bims-netuvo 2022-07-03 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2022–07–03
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Neurobiology of cancer - the role of cancer tissue innervation.
Neuropeptides in Cancer: Friend and Foe?
Electroacupuncture promotes apoptosis and inhibits axonogenesis by activating p75 neurotrophin receptor for triple-negative breast xenograft in mice.
[Analysis of perineural invasion with clinicopathological factors and prognosis for curatively resected gallbladder carcinoma].
Perineural Invasion Is a Significant Indicator of High Malignant Degree and Poor Prognosis in Esophageal Cancer: A Systematic Review and Meta-Analysis.
Predicting perineural invasion using histogram analysis of zoomed EPI diffusion-weighted imaging in rectal cancer.
Recurrence-Free Survival Outcomes Based on Novel Classification Combining Lymphovascular Invasion, Perineural Invasion, and T4 Status in Stage II-III Colon Cancer.
Diffusion-weighted MR is useful to assess peripheral nerve invasion of soft tissue tumor.
Implications for pelvic lymph node irradiation in definitive chemoradiotherapy of node negative muscle invasive bladder cancer based on predictive factors of clinicopathologic discrepancy.

Klin Onkol. 2022 ;35(3): 208-214

Neurobiology of cancer - the role of cancer tissue innervation.

B Mravec, F Blaško.

   BACKGROUND: Experimental and clinical studies have shown that the nervous system also plays an important role in the processes of carcinogenesis, cancer cell proliferation, and metastasis. These studies, focused on the neurobio-logical aspects of cancer, elucidate the mechanisms and pathways by which the nervous system affects tumor macro- and microenvironment. The modulatory effect of the nervous system on the tumor microenvironment is significantly mediated by nerves that innervate cancer tissue. The innervation of cancer tissue is already an accepted fact, and several authors consider it to be another hallmark of cancer.
PURPOSE: The aim of this review article is to present a recent data about the role of innervation of cancer tissue, as well as to describe therapeutic consequences.
CONCLUSION: Based on recent data, it can be concluded that the innervation of cancer tissue represents an important factor in the etiopathogenesis of cancer as well as a potential target for new therapeutic interventions in cancer patients.

Keywords:  cancer innervation; innervation; neurobiology of cancer; parasympathetic nerves; sensory nerves; sympathetic nerves

DOI:  https://doi.org/10.48095/ccko2022208
Adv Biol (Weinh). 2022 Jul 01. e2200111

Neuropeptides in Cancer: Friend and Foe?

Yue Wu, Adrian Berisha, Jeremy C Borniger.

  Neuropeptides are small regulatory molecules found throughout the body, most notably in the nervous, cardiovascular, and gastrointestinal systems. They serve as neurotransmitters or hormones in the regulation of diverse physiological processes. Cancer cells escape normal growth control mechanisms by altering their expression of growth factors, receptors, or intracellular signals, and neuropeptides have recently been recognized as mitogens in cancer growth and development. Many neuropeptides and their receptors exist in multiple subtypes, coupling with different downstream signaling pathways and playing distinct roles in cancer progression. The consideration of neuropeptide/receptor systems as anticancer targets is already leading to new biological and diagnostic knowledge that has the potential to enhance the understanding and treatment of cancer. In this review, recent discoveries regarding neuropeptides in a wide range of cancers, emphasizing their mechanisms of action, signaling cascades, regulation, and therapeutic potential, are discussed. Current technologies used to manipulate and analyze neuropeptides/receptors are described. Applications of neuropeptide analogs and their receptor inhibitors in translational studies and radio-oncology are rapidly increasing, and the possibility for their integration into therapeutic trials and clinical treatment appears promising.

Keywords:  behavior; cancer; neuropeptides; receptors; signaling pathways

DOI:  https://doi.org/10.1002/adbi.202200111
J Chem Neuroanat. 2022 Jun 28. pii: S0891-0618(22)00063-1. [Epub ahead of print] 102133

Electroacupuncture promotes apoptosis and inhibits axonogenesis by activating p75 neurotrophin receptor for triple-negative breast xenograft in mice.

