Slow degrading Mg-based materials induce tumor cell dormancy on an osteosarcoma-fibroblast coculture model

Osteosarcoma is one of the most common cancers in young adults and is commonly treated using surgery and chemotherapy. During the past years, these therapy approaches improved but failed to ameliorate the outcomes. Therefore, novel, targeted therapeutic approaches should be established to enhance treatment success while preserving patient's quality of life. Recent studies suggest the application of degradable magnesium (Mg) alloys as orthopedic implants bearing a potential antitumor activity. Here, we examined the influence of Mg-based materials on an osteosarcoma-fibroblast coculture. Both, Mg and Mg–6Ag did not lead to tumor cell apoptosis at low degradation rates. Instead, the Mg-based materials induced cellular dormancy in the cancer cells indicated by a lower number of Ki-67 positive cancer cells and a higher p38 expression. This dormancy-like state could be reversed by reseeding on non-degrading glass slides but could not be provoked by inhibition of the protein kinase R-like endoplasmic reticulum kinase. By investigating the influence of the disjunct surface-near effects of the Mg degradation on cell proliferation, an increased pH was found to be a main initiator of Mg degradation-dependent tumor cell proliferation inhibition

Optimizing an osteosarcoma-fibroblast coculture model to study antitumoral activity of magnesium-based biomaterials

Osteosarcoma is among the most common cancers in young patients and is responsible for one-tenth of all cancer-related deaths in children. Surgery often leads to bone defects in excised tissue, while residual cancer cells may remain. Degradable magnesium alloys get increasing attention as orthopedic implants, and some studies have reported potential antitumor activity. However, most of the studies do not take the complex interaction between malignant cells and their surrounding stroma into account. Here, we applied a coculture model consisting of green fluorescent osteosarcoma cells and red fluorescent fibroblasts on extruded Mg and Mg–6Ag with a tailored degradation rate. In contrast to non-degrading Ti-based material, both Mg-based materials reduced relative tumor cell numbers. Comparing the influence of the material on a sparse and dense coculture, relative cell numbers were found to be statistically different, thus relevant, while magnesium alloy degradations were observed as cell density-independent. We concluded that the sparse coculture model is a suitable mechanistic system to further study the antitumor effects of Mg-based material

Uroplakin II outperforms uroplakin III in diagnostically challenging settings

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107556/1/his12360.pd

Reporting trends, practices, and resource utilization in neuroendocrine tumors of the prostate gland: A survey of genitourinary (GU) pathologists

