predictive factors were found in this cohort for pNR. Female gender (OR 2.5, 95% CI 1.2-5.3) and squamous cell carcinoma (SCC) (OR 2.6, 95% CI 1.3-5.3) were identified as independent predictive factors for pCR.Conclusions: Patients with a pNR do not benefit from nCRT followed by resection. These patients had a similar OS as those who had a primary esophagectomy alone. Although this indicates that nCRT does not negatively impact the OS of patients with pNR, patients still have an increased morbidity because of nCRT. Hence, it is important to identify factors that predict pNR. The ability to predict pNR (and pCR) will enable tailored and personalized care preventing unnecessary nCRT with increased morbidity.

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.

Background: Although essential in treatment decision making, clinical nodal (cN) staging in esophageal cancer (EC) remains difficult. We assessed the rate of nodal up- and downstaging and its prognostic value on 5-year disease-free survival (DFS) in EC patients treated with surgery-alone or with neoadjuvant chemoradiotherapy (nCRT). Methods: For this retrospective study, we included 395 EC patients who underwent a curative esophagectomy with or without nCRT between 2000 and 2015. The surgery-alone and nCRT group were matched on clinical T-stage (cT), cN-stage, and histopathological type using propensity score matching (n=270). Staging consisted of PET with CT, or PET/CT, and endoscopic ultrasonography (n = 235). We compared cN and pathological N-stage (pN) and scored correct, down- and upstaging. The prognostic value of nodal up- and downstaging and localization of node metastases on 5-year DFS were assessed with multivariate Cox regression analysis (factors with a P-value 25% nodal downstaging. This inaccuracy might impede assessment of true nodal response to nCRT, affording dubious decisions for a 'wait-and-see' strategy.

Aim To report the long term results of the CROSS trial with a minimum follow-up of 10 years. Background Neoadjuvant chemoradiotherapy according to the Dutch randomised controlled ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) has become standard of care for patients with cancer of the oesophagus or oesophagogastric junction. Methods Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction were randomised between neoadjuvant chemoradiotherapy (five weekly cycles of intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m² of body-surface area]) with concurrent 41.4 Gy radiotherapy given in 23 fractions of 1.8 Gy, 5 days per week) plus surgery versus surgery alone. Primary endpoint was overall survival, defined from date of randomisation to date of all-cause death or to last day of follow-up. Analysis was by intention-to-treat. Results Between March 2004 and 2008, eight centres enrolled 368 patients. Some 178 were analysed in the chemoradiotherapy plus surgery group and 188 in the surgery alone group. After a median follow-up for surviving patients of 146.6 months (IQR 133.5-156.6), median overall survival was 49.0 months (95%CI 34.7-76.6) in the neoadjuvant chemoradiotherapy plus surgery group compared to 25.1 months (95%CI 19.1-39.4) in the surgery alone group, which was significantly different (HR 0.71 [95%CI 0.55-0.90]; log-rank p=0·005). Ten-year overall survival was 38% (95%CI 31%-45%) in the neoadjuvant chemoradiotherapy followed by surgery group compared to 26% (95%CI 20%-33%) in the surgery alone group (HR 0.69 [95%CI 0.54-0.89]). For patients with squamous cell carcinoma ten-year overall survival was 46% (95%CI 33%-64%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 23% (95%CI 13%-40%) in the surgery alone group. For patients with adenocarcinoma ten-year overall survival was 36% (95%CI 29%-45%) in the neoadjuvant chemoradiotherapy plus surgery group compared to 26% (95%CI 20%-35%) in the surgery alone group. Conclusion Survival benefit of patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction receiving neoadjuvant chemoradiotherapy persists for at least 10 years compared to patients undergoing surgery alone.

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.

OBJECTIVE: Thyroglobulin (Tg) is an excellent tumour marker, as detectable or increasing Tg levels are highly indicative of persistent or recurrent differentiated thyroid carcinoma (DTC). The clinical value of a highly sensitive (hs)-Tg assay in patients with DTC has not yet been established. The aim of this study was to investigate the additional value of unstimulated hs-Tg measurements (Tg-on) compared to stimulated IRMA-Tg measurements (Tg-off) in the follow-up of patients with DTC. DESIGN, PATIENTS, MEASUREMENTS: We retrospectively studied patients treated for DTC between 2006 and 2013, and compared hs-Tg and IRMA-Tg measurements. The study group consisted of 99 DTC patients in remission; Tg-on was measured 3 months after remnant ablation and Tg-off 6 months after ablation. RESULTS: In the study group, 44 patients showed a hs-Tg-on

