A new CT-based method to quantify radiation-induced lung damage in patients

SummaryA new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT

Accuracy Assessment of Pedicle and Lateral Mass Screw Insertion Assisted by Customized 3D-Printed Drill Guides:A Human Cadaver Study

BACKGROUND: Accurate cervical screw insertion is of paramount importance considering the risk of damage to adjacent vital structures. Recent research in 3-dimensional (3D) technology describes the advantage of patient-specific drill guides for accurate screw positioning, but consensus about the optimal guide design and the accuracy is lacking. OBJECTIVE: To find the optimal design and to evaluate the accuracy of individualized 3D-printed drill guides for lateral mass and pedicle screw placement in the cervical and upper thoracic spine. METHODS: Five Thiel-embalmed human cadavers were used for individualized drill-guide planning of 86 screw trajectories in the cervical and upper thoracic spine. Using 3D bone models reconstructed from acquired computed tomography scans, the drill guides were produced for both pedicle and lateral mass screw trajectories. During the study, the initial minimalistic design was refined, resulting in the advanced guide design. Screw trajectories were drilled and the realized trajectories were compared to the planned trajectories using 3D deviation analysis. RESULTS: The overall entry point and 3D angular accuracy were 0.76 +/- 0.52 mm and 3.22 +/- 2.34 degrees, respectively. Average measurements for the minimalistic guides were 1.20 mm for entry points, 5.61 degrees for the 3D angulation, 2.38 degrees for the 2D axial angulation, and 4.80 degrees for the 2D sagittal angulation. For the advanced guides, the respective measurements were 0.66 mm, 2.72 degrees, 1.26 degrees, and 2.12 degrees, respectively. CONCLUSION: The study ultimately resulted in an advanced guide design including caudally positioned hooks, crosslink support structure, and metal inlays. The novel advanced drill guide design yields excellent drilling accuracy

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

Patient-Derived Papillary Thyroid Cancer Organoids for Radioactive Iodine Refractory Screening

Simple Summary Over the past three decades, the incidence of thyroid cancer has been rising, with 90% being the well-differentiated thyroid cancer subtype. After diagnosis and surgical removal of the thyroid gland, radioactive iodine is administered to induce a localized post-operative radiation treatment. However, in 15-33% of papillary thyroid cancer cases, the cells are unable to take up radioactive iodine, resulting in an ineffective treatment which sometimes has severe side effects. Pre-treatment diagnosis of non-responding patients would prevent ineffective and toxic iodine treatment. Therefore, in this study, we developed a patient-derived papillary thyroid cancer organoid model. Patient-derived organoids responding or not responding to radioactive iodine clearly resembled the tumor of origin, but showed clear differences in sodium/iodide symporter expression. Our results indicate that thyroid cancer organoids might be a suitable tool for the early diagnosis of non-responding patients, in order to eventually reduce radioactive iodine overtreatment and its many side effects for thyroid cancer patients. Patients with well-differentiated thyroid cancer, especially papillary thyroid cancer (PTC), are treated with surgical resection of the thyroid gland. This is followed by post-operative radioactive iodine (I-131), resulting in total thyroid ablation. Unfortunately, about 15-33% of PTC patients are unable to take up I-131, limiting further treatment options. The aim of our study was to develop a cancer organoid model with the potential for pre-treatment diagnosis of these I-131-resistant patients. PTC tissue from thirteen patients was used to establish a long-term organoid model. These organoids showed a self-renewal potential for at least five passages, suggesting the presence of cancer stem cells. We demonstrated that thyroid specific markers, a PTC marker, and transporters/receptors necessary for iodine uptake and thyroid hormone production were expressed on a gene and protein level. Additionally, we cultured organoids from I-131-resistant PTC material from three patients. When comparing PTC organoids to radioactive iodine (RAI)-refractory disease (RAIRD) organoids, a substantial discordance on both a protein and gene expression level was observed, indicating a treatment prediction potential. We showed that patient-derived PTC organoids recapitulate PTC tissue and a RAIRD phenotype. Patient-specific PTC organoids may enable the early identification of I-131-resistant patients, in order to reduce RAI overtreatment and its many side effects for thyroid cancer patients

Tyrosine Phosphatase PTPRO Deficiency in ERBB2-Positive Breast Cancer Contributes to Poor Prognosis and Lapatinib Resistance

Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan–Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro ( +/+ ) and Ptpro ( −/− ) mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer

Operative treatment of anterior thoracic spinal cord herniation:three new cases and an individual patient data meta-analysis of 126 case reports

OBJECTIVE: Anterior thoracic spinal cord herniation is a rare cause of progressive myelopathy. Much has been speculated about the best operative treatment. However, no evidence in favor of any of the promoted techniques is available to date. Therefore, we decided to analyze treatment procedures and treatment outcomes of anterior thoracic spinal cord herniation to identify those factors that determine postoperative outcome. METHODS: An individual patient data meta-analysis was conducted, focusing on age, gender, vertebral segment of herniation, preoperative neurological status, operative interval, operative findings, operative techniques, intraoperative neurophysiological monitoring, postoperative imaging, neurological outcome and follow-up. Three cases from our own institution were added to the material collected. Bivariate analysis tests and multivariate logistic regression tests were used so as to define which variables were associated with outcome after surgical treatment of anterior thoracic spinal cord herniation. RESULTS: Brown-Séquard syndrome and release of the herniated spinal cord appeared to be strong independent factors, associated with favorable postoperative outcome. Widening of the dura defect is associated with the highest prevalence of postoperative motor function improvement when compared with the application of an anterior dura patch (P < 0.036). CONCLUSION: Most patients with anterior thoracic spinal cord herniation require operative treatment because of progressive myelopathy. Patients with Brown-Séquard syndrome have a better prognosis with respect to postoperative motor function improvement. In this review, spinal cord release and subsequent widening of the dura defect were associated with the highest prevalence of motor function improvement. D-wave recording can be a very useful tool for the surgeon during operative treatment of this disorder