Refining PD-1/PD-L1 assessment for biomarker-guided immunotherapy: A review

Anti-programmed cell death ligand 1 (anti-PD-L1)  immunotherapy is an increasingly crucial in cancer treatment. To date, the Federal Drug Administration (FDA) has approved four PD-L1 immunohistochemistry (IHC) staining protocols, commercially available in the form of "kits", facilitating testing for PD-L1 expression. These kits comprise four PD-L1 antibodies on two separate IHC platforms, each utilizing distinct, non-interchangeable scoring systems. Several factors, including tumor heterogeneity and the size of the tissue specimens assessed, can lead to PD-L1 status misclassification, potentially hindering the initiation of therapy. Therefore, the development of more accurate predictive biomarkers to distinguish between responders and non-responders prior to anti-PD-1/PD-L1 therapy warrants further research. Achieving this goal necessitates refining sampling criteria, enhancing current methods of PD-L1 detection, and deepening our understanding of the impact of additional biomarkers. In this article, we review potential solutions to improve the predictive accuracy of PD-L1 assessment in order to more precisely anticipate patients' responses to anti-PD-1/PD-L1 therapy, monitor disease progression and predict clinical outcomes

The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review

The inflammatory process plays a significant role in the development of colon cancer (CRC). Intestinal cytokine networks are critical mediators of tissue homeostasis and inflammation but also impact carcinogenesis at all stages of the disease. Recent studies suggest that inflammation is of greater importance in the serrated pathway than in the adenoma-carcinoma pathway. Interleukins have gained the most attention due to their potential role in CRC pathogenesis and promising results of clinical trials. Malignant transformation is associated with the pro-tumorigenic and anti-tumorigenic cytokines. The harmony between proinflammatory and anti-inflammatory factors is crucial to maintaining homeostasis. Immune cells in the tumor microenvironment modulate immune sensitivity and facilitate cancer escape from immune surveillance. Therefore, clarifying the role of underlying cytokine pathways and the effects of their modulation may be an important step to improve the effectiveness of cancer immunotherapy

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p p p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy

The Prognostic Role of CDK9 in Bladder Cancer

Introduction: Most patients with urothelial carcinoma are diagnosed with non-invasive tumors, but the prognosis worsens with the progression of the disease. Overexpression of cyclin-dependent kinase 9 has been recently linked to increased cancer proliferation, faster progression, and worse prognosis. However, some cancers seem to contradict this rule. In this work, we explored the prognostic role of CDK9 expression in urothelial carcinoma. Materials and Methods: We performed immunohistochemical analysis on 72 bladder cancer samples. To assess a larger group of patients, the Cancer Genome Atlas (TCGA) database containing 406 cases and transcriptomics information through the Human Pathology Atlas were analyzed. Results: CDK9 is overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High CDK9 expression was observed in low-stage, low-grade, and non-muscle-invasive tumors (p < 0.05). The patients with high CDK9 expression had a significantly higher 5-year overall survival rate than those with low CDK9 expression (77.54% vs. 53.6% in the TMA group and 57.75% vs. 35.44% in the TCGA group, respectively) (p < 0.05). The results were consistent in both cohorts. Multivariate Cox regression analysis indicated that low CDK9 status was an independent predictor for poor prognosis in the TCGA cohort (HR 1.60, CL95% 1.1–2.33, p = 0.014). Conclusions: High CDK9 expression predicts a favorable prognosis in urothelial carcinoma and is associated with clinicopathological features characteristic for early-stage disease. The decrease in CDK9 expression can be associated with the build-up of genetic instability and may indicate a key role for CDK9 in the early stages of urothelial carcinoma

SARS-CoV-2 Infection during Delivery Causes Histopathological Changes in the Placenta

Background: SARS-CoV-2 can damage human placentas, leading to pregnancy complications, such as preeclampsia and premature birth. This study investigates the histopathological changes found in COVID-19-affected placentas. Materials and Methods: This study included 23 placentas from patients with active COVID-19 during delivery and 22 samples from patients without COVID-19 infection in their medical history. The samples underwent histopathological examination for pathology, such as trophoblast necrosis, signs of vessel damage, or fetal vascular malperfusion. Results: Newborns from the research group have lower weights and Apgar scores than healthy newborns. In the COVID-19 group, calcifications and collapsed intervillous space were more frequent, and inflammation was more severe than in the healthy group. At the same time, the placenta of SARS-CoV-2-positive patients showed signs of accelerated vascular maturation. Trophoblast necrosis was found only in the placentas of the research group. The expression of CD68+ was elevated in the COVID-19 cohort, suggesting that macrophages constituted a significant part of the inflammatory infiltrate. The increase in lymphocyte B markers was associated with placental infarctions, while high levels of CD3+, specific for cytotoxic T lymphocytes, correlated with vascular injury. Conclusions: SARS-CoV-2 is associated with pathological changes in the placenta, including trophoblast necrosis, calcification, and accelerated villous maturation. Those changes appear to be driven by T cells and macrophages, whose increased expression reflects ongoing histiocytic intervillositis in the placenta