bims-netuvo 2022-05-08 papers

Pharmacol Ther. 2022 Apr 28. pii: S0163-7258(22)00093-6. [Epub ahead of print] 108199

Advances in understanding cancer-associated neurogenesis and its implications on the neuroimmune axis in cancer.

Ismail Yaman, Didem Ağaç Çobanoğlu, Tongxin Xie, Yi Ye, Moran Amit.

Nerves and immunologic mediators play pivotal roles in body homeostasis by interacting with each other through diverse mechanisms. The spread of nerves in the tumor microenvironment increases tumor cell proliferation and disease progression, and this correlates with poor patient outcomes. The effects of sympathetic and parasympathetic nerves on cancer regulation are being investigated. Recent findings demonstrate the possibility of developing therapeutic strategies that target the tumor microenvironment and its components such as immune cells, neurotransmitters, and extracellular vesicles. Therefore, examining and understanding the mechanisms and pathways associated with the sympathetic and parasympathetic nervous systems, neurotransmitters, cancer-derived mediators and their interactions with the immune system in the tumor microenvironment may lead to the development of new cancer treatments. This review discusses the effects of nerve cells, immune cells, and cancer cells have on each other that regulate neurogenesis, cancer progression, and dissemination.

Keywords: Cancer; Neuroimmune axis; Parasympathetic nervous system; Sympathetic nervous system; Tumor microenvironment

DOI: https://doi.org/10.1016/j.pharmthera.2022.108199

Br J Surg. 2022 May 03. pii: znac098. [Epub ahead of print]

Prognostic impact of perineural invasion in intrahepatic cholangiocarcinoma: multicentre study.

Tao Wei, Xu-Feng Zhang, Jin He, Irinel Popescu, Hugo P Marques, Luca Aldrighetti, Shishir K Maithel, Carlo Pulitano, Todd W Bauer, Feng Shen, George A Poultsides, Oliver Soubrane, Guillaume Martel, Bas Groot Koerkamp, Endo Itaru, Yi Lv, Timothy M Pawlik.

BACKGROUND: The aim of this study was to investigate the prognostic impact of perineural invasion (PNI) on tumour recurrence and survival among patients with resected intrahepatic cholangiocarcinoma (ICC).
METHODS: This was a multicentre, retrospective study of patients who underwent resection with curative intent for ICC between 2000 and 2017. The relationship between PNI, clinicopathological characteristics, and long-term survival was analysed in the overall cohort and the subset of patients with early-stage ICC.
RESULTS: Among 1095 patients who underwent resection of ICC, PNI was present in 239 (21.8 per cent). In univariable analysis, PNI was associated with worse disease-free survival (DFS) (median 13.2 versus 16.1 months for patients with and without PNI respectively; P = 0.038) and overall survival (OS) (26.4 versus 41.5 months; P < 0.001). In multivariable analysis, PNI was an independent risk factor associated with reduced DFS (hazard ratio (HR) 1.56, 95 per cent c.i. 1.06 to 2.13; P = 0.019) and OS (HR 1.74, 1.16 to 2.60; P = 0.007). In subgroup analysis of patients with early-stage disease (AJCC T1-2, 981 patients; or N0, 249 patients), PNI remained associated with worse DFS (T1-2: median 13.7 versus 16.6 months in patients with and without PNI respectively, P = 0.019; N0: 11.7 versus 17.5 months, P = 0.022) and OS (T1-2: 28.5 versus 45.7 months, P < 0.001; N0: 34.9 versus 47.5 months, P = 0.036).
CONCLUSION: PNI is a strong independent predictor of tumour recurrence and long-term survival following resection of ICC with curative intent, even among patients with early-stage disease. The presence of PNI should be assessed routinely.

DOI: https://doi.org/10.1093/bjs/znac098

Surg Oncol. 2022 Apr 14. pii: S0960-7404(22)00063-9. [Epub ahead of print]42 101770

Molecular factors governing perineural invasion in malignancy.

Navid Ahmadi, Gretel Kelly, Tsu-Hui Hubert Low, Jonathan Clark, Ruta Gupta.

BACKGROUND: Perinueral invasion (PNI) is recognized as an independent adverse prognostic factor associated with shorter disease free and disease specific survival in a range of malignancies. However, not all histologically detected PNI demonstrate aggressive biologic behaviour. Herein, we systematically review the literature to identify neurotrophic biomarkers that may potentially be used to predict the biologic potential of PNI.
METHOD: A systematic review was conducted based on PRISMA guidelines utilising the search terms 'PNI', 'DNA' and 'RNA' analysis in select malignancies following registry of the search strategy on PROSPERO. The biologic role of the molecular markers identified through the literature review was examined using publicly available databases, such as Gene Cards and Kyoto Encyclopedia of Genes and Genomes (KEGG) with a focused literature review of the identified pathways.
RESULTS: The systematic search identified 256 studies, of which 78 studies were suitable for data extraction. A variety of methodologies including immunohistochemistry, immunoblotting, nucleic acid sequencing, Luciferase assays and CRISPR techniques have been undertaken to evaluate the biologic potential of PNI. The studies evaluated 136 unique molecules. Of these, only 15 molecules were investigated through multiple studies with concordant results or had robust functional analyses. Three pathways were identified as playing a role in PNI, namely; the epithelial-mesenchymal transition pathway, neurotrophic pathway and Notch pathway.
DISCUSSION: Our understanding of the complex and reciprocal interaction between tumour and nerve cells that drives PNI is still evolving. The knowledge gaps can largely be attributed to publication bias, lack of availability of high-quality patient derived tissues and limitations of currently available technology. This review summarises the current knowledge regarding development and progression of PNI that can be harnessed for prognostication and treatment. This review also summarises the lacunae in our understanding of the pathogenesis of PNI thus identifying avenues for future studies.