Background: Neuroendocrine tumors of the prostate gland were recently classified in the WHO. Despite increasing experience in this area, the specifics and the new clinical and molecular emerging data from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, need refinement of the diagnostic terminology to encompass the full spectrum of neuroendocrine differentiation. Use of immunohistochemistry (IHC) as a diagnostic, prognostic, and/or predictive tool remains unclear. This study aims at questionnaire- and scenario-based survey among the GU pathologists. Although some of the questions may appear superfluous, this topic based on discussions at multiple levels has evoked surprisingly passionate responses from some who have adopted a more objective approach using IHC, citing that recommendations imply that IHC is necessary to be certain. Design: An online survey containing 35 questions was undertaken by 39 GU pathologists (with 5 to 10 years, \u3e10 years and \u3e20 years experience) from four continents, focusing on ascertaining practice patterns in this area. Specific questions included whether, when, and how the respondents classify neuroendocrine differentiation/mixed carcinomas/Paneth cell change/neuroendocrine carcinoma (small, SCC/large cell, LCNEC) of the prostate gland. Additionally questions were posed regarding frequency and indications of IHC with respect to these issues. Some therapy and biomarker-related questions were added as well. De-identified respondent data was tabulated and analyzed by routine statistics. The responses were scored in percentage for each question. Results: 70% and 63% of the responders correctly diagnosed a SCC and mixed acinar adenocarcinoma-SCC, respectively. 37% pathologists felt the need of IHC in a SCC, even if the morphology is classical. A majority (87%) of the responders have the correct idea about the immunopanel and therapeutic options for a SCC. Most importantly, pathologists (85%) correctly mentioned that there is no role of TTF1 indifferentiating pulmonary from prostatic SCC, and determination of site of origin of a high-grade neuroendocrine carcinoma has no importance, as these are treated similarly. In the mixed carcinoma cases, exact quantitation of both the elements, grading of the acinar component as the therapy includes both androgen deprivation and platinum-based chemotherapy, and importance of androgen receptor immunoreactivity have been voted by 85% responders. 49% failed to diagnose Paneth cell-like differentiation, nor were they clear about its prognostic implications. Conclusions: 1. Awareness on morphological features and management of SCC across the pathologists was consistent and IHC work up was necessary for a subset of pathologists for confirmation. 2. Majority failed to recognize Paneth cell-like differentiation, nor were they clear about its prognostic implications, while a small subset failed to identify small cell-like PIN. 3. There still lies some confusion in recognizing Gleason 10 acinar adenocarcinoma and large cell neuroendocrine carcinoma. 4. In the mixed carcinoma cases, there seems to have a legitimate call for appropriate IHC work up, including prostatic and neuroendocrine markers and exact quantitation and grading of the acinar component as the therapy includes both androgen deprivation and platinum-based chemotherapy. 5. Based on the responses, practising trends are different between North America and Asia. Further study and consensus on best practice guidelines based on NCCN parameters are needed to provide guidance with regards to the appropriate indications for IHC use in the various scenarios and patterns of neuroendocrine features in the prostate gland

Urothelial dysplasia: Diagnostic value in clinical practice 20 years since the 1998 who/isup consensus

Background: In the 1980-90s, flat neoplastic urothelial lesions were categorized as mild, moderate, and severe dysplasia, and urothelial carcinoma in situ (CIS). Three subsequent WHO classifications have condensed these lesions into urothelial dysplasia and CIS, with CIS including many lesions with moderate to severe dysplasia. Many suggest \u27dysplasia\u27 is infrequent in diagnostic specimens, but little is known of the use of this term in contemporary practice. Design: We surveyed 45 academic uropathologists practicing in 12 countries on their diagnostic practices regarding \u27dysplasia\u27. Deidentified responses to both specific questions regarding diagnostic practice and opinions regarding dysplasia diagnosis in prior and future practice were tabulated. Results: Most respondents diagnosed dysplasia (82%) in the past 10 years, though many noted rarity of usage. Of those who have diagnosed dysplasia (N=37), 38% had done so in a de novo setting, although the majority (86%) made the diagnosis in the setting of antecedent urothelial neoplasm. Further, 31% have diagnosed dysplasia in the upper tract, 39% have diagnosed multifocal dysplasia, 56% diagnosed it with concurrent CIS or papillary neoplasm, and 33% used IHC to assess dysplasia versus CIS. Of those who did not diagnose dysplasia (N=8, 18%), all have reported the possibility of dysplasia in biopsies labeled \u27atypical\u27. Most (83%) consider dysplasia a relevant concept in the pathogenesis of urothelial neoplasms and nearly all (91%) support greater study. Only a minority (11%) could identify any important work supporting dysplasia as a distinct entity in two decades. Overall, nearly half of the participants were for (56%) or against (44%) prospective use of \u27dysplasia\u27 in practice. Conclusions: Among academic uropathologists, there is striking variation in the use of \u27urothelial dysplasia\u27 across diagnostic settings. Most who use the term use it in biopsies with prior or concurrent urothelial neoplasia; some avoid the term, preferring \u27atypia\u27 for lesions falling short of CIS. This discrepancy confirms need for a diagnostic term for lesions with features believed neoplastic but insufficient to designate as CIS. The decrease in urologic pathologists who favor future use of \u27dysplasia\u27 diagnosis (56%) compared to those reporting prior use of the term (84%) may signal the opportunity to promulgate improved terminology to communicate diagnostic concern and uncertainty. Future study will be needed to inform recommended follow-up and management