Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (iCCA), perihilar and distal cholangiocarcinoma (pCCA and dCCA), and gallbladder carcinoma based on the epithelial site of origin. BTCs are highly aggressive tumors associated with poor prognosis due to widespread metastasis and high recurrence. Surgery is the typical curative-intent treatment, yet the cornerstone of cure depends on the anatomical site of the primary tumor, and only a minority of patients (approximately 30%) has an indication necessitating surgery. Similarly, only a small subset of carefully selected patients with early iCCA who are not candidates for liver resection can opt for liver transplantation. Chemotherapy, target therapy, and immunotherapy are the main treatment options for patients who have advanced stage or unresectable disease. The genetic background of each cholangiocarcinoma subtype has been accurately described based on whole gene exome and transcriptome sequencing. Accordingly, precision medicine in targeted therapies has been identified to be aimed at distinct patient subgroups harboring unique molecular alterations. Immunotherapy such as immune checkpoint inhibitors (ICIs) was identified as antitumor responses in a minority of select patients. Current studies indicate that immunotherapy of adoptive cell therapy represents a promising approach in hematological and solid tumor malignancies, yet clinical trials are needed to validate its effectiveness in BTC. Herein, we review the progress of BTC treatment, stratified patients according to the anatomic subtypes of cholangiocarcinoma and the gene drivers of cholangiocarcinoma progression, and compare the efficacy and safety of chemotherapy, targeted therapy, and immunotherapy, which will be conducive to the design of individualized therapies.

/pdf/the-state-of-therapy-modalities-in-clinic-for-biliary-tract-mawkbj0n.pdf

The state of therapy modalities in clinic for biliary tract cancer.

Reducing background signal and improving detection sensitivity is one of the main research directions of optical biosensors. Based on the structure and functional characteristics of MOFs, the optical sensing system is constructed, which does not require the pre-treatment of complex biological samples or the catalysis of biological enzymes, and can be directly used for the detection of HER2 in serum. In this paper, the fluorescence resonance energy transfer effect between Co/Fe-MOFs and HER2 Aptamer modified fluorescent group FAM was used to make FAM-Apt undergo fluorescence quenching. When the target is present, FAM-Apt specifically binds to HER2 and simultaneously disconnects from Co/Fe-MOFs surface. FAM was recovered, and a reproducible fluorescence sensing system was successfully constructed for the detection of HER2 in serum. The two-dimensional nanosheets and bimetallic structures of Co/Fe-MOFs have greater specific surface area and fluorescence quenching ability. The results showed that the sensor system had good reproducibility (RSD=2.4%), and the detection range of HER2 was 0.01–10 ng/mL under the best conditions, and the estimated detection limit was 6.67 pg/mL. 

An ultra-sensitive fluorescent Aptamer sensor based on 2D MOF for detection of HER2 in serum

Epidermal growth factor receptor (EGFR) is frequently overexpressed in multiple malignancies. Icotinib (IH), a new EGFR tyrosine kinase inhibitor, enhances radiosensitivity in various types of cancer, but its effect on nasopharyngeal carcinoma (NPC) remains unclear. Total 115 NPC tissue sections and 30 nasopharyngitis tissue sections were enrolled. The correlation of EGFR expression and clinicopathologic features of NPC was analyzed. Survival analysis was calculated by using univariate and multivariate regression analysis. A radioresistant NPC cell line, CNE-2R, was established with a gradient irradiation schedule. Cell viability, colony formation and EGFR expression of CNE-2/2R cells were examined. Significant higher expression of EGFR was observed in NPC tissues than chronic nasopharyngitis lesions. EGFR expression was significantly correlated with both tumor stage (P < 0.001) and tumor-node-metastasis stage of NPC (P = 0.006). EGFR expression was an independent prognostic factor of disease-free survival (P = 0.047) and the overall survival of NPC (P = 0.016). Cell viability was higher in CNE-2R than CNE-2 on days 1, 2, 4, and 6 after radiation of 4 Gy. The colony number of CNE-2R was significantly higher than that of CNE-2 (P < 0.05), while IH enhanced the radiosensitizing effect of CNE-2R with lower survival fraction (P < 0.05). EGFR mRNA and protein expression levels were significantly higher in CNE-2R cells compared to CNE-2 cells, but significantly decreased after IH treatment (all P < 0.05). In conclusion, high EGFR expression is a poor prognostic factor for NPC patients. IH enhances the radiosensitivity of CNE-2R cells and reduce EGFR expression. 

https://www.techscience.com/oncologie/online/detail/18762/pdf

Icotinib Enhanced Radiosensitization of Nasopharyngeal Carcinoma by Inhibiting the Expression of Epidermal Growth Factor Receptor