BACKGROUND: The purpose of this study was to provide more insight in the course of cytokine concentrations related to pathologic response (pR) and complications after neoadjuvant chemoradiotherapy (NCRT) and esophagectomy in esophageal cancer patients.METHODS: Patients treated with NCRT followed by transthoracic esophagectomy (n = 35) or transthoracic esophagectomy alone (n = 8) were included. Eight different cytokine concentrations were determined during NCRT, esophagectomy, and the first postoperative week.RESULTS: Platelet-activating factor before NCRT was associated with pR (P = .011) and remained elevated in patients with a better response. Concentrations of intestinal fatty acid-binding protein and angiopoietin 1 (Ang-1) were different between patients with and without NCRT. Decreased concentrations of Ang-1 on the third postoperative day were associated with postoperative complications (P = .046).CONCLUSIONS: In this observational study, elevated platelet-activating factor concentrations before NCRT were associated with pR. NCRT is associated with decreased Ang-1 concentrations, whereas reduced Ang-1 concentrations were associated with postoperative complications. (C) 2016 Elsevier Inc. All rights reserved.

Background: Clinical nodal (cN) staging is a key element in treatment decisions in patients with esophageal cancer (EC). The reliability of cN status regarding the effect on response and survival after neoadjuvant chemoradiotherapy (nCRT) with esophagectomy was evaluated in determining the up- and downstaged pathological nodal (pN) status after surgery alone. Material and methods: From a prospective database, we included all 395 EC patients who had surgery with curative intent with or without nCRT between 2000 and 2015. All patients were staged by a standard pretreatment protocol: 16-64 mdCT, 18 F-FDG-PET or 18 F-FDG-PET/CT and EUS ± FNA. After propensity score matching on baseline clinical tumor and nodal (cT/N) stage and histopathology, a surgery-alone and nCRT group (each N = 135) were formed. Clinical and pathological N stage was scored as equal (cN = pN), downstaged (cN > pN) or upstaged (cN p value Results: The surgery-alone and nCRT group did not differ in cT/N status. Pathologic examination revealed equal staging (32 vs. 27%), nodal up (43 vs. 16%) and downstaging (25 vs. 56%), respectively (p p = .002) and lymph-angioinvasion (p = .016) in surgery-alone, and upper abdominal cN metastases (p = .012) and lymph node ratio (p = .034) in the nCRT group. Conclusions: Despite modern staging methods, correct cN staging remains difficult in EC. Nodal overstaging (cN > pN) occurred more often than understaging impeding an adequate assessment of pathologic complete response and prognosis after nCRT. Preoperative assessment of true nodal response after nCRT in EC remains difficult with clinical nodal upstaging (16% vs. 43%) and downstaging (56% vs. 25%) after nCRT and surgery alone, respectively.

BACKGROUND: Extramural venous invasion (EMVI) is a known adverse prognostic factor in patients with colorectal carcinoma. The prevalence and significance of EMVI in esophageal cancer (EC) patients is still unclear.METHODS: From a prospectively maintained database, we retrospectively reviewed the resection specimens of patients with pathologic locally advanced (pT3/T4/N0-3) EC who were treated with curative intent between 2000 and 2015. Patients with previous malignancies and gastroesophageal junction (type II/III) tumors were excluded. Included were 81 patients who underwent surgery alone and 37 patients who underwent neoadjuvant chemoradiotherapy (nCRT). EMVI was assessed on hematoxylin and eosin slides and confirmed or excluded by additional Elastica van Gieson staining. Survival was analyzed using a multivariable Cox regression.RESULTS: EMVI was present in 23.5% (n = 19) of patients in the surgery-alone group and 21.6% (n = 8) of patients in the nCRT group. The prevalence of EMVI after surgery alone was significantly high in squamous cell carcinomas and among tumors located in the mid-esophagus, as well as those with lymphovascular invasion (p CONCLUSIONS: In this study of locally advanced > pT3/N0-3 EC patients, EMVI was present in 23.5% of patients in the surgery-alone group and in 21.6% of patients after nCRT. EMVI was an independent adverse prognostic factor in patients after surgery alone.

Item does not contain fulltext INTRODUCTION: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands. PATIENTS AND METHODS: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis

Background Gastric cancer surgery is increasingly being centralized in the Netherlands, whereas the diagnosis is often made in hospitals where gastric cancer surgery is not performed. The aim of this study was to assess whether hospital of diagnosis affects the probability of undergoing surgery and its impact on overall survival. Methods All patients with potentially curable gastric cancer according to stage (cT1/1b–4a, cN0–2, cM0) diagnosed between 2005 and 2013 were selected from the Netherlands Cancer Registry. Multilevel logistic regression was used to examine the probability of undergoing surgery according to hospital of diagnosis. The effect of variation in probability of undergoing surgery among hospitals of diagnosis on overall survival during the intervals 2005–2009 and 2010–2013 was examined by using Cox regression analysis. Results A total of 5620 patients with potentially curable gastric cancer, diagnosed in 91 hospitals, were included. The proportion of patients who underwent surgery ranged from 53·1 to 83·9 per cent according to hospital of diagnosis (P < 0·001); after multivariable adjustment for patient and tumour characteristics it ranged from 57·0 to 78·2 per cent (P < 0·001). Multivariable Cox regression showed that patients diagnosed between 2010 and 2013 in hospitals with a low probability of patients undergoing curative treatment had worse overall survival (hazard ratio 1·21; P < 0·001). Conclusion The large variation in probability of receiving surgery for gastric cancer between hospitals of diagnosis and its impact on overall survival indicates that gastric cancer decision-making is suboptimal.

Objective: The primary objective was to evaluate the short-and long-term toxic effects of radioiodine (I-131) therapy on bone marrow function in differentiated thyroid carcinoma (DTC) patients. The secondary objective was to define characteristics of patients at risk for impaired bone marrow function after I-131 treatment.Patients and Methods: DTC patients treated with I-131 between 1989 and 2013 were included. We excluded patients with morbidities or treatments that could have influenced blood count parameters. Baseline platelets, leukocytes, and hemoglobin levels were compared with blood counts at 3 and 6 months and at 1 and 5 years after treatment. Logistic multivariate regression analyses were performed to determine patient characteristics associated with thrombocytopenia.Results: We included 331 patients. Mean +/- SD age was 47.5 +/- 17.2 years, and 74.0% were female. Posttreatment platelets were significantly decreased at 6 months and 1 year, as compared with baseline. Leukocyte counts were also decreased at 3 and 6 months and at 1 year after treatment. No decreases in hemoglobin were found. Five years after treatment, platelet and leukocyte counts were comparable with baseline. Fourteen patients (4.2%) developed transient posttreatment thrombocytopenia. Risk factors for thrombocytopenia were older age, T4 tumor stage, male gender, and cumulative dose 131I. After a multivariate regression analysis, the cumulative dose 131I remained independently associated with thrombocytopenia.Conclusion: Posttreatment platelets and leukocytes were transiently decreased compared with pretreatment values in a general DTC population. Cumulative I-131 dose was independently associated with thrombocytopenia. Platelets and leukocytes normalized to baseline levels 5 years after treatment, implying that in most patients the clinical effects of bone marrow toxicity are limited.

Background and purpose: Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype.Material and methods: 101 EC patients treated with nCRT and surgery were included. Sufficient pretreatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group.Results: Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p = 0.002 and CSS HR 3.48, p = 0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p = 0.029) while low,SHH in pretreatment biopsies was an independent prognostic factor for a poor DES (HR 2.27, p = 0.036). No relation between marker expression and response to nCRT was observed.Conclusions: Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Item does not contain fulltext BACKGROUND: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. METHODS: Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2-3N0-1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m(2) of body-surface area] for 23 days) with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. FINDINGS: Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84.1 months (range 61.1-116.8, IQR 70.7-96.6), median overall survival was 48.6 months (95% CI 32.1-65.1) in the neoadjuvant chemoradiotherapy plus surgery group and 24.0 months (14.2-33.7) in the surgery alone group (HR 0.68 [95% CI 0.53-0.88]; log-rank p=0.003). Median overall survival for patients with squamous cell carcinomas was 81.6 months (95% CI 47.2-116.0) in the neoadjuvant chemoradiotherapy plus surgery group and 21.1 months (15.4-26.7) in the surgery alone group (HR 0.48 [95% CI 0.28-0.83]; log-rank p=0.008); for patients with adenocarcinomas, it was 43.2 months (24.9-61.4) in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 months (13.0-41.2) in the surgery alone group (HR 0.73 [95% CI 0.55-0.98]; log-rank p=0.038). INTERPRETATION: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

BACKGROUND: We investigated whether pre-existent goiter and well-differentiated thyroid cancer (WDTC) are associated with survival in anaplastic thyroid carcinoma (ATC).METHODS: We analyzed medical records from 94 ATC patients, drawn from the Netherlands Cancer Registry, diagnosed in 17 hospitals between 1989 and 2009.RESULTS: The 29 patients (31%) with pre-existent goiter, including 8 with WDTC, were younger than those without (median, 69 vs 76 years; P = .02). One-year overall survival was 9% (95% confidence interval [CI], 3% to 14%) with no difference between pre-existent goiter or not (overall survival, 14%; 95% CI, 1% to 26% vs overall survival, 6%; 95% CI, 0% to 13%]). Higher age was associated with a worse survival (hazard rate, 1.03; 95% CI, 1.01 to 1.06]), whereas the hazard to die was lower after surgery and/or radiotherapy (hazard rate, .37; 95% CI, .21 to.67 and hazard rate,. 22; 95% CI, .12 to .41, respectively).CONCLUSIONS: ATC patients with pre-existent goiter were younger, yet survival was not significantly different between those with or without pre-existent goiter or WDTC. (C) 2015 Elsevier Inc. All rights reserved.