Yehong Tian, Xiaowei Qiu, Xuewei Qi, Zhenzhen Dong, Jianxin Zhao, Jinchang Huang, Xin Jiang.

   PURPOSE: The aim of this study was to investigate the anti-tumor effect of electroacupuncture (EA) on mice bearing breast tumors by regulating p75 neurotrophin receptor (p75NTR) and remodelling intratumoral innervation.
METHODS: Female BALB/c mice were implanted with 4T1 breast tumor cells to establish a murine mammary cancer model. Tumor volume and weight were measured to evaluate tumor growth. Cell apoptosis was assessed by TUNEL assay. The relative expression of p75NTR, TrkA, TrkB, NGF and proNGF were detected by immunohistochemistry. Neurotransmitter and neurotrophin were detected by enzyme-linked immunosorbent assay. Intratumoral innervation was confirmed by β3-tubulin and TH labeling immunohistochemistry. The antagonist TAT-Pep5 was employed to determine if the effects of EA on tumor growth and cell apoptosis were mediated by p75NTR.
RESULTS: Peritumoral EA alleviated tumor growth especially after 14 days of intervention. Apoptosis index in the tumor tissue was obviously decreased after EA. Meanwhile, EA intervention significantly upregulated the expression of p75NTR and proNGF, along with a decline in the tumor growth and an increase in the cell apoptosis. Besides, EA reduced local sympathetic innervation and downregulated sympathetic neurotransmitter NE level in the local tumor. Furthermore, p75NTR antagonist alleviated EA-mediated cell apoptosis and intratumoral innervation.
CONCLUSIONS: One mechanism of EA intervention for alleviating tumor progression is mediated by p75NTR to promote apoptosis and decrease intratumoral axonogenesis in the tumor microenvironment.

Keywords:  Electroacupuncture; apoptosis; axonogenesis; breast cancer; p75NTR

DOI:  https://doi.org/10.1016/j.jchemneu.2022.102133
Zhonghua Wai Ke Za Zhi. 2022 Jul 01. 60(7): 695-702

[Analysis of perineural invasion with clinicopathological factors and prognosis for curatively resected gallbladder carcinoma].

J J Lei, J Zhang, C Chen, Q Li, J B Su, D Zhang, R Zhang, Z C Jin, Z M Geng.

Objective: To examine the correlation between perineural invasion and clinicopathological factors and the role of perineural invasion on the prognosis of patients with curatively resected gallbladder carcinoma. Methods: The clinicopathological and follow-up data of 548 patients with gallbladder carcinoma who underwent radical surgery from the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to December 2020 were analyzed retrospectively. There were 173 males and 375 females,with age(M(IQR)) of 62(14)years(range:30 to 88 years). The correlations between perineural invasion and the clinicopathological features were analyzed. The relationship between prognosis and clinicopathological factors were further analyzed. The survival curve was drawn using the Kaplan-Meier method. The univariate analysis and multivariate analysis were done using the Log-rank test and Cox proportional hazard model respectively. Results: Radical resection was performed in 548 cases,including 59 cases(10.8%) with perineural invasion. The results of univariate analysis showed that perineural invasion was related to serum bilirubin level,serum carcinoembryonic antigen(CEA) level,CA19-9 level,T stage,lymph node metastasis,liver invasion,vessel invasion and tumor location(all P<0.05).The results of multivariate analysis showed that jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder were independent risk factors of perineural invasion in gallbladder carcinoma. Survival of 367 patients in T3-T4 stages were analyzed. The prognosis of gallbladder carcinoma patients with perineural invasion was significantly worse than that of patients without perineural invasion(median survival time:12.0 months vs. 34.7 months,P<0.01). Univariate analysis showed that perineural invasion,gallbladder stones,gallbladder polyps,CA125,CEA,CA19-9,serum bilirubin level,tumor location,N stage,liver invasion and pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). The results of Cox proportional hazard model showed that perineural invasion,N stage,liver invasion,gallbladder stones,pathological differentiation were independent risk factors affecting prognosis of patients with gallbladder carcinoma(all P<0.05). Conclusions: Jaundice,high-level serum CA19-9,high-level serum CEA,T4 stage,vessel invasion and tumor located in the neck or cystic duct of the gallbladder are independent risk factors for perineural invasion of gallbladder carcinoma. Perineural invasion is one of the independent risk factors affecting the prognosis of T3-T4 stage gallbladder carcinoma.