Background: Breast cancer (BC) comprises multiple subtypes with distinct molecular features, which differ in their interplay with host immunity, prognosis, and treatment. Non-invasive blood analyses can provide valuable insights into systemic immunity during cancer. The aim of this study was to analyze the expression of transcriptional isoforms in peripheral blood mononuclear cells (PBMCs) from BC patients and healthy women to identify potential BC immune biomarkers. Methods: RNA sequencing and isoform-level bioinformatics were performed on PBMCs from 12 triple-negative and 13 luminal A patients. Isoform expression validation by qRT-PCR and clinicopathological correlations were performed in a larger cohort (156 BC patients and 32 healthy women). Results: Transcriptional analyses showed a significant (p &lt; 0.001) decrease in the ENST00000374459 RASGEF1A isoform in PBMCs of BC compared to healthy subjects, indicating disease-related expression changes. The decrease was associated with higher ctDNA and Ki-67 values. Conclusions: The levels of the RASGEF1A transcriptional isoform ENST00000374459 may have the potential to distinguish between BC and healthy subjects. The downregulation of ENST00000374459 in breast cancer is associated with higher proliferation and ctDNA shedding. Specialized bioinformatics analyses such as isoform analyses hold significant promise in the detection of biomarkers, since standard RNA sequencing analyses may overlook specific transcriptional changes that may be disease-associated and biologically important. 

Isoform-Level Transcriptome Analysis of Peripheral Blood Mononuclear Cells from Breast Cancer Patients Identifies a Disease-Associated RASGEF1A Isoform

Morphological and immunohistochemical studies of solid arrangement canine mammary carcinomas have shown that the different histological types may be characterized by proliferation of epithelial and/or myoepithelial cells. However, little is known about immunophenotypes and the importance of inflammation as prognostic factors in these neoplasms. The objective of the present study was to characterize the immunophenotype and degree of inflammation in the solid type of canine mammary neoplasm and to investigate their association with metastasis, Ki-67 index, tumour size, necrosis and survival. Sixty-five carcinomas with solid pattern, basaloid carcinomas, solid papillary carcinomas, malignant adenomyoepitheliomas (MAMEs) or malignant myoepitheliomas (MMEs) were investigated. Luminal A, luminal B HER2 negative and HER2 positive, HER2 overexpressed and triple negative immunophenotypes were immunolabelled as were Ki-67 protein and cyclooxygenase-2 (Cox-2). Histological peritumoural and intratumoural inflammatory infiltrates were graded (distribution × intensity) and the presence of necrosis identified. We found a statistical difference between histological types and immunophenotypes, with MME and MAME having a higher occurrence of luminal A, whereas most neoplasms had the luminal B HER-negative immunophenotype. There was no correlation between immunophenotype and degree of peri- and intratumoural inflammation, nodal metastasis, necrosis or tumour size. An increased degree of peri- and intratumoural inflammation was significantly associated with lymph node metastasis, and more severe intratumoural inflammation was associated with the presence of tumour necrosis. Tumour size, Ki-67 index and Cox-2 score were not associated with inflammation in either peri- or intratumoural regions. No difference was observed in survival in relation to immunophenotype or degree of inflammation, but the Cox regression model revealed that nodal metastasis influenced the risk of death. 

Evaluation of immunophenotype and inflammation in canine mammary neoplasms with solid arrangement

The immune response to cancer serves an important role in disease progression and patient prognosis. For triple-negative breast cancer showing aggressive behavior, immunotherapy has a good efficacy because of the potent immunogenicity of this type of cancer. However, the dominant subtype, luminal human epidermal growth factor receptor-2 (HER2)-negative breast cancer, is less immunogenic. To determine whether luminal HER2-negative cancer reacts to the anticancer immune response, the present study analyzed the status and prognostic value of the principal immunological biomarkers of breast cancer, including tumor-infiltrating lymphocytes (TILs), CD8+ T lymphocytes, the major histocompatibility complex and programmed cell death ligand-1 (PD-L1). The biomarkers were compared between patients with luminal HER2-negative breast cancer and those with immunogenic subtypes including triple-negative and HER2-overexpressed breast cancer. A total of 71 patients with primary breast cancer were classified into the immunogenic non-luminal (n=23) and less immunogenic luminal HER2-negative groups (n=48) based on immunogenicity. In the luminal HER2-negative group, compared with patients with low TIL levels, those with high TIL levels were at an advanced stage of cancer (P=0.024) and showed worse relapse-free survival (P=0.057); however, the remaining biomarkers exhibited no association with cancer progression or prognosis. In the non-luminal group, patients with high TIL levels showed significantly better RFS than those with low TIL levels (P=0.014). Compared with non-luminal patients negative for PD-L1, those positive for PD-L1 exhibited better overall survival (P=0.064). Notably, TIL status was found to exhibit contrasting prognostic predictions based on immunogenicity. In conclusion, TILs are a strong candidate for prognostic prediction in breast cancer, regardless of the subtype. PD-L1 is a potential candidate for prognostic prediction in immunogenic breast cancers, but not in the luminal HER2-negative subtype.

/pdf/status-and-prognostic-value-of-immunological-biomarkers-of-snkgu87y.pdf

Status and prognostic value of immunological biomarkers of breast cancer

Prolonged Survival in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressed Metastatic Breast Cancer after Targeted Therapy is Dominantly Contributed by Luminal-Human Epidermal Growth Factor Receptor-2 Population

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Status and prognostic value of immunological biomarkers of breast cancer

Prolonged Survival in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressed Metastatic Breast Cancer after Targeted Therapy is Dominantly Contributed by Luminal-Human Epidermal Growth Factor Receptor-2 Population