Locoregional Residual Esophageal Cancer after Neo-adjuvant Chemoradiotherapy and Surgery Regarding Anatomic Site and Radiation Target Fields A Histopathologic Evaluation Study:A Histopathologic Evaluation Study

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

Prognostic factors and patterns of recurrence in esophageal cancer assert arguments for extended two-field transthoracic esophagectomy

BACKGROUND: High recurrence rates determine the dismal outcome in esophageal cancer. We reviewed our experiences and defined prognostic factors and patterns of recurrences after curatively, intended transthoracic esophagectomy. METHODS: Between January 1991 and December 2005, 212 consecutive patients underwent a radical transthoracic esophagectomy with extended 2-field lymphadenectomy. Recurrence rates, survival, and prognostic factors were analyzed (minimal follow-up period, 2 y). RESULTS: Radicality was obtained in 85.6%. The median follow-up period was 26.6 months. The overall recurrence rate at I, 3, and 5 years was 28%, 44%, and 64%, respectively, and locoregional recurrence rate was 17%, 27%, and 43%, respectively. Overall survival rates, including postoperative deaths, were 45% and 34% at 3 and 5 years, respectively. pT stage and lymph node (LN) ratio greater than .20 were independent prognostic factors for survival and recurrences. Radicality was most prognostic for survival, and for N+ greater than 4 positive LN for recurrences. CONCLUSIONS: Radicality and LN ratio are strong prognostic factors. High radicality and adequate nodal assessment are guaranteed by an extended transthoracic approach. (C) 2010 Elsevier Inc. All rights reserved

Prevalence and Prognostic Significance of Extramural Venous Invasion in Patients with Locally Advanced Esophageal Cancer

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  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

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

The diagnostic value of 124I-PET in patients with differentiated thyroid cancer

Background The purpose of this prospective study was to evaluate the clinical diagnostic value of iodine- 124 ( I-124)positron emission tomography ( PET) in patients with advanced differentiated thyroid carcinoma ( DTC) and to compare the I-124- PET imaging results with the I-131 wholebody scan ( WBS). Materials and methods Twenty patients with histologically proven advanced DTC ( including T4, extra- nodal tumour growth, or distant metastases) underwent diagnostic (IWBS)-I-131, I-124- PET scan, and post-treatment I-131- WBS 4 months after ablation. The findings on the I-124- PET were compared with the findings on the diagnostic and post-therapeutic I-131- WBS and were also correlated with radiologic and/ or cytological investigations. Results I-124- PET vs diagnostic I-131- WBS. Eleven patients showed uptake on the I-124- PET. Only 3 of these 11 patients also showed uptake on the diagnostic I-131 scan, but the uptake was more clearly visible and the abnormalities were more extensive on the I-124- PET. I-124- PET vs post-treatment I-131- WBS. Eleven patients showed uptake on the I-124- PET, which was also visible on the post-treatment scan in nine patients; in the other two patients, no uptake was observed on the post-treatment scan and no anatomical localisation could be confirmed. Two patients showed only uptake on the post-treatment scan without uptake on the I-124- PET: in one, the uptake was confirmed by MRI, and in the other, no anatomical localisation was found. In seven patients, no uptake was observed on both the scans. Conclusion I-124- PET proved to be a superior diagnostic tool as compared to low-dose diagnostic I-131 scans and adequately predicted findings on subsequent high-dose post-treatment I-131 scans

Late cardiac toxicity of neo-adjuvant chemoradiation in esophageal cancer survivors:A prospective cross-sectional pilot study

Purpose: Although cure rates in esophageal cancer (EC) have improved since the introduction of neoadjuvant chemoradiation (nCRT), evidence for treatment-related cardiac toxicity is growing, of which the exact mechanisms remain unknown. The primary objective of this study was to identify (subclinical) cardiac dysfunction in EC patients after nCRT followed by surgical resection as compared to surgery alone. Materials and Methods: EC survivors followed for 5-15 years after curative resection with (n = 20) or without (n = 20) nCRT were enrolled in this prospective cross-sectional pilot study. All patients underwent several clinical and diagnostic tests in order to objectify (sub)clinical cardiac toxicity including cardiac CT and MRI, echocardiography, ECG, 6-minutes walking test, physical examination and EORTC questionnaires. Results: We found an increased rate of myocardial fibrosis (Linear late gadolinium enhancement (LGE) 4 vs. 1; p = 0.13; mean extracellular volume (ECV) 28.4 vs. 24.0; p < 0.01), atrial fibrillation (AF) (6 vs. 2; p = 0.07) and conduction changes in ECG among patients treated with nCRT as compared to those treated with surgery alone. The results suggested an impact on quality of life in terms of worse role functioning for this patient group (95.0 vs. 88.8; p = 0.03). Conclusion: Based on our analyses we hypothesize that in EC patients, radiation-induced myocardial fibrosis plays a central role in cardiac toxicity leading to AF, conduction changes and ultimately to decreased role functioning. The results emphasize the need to verify these findings in larger cohorts of patients. (C) 2021 The Author(s). Published by Elsevier B.V

A comprehensive motion analysis - consequences for high precision image-guided radiotherapy of esophageal cancer patients

Background and purpose When 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 methods A 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. Results Variation 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. Conclusions Despite 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

Retrospective Denial as A Coping Method

Worldwide, gastric cancer is one of the most common and fatal cancers. The majority of patients present with an advanced stage of disease. Even with use of palliative chemotherapy most patients die within 1 year after diagnosis. Medical psychological attention after a diagnosis of incurable cancer is focused on end of life support. This paper presents the care of a patient treated with palliative intent with chemotherapy for an irresectable histologically confirmed gastric cancer. When, unexpectedly prolonged symptom free survival followed, the reaction of the patient came as a surprise to the attending medical team. In this case history we urge those who care for incurable cancer patients, that the rare patient who survives against all odds may require special psychological care

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

Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids

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 thyroidderived 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-lineagespecific 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