bims-netuvo 2022-10-02 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2022–10–02
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

The complementary role of lymphovascular invasion and perineural invasion in the TNM staging process of rectal cancer.
In Vitro and In Vivo Assays Characterizing MAO A Function in Cancers.
Downregulation of MMP1 functions in preventing perineural invasion of pancreatic cancer through blocking the NT-3/TrkC signaling pathway.
Perineural invasion as predictor of biochemical recurrence in prostate cancer following open radical prostatectomy: a single-center experience.
Cancer activates microglia to the same extent as chronic stress throughout stress neurocircuitry in a mouse model of breast cancer.
Patterns and predictors of site-specific recurrence in cervical cancer after radical hysterectomy.
Low HES-1 and positive DLL4 expression predicts poor prognosis of colorectal cancers.
Nomogram to predict permanent stoma in rectal cancer patients after sphincter-saving surgery.
Atypically Located Solitary Neurofibroma of the Ulnar Nerve as Inaugural Presentation of a New Genetic Variant of Neurofibromatosis Type 1: A Case Report.

Medicine (Baltimore). 2022 Sep 30. 101(39): e30687

The complementary role of lymphovascular invasion and perineural invasion in the TNM staging process of rectal cancer.

Tong Chen, Mingchuan Wang, Xianbin Cheng, Yizhuo Wang, Yang Jiang, Xuedong Fang, Huijie Xiao.

The aim of this study is to clarify the association between lymphovascular invasion (LVI) and/or perineural invasion (PNI) and the clinical characteristics and prognostic importance of rectal cancer, to provide a basis for early adjuvant treatment of rectal cancer. We retrospectively analyzed patients diagnosed with rectal cancer. This study involved rectal cancer tissue samples were obtained by surgical methods. Data on histological form, tumor classification, tumor size, gross growth pattern, blood and lymphatic vessel invasion, and PNI of the slice by HE staining were obtained from pathological examination. Immunohistochemical analysis of tissue samples was performed to determine p53 and EGFR expressions. There were 330 rectal cancer patients included in the study. LVI and/or PNI can be used as a high-risk factor for the prognosis of rectal cancer, predict prognostic survival, and guide adjuvant therapy. The detection rates of LVI and PNI were 32.1% and 16.1%. Differentiation grade, Union for International Cancer Control staging, tumor-lymph node-metastasis staging are significantly related to LVI or PNI. Multivariate logistic regression analysis shows that poor differentiation and N ≥ 1 can be used as independent risk factors and predictive factors for LVI. At the same time, poor differentiation and T > 3 is an independent risk factor for PNI. Only poor differentiation is the risk factor for poor prognosis in Cox risk regression analysis. In addition, the simultaneous occurrence of LVI and PNI is an independent prognostic factor.

DOI: https://doi.org/10.1097/MD.0000000000030687
Methods Mol Biol. 2023 ;2558 171-182

In Vitro and In Vivo Assays Characterizing MAO A Function in Cancers.

Boyang Jason Wu, Jean C Shih.

  Emerging studies, including ours, have revealed the novel essential roles of monoamine oxidase A (MAO A) in mediating the growth and progression of several types of cancers. Recently, we presented the first evidence of MAO A's ability to promote cancer cell perineural invasion, the neoplastic invasion of nerves widely recognized as a significant route for cancer metastasis. Here, we describe a perineural invasion in vitro assay using a 3D coculture with a cancer cell line and an immortalized dorsal root ganglion neuronal cell line for rapid examination of MAO A's roles in cancer-nerve cell crosstalk and evaluating the efficacy of MAO A inhibitors for disrupting perineural invasion. We also summarized the fundamental methods for determining MAO A's effects on cancer cell proliferation in vitro and tumorigenesis in vivo.

Keywords:  3D cell co-culture; Cancer cell proliferation; Cancer-nerve cell interaction; Dorsal root ganglia; Monoamine oxidase A; Perineural invasion; Tumorigenesis

DOI:  https://doi.org/10.1007/978-1-0716-2643-6_13
J Clin Lab Anal. 2022 Sep 30. e24719

Downregulation of MMP1 functions in preventing perineural invasion of pancreatic cancer through blocking the NT-3/TrkC signaling pathway.

Xiaoqing Xu, Xiaomin Lu, Liping Chen, Ke Peng, Fuhai Ji.