DOI: https://doi.org/10.3760/cma.j.cn112139-20220108-00016
Front Oncol. 2022 ;12 816270

Perineural Invasion Is a Significant Indicator of High Malignant Degree and Poor Prognosis in Esophageal Cancer: A Systematic Review and Meta-Analysis.

Liuyang Bai, Liangying Yan, Yaping Guo, Luyun He, Zhiyan Sun, Wenbo Cao, Jing Lu, Saijun Mo.

   Background: Perineural invasion (PNI) is a malignant metastatic mode of tumors and has been reported in many tumors including esophageal cancer (EC). However, the role of PNI in EC has been reported differently. This systematic review and meta-analysis aims to focus on the role of PNI in EC.
Methods: Eight databases of CNKI, VIP, Wanfang, Scopus, Wiley, ISI, PubMed, and EBSCO are used for literature search. The association of PNI with gender, pathological stages of T and N (pT and pN), lymphovascular invasion (LVI), lymph node metastasis, 5-year overall survival (OS), and 5-year disease-free survival (DFS) was examined in the meta-analysis by Revman5.0 Software. The pooled OR/HR and 95% CI were used to assess the risk and prognostic value.
Results: Sixty-nine published studies were screened for analysis of PNI in EC. The incidence of PNI in esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC) was different, but not statistically significant (p > 0.05). The PNI-positive patients had a significantly higher risk of pT stage (OR = 3.85, 95% CI = 2.45-6.05, p < 0.00001), pN stage (OR = 1.86, 95% CI = 1.52-2.28, p < 0.00001), LVI (OR = 2.44, 95% CI = 1.55-3.85, p = 0.0001), and lymph node metastasis (OR = 2.87, 95% CI = 1.56-5.29, p = 0.0007). Furthermore, the cumulative analysis revealed a significant correlation between PNI and poor OS (HR = 1.37, 95% CI = 1.24-1.51, p < 0.0001), as well as poor DFS (HR = 1.55, 95% CI = 1.38-1.74, p < 0.0001).
Conclusion: PNI occurrence is significantly related to tumor stage, LVI, lymph node metastasis, OS, and DFS. These results indicate that PNI can serve as an indicator of high malignant degree and poor prognosis in EC.

Keywords:  esophageal cancer; lymph node metastasis; lymphovascular invasion; perineural invasion; prognosis

DOI:  https://doi.org/10.3389/fonc.2022.816270
Abdom Radiol (NY). 2022 Jul 02.

Predicting perineural invasion using histogram analysis of zoomed EPI diffusion-weighted imaging in rectal cancer.

Lijuan Wan, Wenjing Peng, Shuangmei Zou, Qinglei Shi, Peihua Wu, Qing Zhao, Feng Ye, Xinming Zhao, Hongmei Zhang.