The treatment for metastasised medullary thyroid cancer is still a topic of discussion. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. The diagnostic and treatment strategies for this tumour are discussed and possible new developments commented. Approaches that target rearranged during transfection (RET) are preferable to those that target RET downstream proteins as, theoretically, blocking RET downstream targets will block only one of the many pathways activated by RET. Combining several agents would seem to be more promising, in particular agents that target RET with those that independently target RET signalling pathways or the more general mechanism of tumour progression.

Esophageal and gastric cancer is associated with a poor prognosis since many patients develop recurrent disease. Treatment requires specific expertise and a structured multidisciplinary approach. In the Netherlands, this type of expertise is mainly found at the University Medical Centers (UMCs) and a few specialized nonacademic centers. Aim of this study is to implement a national infrastructure for research to gain more insight in the etiology and prognosis of esophageal and gastric cancer and to evaluate and improve the response on (neoadjuvant) treatment. Clinical data are collected in a prospective database, which is linked to the patients' biomaterial. The collection and storage of biomaterial is performed according to standard operating procedures in all participating UMCs as established within the Parelsnoer Institute. The collected biomaterial consists of tumor biopsies, blood samples, samples of malignant and healthy tissue of the resected specimen and biopsies of recurrence. The collected material is stored in the local biobanks and is encoded to respect the privacy of the donors. After approval of the study was obtained from the Institutional Review Board, the first patient was included in October 2014. The target aim is to include 300 patients annually. In conclusion, the eight UMCs of the Netherlands collaborated to establish a nationwide database of clinical information and biomaterial of patients with esophageal and gastric cancer. Due to the national coverage, a high number of patients are expected to be included. This will provide opportunity for future studies to gain more insight in the etiology, treatment and prognosis of esophageal and gastric cancer.

Objective The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC. Design and methods Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age 35 years at follow-up, a follow-up period n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used. Results We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales. Conclusions Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.

Background: Barrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia-dysplasia-carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma.Aim: To study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma.Methods: Two retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease-free survival.Results: The percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P Conclusion: GATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma. (C) 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Introduction: Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers. Methods: In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis 18 years and follow-up 5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e) less than 2 SD of mean age-adjusted reference data. Results: The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction P = 0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed.Conclusion: While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac aging.

Adequate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (EC) patients is important in a more personalized treatment. The current best clinical method to predict pathologic complete response is SUVmax in F-18-FDG PET/ CT imaging. To improve the prediction of response, we constructed a model to predict complete response to nCRT in EC based on pretreatment clinical parameters and F-18-FDG PET/CT-derived textural features. Methods: From a prospectively maintained single institution database, we reviewed 97 consecutive patients with locally advanced EC and a pretreatment F-18-FDG PET/CT scan between 2009 and 2015. All patients were treated with nCRT (carboplatin/paclitaxe1/41.4 Gy) followed by esophagectomy. We analyzed clinical, geometric, and pretreatment textural features extracted from both F-18-FDG PET and CT. The current most accurate prediction model with SUVmax as a predictor variable was compared with 6 different response prediction models constructed using least absolute shrinkage and selection operator regularized logistic regression. Internal validation was performed to estimate the model's performances. Pathologic response was defined as complete versus incomplete response (Mandard tumor regression grade system 1 vs. 2-5). Results: Pathologic examination revealed 19 (19.6%) complete and 78 (80.4%) incomplete responders. Least absolute shrinkage and selection operator regularization selected the clinical parameters: histologic type and clinical T stage, the 18F-FDG PET-derived textural feature long run low gray level emphasis, and the CT-derived textural feature run percentage. Introducing these variables to a logistic regression analysis showed areas under the receiver-operating-characteristic curve (AUCs) of 0.78 compared with 0.58 in the SUVmax model. The discrimination slopes were 0.17 compared with 0.01, respectively. After internal validation, the AUCs decreased to 0.74 and 0.54, respectively. Conclusion: The predictive values of the constructed models were superior to the standard method (SUVmax). These results can be considered as an initial step in predicting tumor re sponse to nCRT in locally advanced EC. Further research in refining the predictive value of these models is needed to justify omission of surgery.