Real-World Experience of Patient's Compliance and Clinical Outcomes for Trimodality Treatment for Esophageal Cancer: a Study from a Cancer Center in North-East India.

Preoperative chemoradiotherapy is a standard treatment for patients with locally advanced, resectable esophageal cancer. The treatment completion rates impact the survival outcomes (Eyck et al J Clin Oncol 39(18):1995-2004, 2021). Thus, we aimed to estimate the effect of neoadjuvant chemoradiotherapy (NACRT) in terms of treatment completion rates and survival in this subset of patients and bring out the clinical outcomes in that context. This was a retrospective study done at a tertiary cancer center in North-East India. The study period was from 1 January 2018 to 31 December 2021. We included patients diagnosed with locally advanced and resectable esophageal cancer (cT2-3NanyM0) involving the middle and/or lower thoracic esophagus and who were planned for trimodality treatment in the Joint Tumor Board. Out of the 82 patients who were planned for trimodality treatment, all were squamous cell carcinomas. We found that 54.9% of patients completed the entire trimodality treatment. The median age was 56 years (range 34 to 73 years). The male to female ratio was 59:23. Adverse events, of any grade, were seen in 76% of patients who received NACRT. Fatigue (66%) was the most common toxicity. The common hematologic toxicities were neutropenia and anemia (7.3% each). A total of 45 patients (54.9%) were able to complete all the three modalities of treatment. Transthoracic esophagectomy was the preferred approach (84.4%). The site of anastomosis was in the neck of all the patients. Anastomotic leak was seen in 17.7% of patients. Postoperative pulmonary and cardiac complications occurred in 31.1% and 8.9% of patients respectively. The 30-day mortality was 6.7% (three deaths). A pathological complete response was seen in 35.6% among patients who underwent an esophagectomy. R0 resection was achieved in 93.3% of patients. The median overall survival and disease-free survival were 19 months and 17 months respectively. The completion rate of trimodality treatment in the real-world scenario was found to be low in our study, the reasons for which need to be identified and effectively resolved. Oncological outcomes were similar to the published literature.

A Preliminary Study of Thermosets from Epoxy Resins Made Using Low-Toxicity Furan-Based Diols.

Glycidyl ethers are prepared from a series of furan-based diols and cured with a diamine to form thermosets. The furan diols demonstrate lower toxicity than bisphenol-A in a prior study. The diglycidyl ethers show improved thermal stability compared to the parent diols. Cured thermosets are prepared at elevated temperature using isophorone diamine (IPDA). Glass transition temperatures are in the range of 30-54 °C and depend on the structure of the furan diol. Coatings are prepared on steel substrates and show very high hardness, good adhesion, and a range of flexibility. Properties compare favorably with a control based on a bisphenol-A epoxy resin. The study demonstrates that epoxy resins based on furan diols, which have been shown to have lower toxicity than bisphenol-A, can form thermosets having properties comparable to a standard epoxy resin system; and thus, are viable as replacements for bisphenol-A epoxy resins.

The G-protein-coupled estrogen receptor, a gene co-expressed with ERα in breast tumors, is regulated by estrogen-ERα signalling in ERα positive breast cancer cells.

GPER is a seven transmembrane G-protein-coupled estrogen receptor that mediates rapid estrogen actions. Large volumes of data have revealed its association with clinicopathological variables in breast tumors, role in epidermal growth factor (EGF)-like effects of estrogen, potential as a therapeutic target or a prognostic marker, and involvement in endocrine resistance in the face of tamoxifen agonism. GPER cross-talks with estrogen receptor alpha (ERα) in cell culture models implicating its role in the physiology of normal or transformed mammary epithelial cells. However, discrepancies in the literature have obfuscated the nature of their relationship, its significance, and the underlying mechanism. The purpose of this study was to assess the relationship between GPER, and ERα in breast tumors, to understand the mechanistic basis, and to gauge its clinical significance. We mined The Cancer Genome Atlas (TCGA)-BRCA data to examine the relationship between GPER and ERα expression. GPER mRNA, and protein expression were analyzed in ERα-positive or -negative breast tumors from two independent cohorts using immunohistochemistry, western blotting, or RT-qPCR. The Kaplan-Meier Plotter (KM) was employed for survival analysis. The influence of estrogen in vivo was studied by examining GPER expression levels in estrus or diestrus mouse mammary tissues, and the impact of 17ß-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ERα agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ERα knockdown. ERα-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation (ChIP) assay. Clinical data revealed significant positive association between GPER and ERα expression in breast tumors. The median GPER expression in ERα-positive tumors was significantly higher than ERα-negative tumors. High GPER expression was significantly associated with longer overall survival (OS) of patients with ERα-positive tumors. In vivo experiments showed a positive effect of E2 on GPER expression. E2 induced GPER expression in MCF-7 and T47D cells; an effect mimicked by PPT. Tamoxifen or ERα-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ERα occupancy in the upstream region of GPER. Furthermore, treatment with 17ß-estradiol or PPT significantly reduced the IC50 of the GPER agonist (G1)-mediated loss of MCF-7 or T47D cell viability. In conclusion, GPER is positively associated with ERα in breast tumors, and induced by estrogen-ERα signalling axis. Estrogen-mediated induction of GPER makes the cells more responsive to GPER ligands. More in-depth studies are warranted to establish the significance of GPER-ERα co-expression, and their interplay in breast tumor development, progression, and treatment.

BMP4 enhances anoikis resistance and chemoresistance of breast cancer cells through canonical BMP signaling.

Bone morphogenetic proteins (BMPs) regulate cell fate during development and mediate cancer progression. In this study, we investigated the role of BMP4 in proliferation, anoikis resistance, metastatic migration, and drug resistance of breast cancer cells. We utilized breast cancer cell lines and clinical samples representing different subtypes to understand the functional effect of BMP4 on breast cancer. The BMP pathway was inhibited with the small molecule inhibitor LDN193189 hydrochloride (LDN). BMP4 signaling enhanced the expression of stem cell genes CD44, ALDH1A3, anti-apoptotic gene BCL2 and promoted anoikis resistance in MDA-MB-231 breast cancer cells. BMP4 enhanced self-renewal and chemoresistance in MDA-MB-231 by upregulating Notch signaling while LDN treatment abrogated anoikis resistance and proliferation of anoikis resistant breast cancer cells in the osteogenic microenvironment. Conversely, BMP4 downregulated proliferation, colony-forming ability, and suppressed anoikis resistance in MCF7 and SkBR3 cells, while LDN treatment promoted tumor spheroid formation and growth. These findings indicate that BMP4 has a context-dependent role in breast cancer. Further, our data with MDA-MB-231 cells representing triple-negative breast cancer suggest that BMP inhibition might impair its metastatic spread and colonization.

Reconstruction and Outcome of Foot Defects Following Oncological Resection-Experience from a Cancer Centre in North-East India.

Solid tumours around the foot are rare and include soft tissue sarcomas, skin and bone malignancies. Extended soft tissue defects due to oncological resection result in the loss of shock-absorbing and friction resistant tissue, which leads to altered walking patterns and pain. Replacement of plantar tissue requires soft tissue resistant to weight, pressure and shear stress. The other important desired goal of foot reconstruction is short wound healing time in order to allow adjuvant therapy at stipulated time. This is a retrospective study from March 2016 to October 2019. A total of twenty-one (n = 21) patients were operated for foot malignancies during this period in our institute and the resulting defects were reconstructed using various methods. Different reconstructive surgeries were performed depending on tumour size, location and general health status of patients. The length of hospitalization and the presence of local postoperative complications were assessed. Functional outcomes were measured in terms of MSTS score. Average age of the series is 53.1 years. Sixty-six percent of the patients (n = 14) presented with tumour at the weight bearing areas and 33% patients (n = 7) at the non-weight bearing areas of the foot. Fifty-seven percent of patients (n = 12) presented with malignant melanoma of foot, squamous cell carcinoma was seen in 33% (n = 7) patients and 4% patients (n = 1 each) presented as osteosarcoma and malignant peripheral nerve sheath tumour respectively. The mean MSTS score in patients with weight bearing areas (location) is statistically significant (p = 0.031). There is a significant correlation between the surgical complications and follow up MSTS score (p = 0.046) which signifies that flap related complications result in lower MSTS score. The mean MSTS score was 22.71/30. Complications were observed in three cases which included partial flap necrosis, graft loss and foot stiffness. Simple skin grafts to local flaps maybe a viable option in a limited resource setting based on the location of defect. Free tissue transfer is the ideal choice in case of weight bearing areas to achieve acceptable outcomes.