   PURPOSE: To investigate the utility of histogram analysis of zoomed EPI diffusion-weighted imaging (DWI) for predicting the perineural invasion (PNI) status of rectal cancer (RC).
METHODS: This prospective study evaluated 94 patients diagnosed with histopathologically confirmed RC between July 2020 and July 2021. Patients underwent preoperative rectal magnetic resonance imaging (MRI) examinations, including the zoomed EPI DWI sequence. Ten whole-tumor histogram parameters of each patient were derived from zoomed EPI DWI. Reproducibility was evaluated according to the intra-class correlation coefficient (ICC). The association of the clinico-radiological and histogram features with PNI status was assessed using univariable analysis for trend and multivariable logistic regression analysis with β value calculation. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance.
RESULTS: Forty-two patients exhibited positive PNI. The inter- and intraobserver agreements were excellent for the histogram parameters (all ICCs > 0.80). The maximum (p = 0.001), energy (p = 0.021), entropy (p = 0.021), kurtosis (p < 0.001), and skewness (p < 0.001) were significantly higher in the positive PNI group than in the negative PNI group. Multivariable analysis showed that higher MRI T stage [β = 2.154, 95% confidence interval (CI) 0.932-3.688; p = 0.002] and skewness (β = 0.779, 95% CI 0.255-1.382; p = 0.006) were associated with positive PNI. The model combining skewness and MRI T stage had an area under the ROC curve of 0.811 (95% CI 0.724-0.899) for predicting PNI status.
CONCLUSION: Histogram parameters in zoomed EPI DWI can help predict the PNI status in RC.

Keywords:  Diffusion-weighted imaging; Magnetic resonance imaging; Peripheral nerve; Rectal neoplasms

DOI:  https://doi.org/10.1007/s00261-022-03579-1
Cancer Manag Res. 2022 ;14 2031-2040

Recurrence-Free Survival Outcomes Based on Novel Classification Combining Lymphovascular Invasion, Perineural Invasion, and T4 Status in Stage II-III Colon Cancer.

Jae Hyun Kang, Il Tae Son, Byung Chun Kim, Jun Ho Park, Jeong Yeon Kim, Jong Wan Kim.

   Background: T4 tumor, lymphovascular invasion (LVI) and perineural invasion (PNI) are regarded as one of risk factors and associated with poor outcomes in colorectal cancer. The relationship between these three combined risk factors and the prognosis for colon cancer is not yet clear. The purpose of this study was to evaluate the prognostic value of combining the risk factors T4 tumor, LVI, and PNI in stage II-III colon cancer.
Methods: Between January 2011 and December 2019, we retrospectively reviewed the medical records of patients who underwent curative resection for stage II-III colon cancer at four Hallym University-affiliated hospitals. These patients are categorized into three groups based on T4, LVI and PNI: no-risk group (no risk factors), low-risk group (one risk factor), and high-risk group (two or more risk factors).
Results: Of 1684 patients, the incidence of no-, low-, and high-risk group were 49.3%, 32.6%, 18.0%, respectively. The median follow-up period was 48.9 months, and the 5-year recurrence-free survival (RFS) rate decreased from 78.5% to 58.7% as the number of risk factors increased (P < 0.001). Cox's proportional hazard regression models showed that T4 (P < 0.001), LVI (P = 0.043), and PNI (P = 0.018) were independent prognostic factors for poor RFS. In subgroup analysis in stage II colon cancer, patients with one or more risk factors showed the better 5-year RFS rate when they received adjuvant chemotherapy than in those who did not (P < 0.001). Poor/mucinous differentiation, obstruction, and lymph-node positivity were independent predictors in the high risk group.
Conclusion: The present study showed the histological combination of LVI, PNI, and T4 indicates a poor prognosis for RFS in patients with stage II-III colon cancer. Therefore, patients with one of these risk factors should be considered for chemotherapy and have close follow-up.

Keywords:  T4 tumor; colon cancer; lymphovascular invasion; perineural invasion

DOI:  https://doi.org/10.2147/CMAR.S358939
Medicine (Baltimore). 2022 Jul 01. 101(26): e29779

Diffusion-weighted MR is useful to assess peripheral nerve invasion of soft tissue tumor.

Gang Wu, Liangjin Liu, Zou Mei, Xiaoming Li.

