CA : A Cancer Journal for Clinicians

Perineural invasion (PNI) can be found in a variety of malignant tumors. It is a sign of tumor metastasis and invasion and portends the poor prognosis of patients. The pathological description and clinical significance of PNI are clearly understood, but exploration of the underlying molecular mechanism is ongoing. It was previously thought that the low-resistance channel in the anatomic region led to the occurrence of PNI. However, with rapid development of precision medicine and molecular biology, we have gradually realized that the occurrence of PNI is not the result of a single factor. The latest study suggests that PNI of cancer is a continuous and multistep process. A specific peripheral microenvironment, also called the perineural niche, is formed by neural cells, supporting cells, recruited inflammatory cells, altered extracellular matrix, blood vessels, and immune components in the background of carcinoma. Various soluble signaling molecules and their receptors comprise a complex signal network, which achieves the interaction between nerve and tumor. Nerve cells and tumor cells can interact directly or through the opening and closing of the signal transduction pathways and/or the recognition and response of the ligands and receptors. The information is transferred to the targets accurately and effectively, leading to the specific interactions between the nerve cells and the malignant tumor cells. PNI occurs through changes in nerve cells and supporting cells in the background of cancer; change and migration of the perineural matrix; enhancement of the viability, mobility, and invasiveness of the tumor cells; injury and regeneration of nerve cells; interaction, chemotactic movement, contact, and adherence of the nerve cells and the tumor cells; escape from autophagy, apoptosis, and immunological surveillance of tumor cells; and so on. Certainly, exploring the mechanism of PNI clearly has great significance for blocking tumor progression and improving patient survival. The current review aims to elucidate the cellular and molecular mechanisms of PNI, which may help us find a strategy for improving the prognosis of malignant tumors.

Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche.

Abstract Tumor biomarkers, the substances which are produced by tumors or the body’s responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin. 

Tumor biomarkers for diagnosis, prognosis and targeted therapy.

Bladder cancer is the most common tumor in the urinary system, with approximately 420,000 new cases and 160,000 deaths per year. The European Organization for Research and Treatment of Cancer (EOTRC) classifies non-muscular invasive bladder cancer (NMIBC) into low-risk, medium-risk and high-risk groups based on a comprehensive analysis of NMIBC pathological parameters and the risk of recurrence and progression to muscular invasive bladder cancer (MIBC). Traditional classification systems are based on pathologic grading, staging systems, and clinical prognosis. However, the pathological parameters of the tumor cannot fully reflect the "intrinsic characteristics" of bladder cancer, and tumors with a similar pathology exhibit different biological behaviors. Furthermore, although the traditional classification system cannot accurately predict the risk of recurrence or the progression of bladder cancer patients (BCs) individually, this method is widely used in clinical practice because of its convenient operation. With the development of sequencing and other technologies, the genetics-based molecular subtyping of bladder cancer has become increasingly studied. Compared with the traditional classification system, it provides more abundant tumor biological information and is expected to assist or even replace the traditional typing system in the future.

Traditional Classification and Novel Subtyping Systems for Bladder Cancer.

Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.

Tumour innervation and neurosignalling in prostate cancer.

Tumor necrosis (TN) correlates with adverse outcomes in numerous solid tumors. However, its prognostic value in renal cell carcinoma (RCC) remains unclear. In this study, we performed a meta-analysis to evaluate associations between TN and cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and progression-free-survival (PFS) in RCC. Electronic searches in PubMed, EMBASE and Web of Science were conducted according to the PRISMA statement. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to evaluate relationships between TN and RCC. A fixed- or random-effects model was used to calculate pooled HRs and 95%CIs according to heterogeneity. A total of 34 cohort studies met the eligibility criteria of this meta-analysis. The results showed that TN was significantly predictive of poorer CSS (HR = 1.37, 95% CI: 1.23–1.53, p < 0.001), OS (HR = 1.29, 95% CI: 1.20–1.40, p < 0.001), RFS (HR = 1.55, 95% CI: 1.39–1.72, p < 0.001) and PFS (HR = 1.31, 95% CI: 1.17–1.46, p < 0.001) in patients with RCC. All the findings were robust when stratified by geographical region, pathological type, staging system, number of patients, and median follow-up. The present study suggests that TN is associated with CSS, OS, RFS and PFS clinical outcomes of RCC patients and may serve as a predictor of poor prognosis in these patients.