RUNX1T1, a potential prognostic marker in breast cancer, is co-ordinately expressed with ERα, and regulated by estrogen receptor signalling in breast cancer cells.

BACKGROUND: RUNX1T1 is extensively studied in the context of AML1-RUNX1T1 fusion protein in acute myeloid leukemia. Little is known about the function of RUNX1T1 itself, although data on its function and regulation have begun to emerge from clinical, and in vitro studies. It is a putative tumor suppressor, whose expression is altered in a variety of solid tumors. Recently, reduced expression of RUNX1T1 in triple-negative breast tumors, and its influence on prognosis was reported. METHODS AND RESULTS: The Kaplan-Meier Plotter online tool was used to study the relationship between RUNX1T1 expression and survival of breast cancer patients. High RUNX1T1 expression was associated with longer overall survival (OS), relapse-free survival (RFS) and distant metastasis free survival (DMFS). RUNX1T1 expression positively and negatively influenced OS of patients with ERα-positive and ERα-negative breast tumors, respectively. It was also associated with prolonged RFS, and DMFS in tamoxifen-treated patients. Expression of RUNX1T1 and ERα mRNA was analyzed in 40 breast tumor samples, and breast cancer cell lines using RT-PCR. TCGA-BRCA data was mined to study the relationship between RUNX1T1 and ERα mRNA expression. ERα-positive breast tumors showed significantly higher RUNX1T1 mRNA expression compared to ERα-negative tumors. RUNX1T1 mRNA expression was analyzed by qRT-PCR in MCF-7 or T47D cells, which were treated with 17ß-estradiol, or the ERα agonist PPT, alone or in combination with 4-hydroxytamoxifen. Effect of ERα knockdown was also investigated. Results indicate that estrogen downmodulated RUNX1T1 mRNA expression via ERα. CONCLUSION: Higher expression of RUNX1T1 in breast tumors is associated with favourable prognosis. RUNX1T1 and ERα show co-ordinated expression in breast tumors, and breast cancer cell lines. Estrogen-ERα signalling downmodulates the expression of RUNX1T1 mRNA in ERα-positive breast cancer cells. In-depth investigations on the interaction between RUNX1T1 and ERα are warranted to unravel the role and relevance of RUNX1T1 in breast cancer.

Development and Processing of Novel Heparin Binding Functionalized Modified Spider Silk Coating for Catheter Providing Dual Antimicrobial and Anticoagulant Properties.

Tailored surface coatings have been used for decades to improve material performance in blood. Among different approaches, heparin based biomedical coatings have found great success in the commercial catheter market. However, they have their own limitations. Coating of a vascular device with a heparin binding peptide (HBP), which can sequester the circulating heparin, presents numerous advantages over both systemic heparin therapy and direct heparin bound surfaces. Embedding HBP in a silk biopolymer provides the mechanical integrity necessary under dynamic flow conditions to both insert the catheter and maintain proper blood flow. Furthermore, due to the similarity in structure of HBP with antimicrobial peptides, it is predicted that the fusion protein will also show antimicrobial property, a critical and unique aspect to combat catheter related blood stream infections and extend the longevity of hemodialysis catheters. To assess this hypothesis, a recombinant fusion protein (S4H4) containing both silk amino acid motifs and HBP was assessed as a coating on a silicone surface. After validating that, the protein was deposited on the surface via XPS, Raman spectroscopy, ATR and SEM imaging, antimicrobial and anticoagulant activities were evaluated. The coating was able to prevent not only planktonic bacterial growth but also prevented the growth of a biofilm. Finally, the coating had both antibacterial and anticoagulant effect simultaneously. This study proves the successful production of a silk-based biopolymer that can be embedded with a heparin-binding functionality to create a dual functional device coating that can prevent infection and thrombosis together.