To investigate the feasibility of readout-segmented diffusion-weighted (rsDW) magnetic resonance (MR) in assessing nerve invasion of soft tissue tumor. Forty-four patients with soft tissue mass in upper leg suspected of nerve invasion underwent rsDW MR. Nerve invasion by tumor was rated by 2 radiologists, respectively. Sensitivity and specificity of rsDW MR in identifying nerve invasion were calculated, with operation findings as reference of standard. Apparent diffusion coefficient and fraction of anisotropy of nerve were obtained using DW MR, and then were compared between invaded nerves and noninvasion cases. Inter-reader agreement in using rsDW MR to rate nerve invasion was excellent (kappa = 0.891 ± 0.043, P < 0.001). Sensitivity and specificity of rsDW MR in identifying nerve invasion were 89% and 88%, respectively. Apparent diffusion coefficient was significantly higher in invaded nerves versus normal nerves (1.45 ± 0.67 × 10-3 mm2/s vs 1.39 ± 0.46 × 10-3 mm2/s, P < 0.05). Fraction of anisotropy was significantly lower in invaded nerves versus normal nerves (0.22 ± 0.11 vs 0.37 ± 0.13, P < .05). Readout-segmented DW MR was feasible in assessing sciatic nerve invasion by soft tissue tumor in selected patients.

DOI: https://doi.org/10.1097/MD.0000000000029779
J Cancer Res Clin Oncol. 2022 Jun 28.

Implications for pelvic lymph node irradiation in definitive chemoradiotherapy of node negative muscle invasive bladder cancer based on predictive factors of clinicopathologic discrepancy.

Arefeh Saeedian, Afsaneh Maddah Safaei, Amirali Azimi, Kasra Kolahdouzan, Fatemeh-Sadat Tabatabaei, Ebrahim Esmati.

   PURPOSE: To identify pre-surgical imaging predictive value and factors associated with the clinicopathologic discrepancy for implication of definitive pelvic radiotherapy in clinically node-negative bladder cancer.
METHOD: The documented data of bladder cancer patients who underwent radical cystectomy plus pelvic lymphadenectomy were collected retrospectively. Patients' characteristics, last imaging, pathology reports, disease-specific survival and overall survival were retrieved.
RESULTS: From 142 patients, pre-surgical imaging had a sensitivity of 76.4%, specificity of 73.7%, positive predictive value (PPV) of 94.9%, and negative predictive value (NPV) of 32.6% (p value < 0.0001) for detection of muscle invasion. Also, for detection of positive lymph nodes, imaging had a sensitivity of 31.8%, specificity of 85.7%, PPV of 50%, and NPV of 73.7% (p value: 0.022). 44.4% of study population were upstaged after surgery (24.6% associated with N-upstaging) and 18.3% were downstaged (12% associated with N-downstaging). Receipt of neoadjuvant chemotherapy and T-stage were not correlated with N-upstaging. On multivariate analysis, lymphovascular invasion (LVI) maintained its significance for independent prediction of upstaging (OR 3.3, 95% CI 1.5-7.5, p value: 0.004) and inversely with downstaging (OR 0.34, 95% CI 0.12-0.96, p value: 0.04). Older age (OR 1.03, 95% CI 1.0-1.05, p value 0.047), positive margins (OR 2.1, 95% CI 1.2-3.8, p value 0.011), presence of LVI (OR 2.5, 95% CI 1.4-4.7, p value 0.003), perineural invasion (OR 2.0, 95% CI 1.2-3.4, p value 0.013), and lymph node ratio (OR 1.011, 95% CI 1.001-1.021, p value 0.03) were associated with worse survival. Also, N-upstaging independently predicted a worse survival after controlling for surgical pathology stage (OR 2.3, 95% CI 1.2-4.5, p value 0.011).
CONCLUSIONS: The optimal target volume in definitive chemoradiotherapy of node-negative bladder cancer patients remains to be established. Since then, customizing the treatment is considered especially for positive LVI in TURBT specimen.

Keywords:  Bladder cancer; Chemoradiotherapy; Lymphovascular invasion; Pelvic lymph nodes

DOI:  https://doi.org/10.1007/s00432-022-04153-4