Keywords: Adenoid cystic carcinoma; Base sequence; Biomarkers; Carcinoma; Neoplasms; Pancreatic neoplasms; Perineural invasion; Peripheral nerves; Peripheral nervous system neoplasms; RNA Sequence analysis

DOI: https://doi.org/10.1016/j.suronc.2022.101770

Zhonghua Bing Li Xue Za Zhi. 2022 May 08. 51(5): 419-424

[Pathological features related to onco-immunity and their clinical significance of pancreatic ductal adenocarcinoma].

C M Wang, C Y Xu, S Jiang, Q Zhou, Z J Jiang, G P Cheng, M J Wu, T T Feng, W J Yin.

Objective: To investigate the tumor immunity-related pathologic features and clinical significance in pancreatic ductal adenocarcinoma (PDAC). Methods: All pathologic materials and clinical information of 192 PDAC patients from the Cancer Hospital of the University of Chinese Academy of Sciences from January 2010 to December 2020 were collected. The onco-immune microenvironment associated morphologic features were evaluated, and MHC-Ⅰ, PD-L1, CD3, and CD8 expression were detected by immunohistochemistry (IHC). Then the correlation between the factors and their influence on prognosis was analyzed. Results: There were 163 cases of non-specific adenocarcinoma (163/192, 84.90%), 18 cases of adeno-squamous carcinoma (18/192, 9.37%), and 11 cases of other rare subtypes (11/192, 5.73%). Perineural invasion was observed in 110 cases (110/192, 57.29%) and vascular invasion in 86 cases (86/192, 44.79%). There were 84 cases (84/182, 46.15%) with severe chronic inflammation. Tumor infiltrating immune cell numbers (TII-N) were increased in 52 cases (52/192, 27.08%). Lymphocytes and plasma cells were the main infiltrating immune cells in 60 cases (60/192, 31.25%), whereas in 34 cases (34/192, 17.71%) the tumors were mainly infiltrated by granulocytes, and 98 cases (98/192, 51.04%) showed mixed infiltration. CD3+T cells were deficient in 124 cases (124/192, 66.31%). CD8+T cells were deficient in 152 cases (152/192, 79.58%). MHC-Ⅰ expression was down-regulated in 156 cases (156/192, 81.25%), and PD-L1 was positive (CPS≥1) in 46 cases (46/192, 23.96%). Statistical analysis showed that TII-N was negatively correlated with vascular invasion (P=0.035), perineural invasion (P=0.002), stage (P=0.004) and long-term alcohol consumption (P=0.039). The type of immune cells correlated positively with chronic pancreatic inflammation (P=0.002), and negatively with tumor differentiation (P=0.024). CD8+T cells were positively correlated with CD3+T cells (P=0.032), MHC-Ⅰ expression (P<0.001) and PD-L1 expression (P=0.001), and negatively correlated with long-term smoking (P=0.016). Univariate analysis showed that histological nonspecific type (P=0.013) and TII-N (P<0.001) were the factors for good prognosis. Vascular invasion (P=0.032), perineural invasion (P=0.001), high stage (P=0.003) and long-term alcohol consumption (P=0.004) were adverse prognostic factors. COX multivariate risk analysis found that TII-N was an independent favorable factor for PDAC, while perineural invasion was an independent adverse risk factor. Conclusions: TII-N is an independent superior prognostic factor for PDAC, and significantly correlated with many factors; chronic alcohol consumption and smoking may inhibit onco-immunity in PDAC patients.

DOI: https://doi.org/10.3760/cma.j.cn112151-20210902-00641

Endoscopy. 2022 May 04.

Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer.

Victoria Arthursson, Selma Medic, Ingvar Syk, Carl-Fredrik Rönnow, Henrik Thorlacius.

BACKGROUND: The long-term outcome after local excision of T1 colorectal cancer (CRC) remains unknown. The aim of this study was to examine clinical and histopathological risk factors for recurrence in patients with T1 CRC undergoing endoscopic resection.
METHODS: This was a retrospective registry-based population study on prospectively collected data of all patients with nonpedunculated T1 CRC undergoing only local excision (no salvage surgery) in Sweden between 2009 and 2018. Potential risk factors for recurrence, including age, sex, tumor location, resection margins, lymphovascular, perineural, and submucosal invasion, grade of differentiation, and mucinous subtype, were analyzed using univariate and multivariate cox regression.
RESULTS: Median follow-up time was 60 months, and 28 /602 patients (4.7 %) had a recurrence (13 local and 18 distant). Recurrence rate stratified by submucosal invasion was: Sm1 3.5 % (14 /397), Sm2 6.0 % (8 /133), and Sm3 8.3 % (6 /72), with no significant differences. Resection margins, lymphovascular and perineural invasion, grade of differentiation, mucinous subtype, and age were not significant risk factors for recurrence. In contrast, rectal location was found to be a significant risk factor for tumor recurrence in multivariate analysis (hazard ratio 3.08, P = 0.006). The 3- and 5-year disease-free survival was 96.2 % and 91.1 %, respectively, in T1 CRC patients undergoing endoscopic resection.
CONCLUSION: Tumor recurrence was rare (4.7 %) in this large population-based study on recurrence after local excision of nonpedunculated T1 CRC. Rectal location was an independent risk factor for recurrence, suggesting the need for strict surveillance after endoscopic resection of early rectal cancer.

DOI: https://doi.org/10.1055/a-1814-4434