/pdf/tumor-necrosis-as-a-prognostic-variable-for-the-clinical-1rmx53uizg.pdf

Tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis

Assessing the prognostic significance of specific clinicopathological features plays an important role in surgical management after radical cystectomy. This study investigated the association between ten clinicopathological characteristics and cancer-specific survival (CSS) in patients with bladder cancer. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a literature search was conducted through the PubMed, EMBASE and Web of Science databases using appropriate search terms from the dates of inception until November 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the CSS. Fixed- or random-effects models were constructed according to existence of heterogeneity. Thirty-three articles met the eligibility criteria for this systematic review, which included 19,702 patients. The overall results revealed that CSS was associated with advanced age (old vs. young: pooled HR = 1.01; 95% CI:1.00–1.01; P < 0.001), higher tumor grade (3 vs. 1/2: pooled HR = 1.29; 95% CI:1.15–1.45; P < 0.001), higher pathological stage (3/4 vs. 1/2: pooled HR = 1.60; 95% CI:1.37–1.86; P < 0.001), lymph node metastasis (positive vs. negative: pooled HR = 1.51; 95% CI:1.37–1.67; P < 0.001), lymphovascular invasion (positive vs. negative: pooled HR = 1.36; 95% CI:1.28–1.45; P < 0.001), and soft tissue surgical margin (positive vs. negative: pooled HR = 1.42; 95% CI:1.30–1.56; P < 0.001). However, gender (male vs. female: pooled HR = 0.98; 95% CI: 0.96–1.01; P = 0.278), carcinoma in situ (positive vs. negative: pooled HR = 0.98; 95% CI: 0.88–1.10; P = 0.753), histology (transitional cell cancer vs variant: pooled HR = 0.90; 95% CI: 0.79–1.02; P = 0.089) and adjuvant chemotherapy (yes vs. no: pooled HR = 1.16; 95% CI: 1.00–1.34; P = 0.054) did not affect CSS after radical resection of bladder cancer. Our results revealed that several clinicopathological characteristics can predict CSS risk after radical cystectomy. Prospective studies are needed to further confirm the predictive value of these variables for the prognosis of bladder cancer patients after radical cystectomy.

/pdf/clinicopathological-factors-in-bladder-cancer-for-cancer-26b5hzd3oj.pdf

Clinicopathological factors in bladder cancer for cancer-specific survival outcomes following radical cystectomy: a systematic review and meta-analysis

Background and Objectives: Published data from individual studies present conflicting evidence about the relationship between clinicopathological risk factors and oncological outcomes in renal cell cancer (RCC) following nephron-sparing surgery (NSS). This study was conducted to explore the potential risk factors for RCC progress after NSS. Methods: Studies published in PubMed, Web of Science, and EMBASE were systematically reviewed from inception to March 2019 to determine risk factors for RCC following NSS. The predictive ability of identified predictors was assessed by hazard ratios (HRs) with 95% confidence intervals (CIs). A fixed-effect or random-effect was used to pool the estimates. Subgroup analyses were performed to explore the source of heterogeneity. Results: Seventeen studies including 38,522 patients with RCC were analyzed. The meta-analysis indicated that positive surgical margin (pooled HR = 1.47; 95% CI:1.24-1.73; P < 0.001), higher Fuhrman grade (pooled HR = 1.58; 95% CI:1.10-2.28; P = 0.013), higher pathological stage (pooled HR = 1.72; 95% CI:1.40-2.12; P < 0.001) and large tumor size (pooled HR = 1.09; 95% CI:1.03-1.16; P = 0.003) were significantly associated with recurrence risk. However, age (pooled HR = 1.00; 95% CI: 1.00-1.01; P = 0.257), sex (male vs. female) (pooled HR = 1.04; 95% CI: 0.89-1.21; P = 0.605) and surgical approach (laparoscope vs. open) (pooled HR = 0.80; 95% CI: 0.59-1.07; P = 0.129) had no effect on recurrence after NSS. In addition, we found that positive surgical margin was significantly associated with recurrence-free survival (pooled HR = 1.87; 95% CI: 1.32-2.66; P < 0.001) and overall mortality (pooled HR = 1.15; 95% CI: 1.07-1.23; P < 0.001), as well as large tumor size for recurrence-free survival (pooled HR = 1.18; 95% CI: 1.06-1.30; P = 0.002)and overall mortality (pooled HR = 1.01; 95% CI: 1.00-1.02; P = 0.004). Conclusions: Unfavorable pathological characteristics were distinctly related to worse oncological outcomes in RCC patients following NSS. These results may contribute to proposed prediction models for RCC patients to aid in counseling and risk stratification.

/pdf/the-clinicopathological-risk-factors-in-renal-cell-cancer-2hd9u4whpn.pdf

The Clinicopathological Risk Factors in Renal Cell Cancer for the Oncological Outcomes Following Nephron-Sparing Surgery: A PRISMA Systematic Review and Meta-Analysis.

Although numerous studies have shown that perineural invasion (PNI) is linked to prostate cancer (PCa) risk, the results have been inconsistent. This study aimed to explore the association between PNI and biochemical recurrence (BCR) in patients with PCa following radical prostatectomy (RP) or radiotherapy (RT). According to the PRISMA statement, we searched the PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) and Wan Fang databases from inception to May 2017. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted from eligible studies. Fixed or random effects model were used to calculate pooled HRs and 95% CIs according to heterogeneity. Publication bias was calculated by Begg’s test. Ultimately, 19 cohort studies that met the eligibility criteria and that involved 13,412 patients (82-2,316 per study) were included in this meta-analysis. The results showed that PNI was associated with higher BCR rates in patients with PCa after RP (HR=1.23, 95% CI: 1.11, 1.36, p<0.001) or RT (HR=1.22, 95% CI: 1.12, 1.34, p<0.001). No potential publication bias was found among the included studies in the RP group (p-Begg = 0.124) or the RT group (p-Begg = 0.081). This study suggests that the presence of PNI by histopathology is associated with higher risk of BCR in PCa following RP or RT, and could serve as an independent prognostic factor in patients with PCa.

/pdf/perineural-invasion-as-an-independent-predictor-of-psg16tssyh.pdf

Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis.

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Papers

Tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis

Clinicopathological factors in bladder cancer for cancer-specific survival outcomes following radical cystectomy: a systematic review and meta-analysis

The Clinicopathological Risk Factors in Renal Cell Cancer for the Oncological Outcomes Following Nephron-Sparing Surgery: A PRISMA Systematic Review and Meta-Analysis.

Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis.