The tumor microenvironment is related to the metabolism of cancer cells and local immune reactions. Previous studies have established TILs could be a significant prognostic factor, especially for ...triple-negative breast cancers (TNBC) and human epithelial growth factor receptor 2 (HER2)-positive breast cancers. We explore the association between metabolic information on PET/MRI with TILs in TNBC and HER2-positive breast cancer.
We retrospectively reviewed the cases of 55 women with triple-negative or HER2-positive invasive ductal carcinomas who had undergone
F-FDG PET/MRI without neo-adjuvant treatment for pre-operative evaluation. FDG uptake was quantified as standardized uptake value (SUV) max. The existence of peritumoral edema on PET/MRI was also recorded. The TIL score of the breast cancers was defined histologically on the basis of the proportion of the area infiltrated by lymphocytes, and classified as low (<10 %), intermediate (10-50 %), and high (>50 %). The association between PET/MRI findings and TILs was assessed using Kruskal-Wallis test and Wilcoxon signed-rank test.
There were 14 high TIL, 20 intermediate TIL and 21 low TIL lesions. Higher values of SUVmax were found in the high and intermediate TIL group as compared to the low TIL group (P = 0.013). On the other hand, the lesions with peritumoral edema in the low TIL group tended to show high SUVmax (P = 0.014).
F-FDG uptake on PET/MRI correlated with TIL levels in patients with TNBC and HER2-positive breast cancer. This finding suggests that preoperative PET/MRI may be useful as a non-invasive tool for guiding the treatment plan.
Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). ...Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
Objective : The aim of this study was to elucidate the usefulness of liquid based cytology (LBC) in fine needle aspiration cytology (FNAC) for breast lesions. We conducted a prospective study to ...examine whether LBC could improve the quality of FNAC and whether immunocytochemistry might have a clinical impact on the differential diagnosis.Study Design : We compared the proportion of “inadequate” cases between conventional smear plus LBC and LBC only. LBC specimens were immunostained with CK5/6 and p63, and the percentage of positive results was compared with the clinicopathological final diagnosis.Results : Among the 127 enrolled cases, we excluded one case of simple cyst and included 120 cases in which aspiration was conducted by a board-certificated breast surgeon. The proportion of inadequate cases decreased significantly from 32% (18/56 : conventional smear plus LBC) to 16% (10/64 : LBC only) (p=0.03). Most of the malignant tumors were CK5/6-negative (91%), and 77% of the benign lesions were CK5/6-positive. Most malignant tumors were p63-negative (84%), and 83% of the benign lesions were p63-positive. When we set a cutoff point of a positive cluster at 40%, the sensitivity and specificity of CK5/6 negativity for malignancy were 91% and 83%, respectively (n=62).Conclusion : LBC in breast FNAC can contribute to precise diagnosis by allowing more cells to be collected, and immunocytochemical staining is useful in the differentiation between benign and malignant lesions.
Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical ...trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
The ferric nitrilotriacetate-induced carcinogenesis model is unique in that reactive oxygen species-free radicals are involved in the carcinogenic process. But the effects of iron-withdrawal in the ...progression of renal cell carcinoma are not well understood. We performed repeated phlebotomies on animals that had been administered ferric nitrilotriacetate in the initiation stage of renal cell carcinoma (phlebotomy group), and compared the development of renal tumors with those not receiving repeated phlebotomies (non-phlebotomy group). Ferric nitrilotriacetate-treated male Wistar rats were randomly divided into 2 groups: a phlebotomy group (21 rats) and a non-phlebotomy group (17 rats). Ten age-adjusted normal rats were also observed as a normal group. Hematocrit was maintained under 25% in the phlebotomy group. Hematocrit levels in the normal group and in the non-phlebotomy group were not significantly different. As a result, the incidence of renal cell carcinoma was not significantly different between phlebotomy and non-phlebotomy animals. However, the total weight of the renal cell carcinoma was significantly heavier in the animals from non-phlebotomy group than in those from the phlebotomy group (23.64 g +/- 18.54 vs. 54.40 g +/- 42.40, P < 0.05). The present study demonstrated that phlebotomy after the administration of ferric nitrilotriacetate did not reduce the incidence of renal cell carcinoma. In addition, we showed that iron withdrawal at the promotion stage of carcinogenesis will retard tumor growth.
Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular ...barrier and contribute to hematogenous metastasis; however, the role of oral bacteria‐induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier‐associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF‐κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)‐cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans‐stimulated ECs. Furthermore, S. mutans‐induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.
The oral bacterium, Streptococcus mutans (S. mutans) invades endothelial cells (ECs) accompanied by inflammation. S.mutans disrupts endothelial integrity and subsequently promotes tumor cell extravasation and finally promotes breast cancer cell metastasis to the lungs.
A four-level system is a prerequisite for the controlled-NOT (CNOT) gate and is realized with excitons confined in the coupled quantum dots (QDs). The coupled QDs are fabricated by chemically bonding ...the collagen model peptides to a single-walled carbon nanotube. An interdot exciton–exciton interaction and an exciton four-level system based on it are confirmed through photoluminescence measurements. Rabi oscillations of the exciton populations are observed, which allow the manipulations of the exciton four-level system with designed laser-pulse sequences. The tests on whether the exciton four-level system operates as a CNOT gate are conducted, and the quantum process fidelity is estimated to be approximately 0.7–0.8. The SWAP operation is also demonstrated by employing the CNOT gate three times.
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