   BACKGROUND: Pancreatic cancer (PC) is a fatal malignancy that frequently involves perineural invasion (PNI). This study aims to investigate the function and underlying mechanisms of matrix metalloproteinase-1 (MMP1) in PNI of PC.
METHODS: Human pancreatic cancer PANC-1 cells were co-cultured with dorsal root ganglion in vitro. The expression of MMP1, epithelial-mesenchymal transition (EMT) markers, Schwann cell markers, neurotrophic factors, NT-3, and TrkC was measured by qRT-PCR or Western blot. Transwell assay was performed to evaluate cell migration and invasion. In vivo model of PNI was established via inoculating PANC-1 cells into mice. PANC-1 cells and mice were also treated with LM22B-10 (an activator of TrkC) to confirm the mechanisms involving NT-3/TrkC in PNI of PC both in vivo and in vitro.
RESULTS: The expression of MMP1 was significantly higher in PDAC tissues than non-cancerous tissues, which was positively associated with PNI. MMP1 knockdown repressed the migration and invasion of PANC-1 cells. Except for E-cadherin, the expression of EMT markers, Schwann cell markers, neurotrophic factors, NT-3, and TrkC was inhibited by MMP1 silencing. The same effects of MMP1 knockdown on the above factors were also observed in the PNI model. Moreover, MMP1 knockdown elevated the sciatic nerve function and reduced PNI in the model mice. LM22B-10 partially abolished the effects of MMP1 knockdown both in vivo and in vitro.
CONCLUSIONS: Silencing of MMP1 prevents PC cells from EMT and Schwann-like cell differentiation via inhibiting the activation of the NT-3/TrkC signaling pathway, thus alleviating the PNI of PC.

Keywords:  NT-3/TrkC signaling pathway; Schwann-like cell differentiation; epithelial-mesenchymal transition; matrix metalloproteinase-1; perineural invasion

DOI:  https://doi.org/10.1002/jcla.24719
World J Urol. 2022 Sep 24.

Perineural invasion as predictor of biochemical recurrence in prostate cancer following open radical prostatectomy: a single-center experience.

Mladen Stankovic, Laura Wolff, Teresa Wieder, Joao Mendes, Bastian Schumacher.

   PURPOSE: To explore the association between perineural invasion (PNI) and biochemical recurrence (BCR) in patients undergoing open radical prostatectomy (ORP).
METHODS: A retrospective observational study was conducted, in which we analyzed patients who underwent ORP at our institution between 2003 and 2020. The biochemical recurrence (BCR)-free survival and overall survival (OS) rates were defined using the Kaplan-Meier method and log-rank analysis. Multivariable Cox-regression models were used to test the effect of other different factors such as preoperative PSA, Gleason score and T stage on biochemical recurrence. The Clavien-Dindo classification was used to report the complication rates.
RESULTS: In total, 1040 patients were included. PNI was found in 458 (44.1%) and BCR occurred in 212 patients (20.4%) at a median follow-up of 91.2 months. After undergoing the procedure, 216 patients received adjuvant external beam radiotherapy (EBRT). Despite receiving adjuvant treatment, the BCR-free survival was still significantly shorter for PNI-positive patients (mean 32.2 vs. 62.3 months, p < 0.001). The 5- and 10-year BCR-free survival rates for patients without PNI were 90% and 81%, respectively. For the same period of time, BCR-free survival rates for patients with PNI were 75 and 63%, respectively. Therefore, PNI was a strong predictor of BCR (p < 0.001). These results remained even after controlling for established predictors of biochemical recurrence. Limitations include retrospective and single-center study design.
CONCLUSION: In conclusion, despite its limitations, our study emphasizes the prognostic importance of PNI in prostate cancer patients. The results demonstrate that the presence of PNI is associated with a high risk of BCR.

Keywords:  Biochemical recurrence; Perineural invasion; Radical prostatectomy

DOI:  https://doi.org/10.1007/s00345-022-04158-1
Psychoneuroendocrinology. 2022 Sep 21. pii: S0306-4530(22)00279-7. [Epub ahead of print]146 105938

Cancer activates microglia to the same extent as chronic stress throughout stress neurocircuitry in a mouse model of breast cancer.

Delyse McCaffrey, Adam J Lawther, Cynthia Shannon Weickert, Adam K Walker.

  The prevalence of stress-related comorbidities is increased approximately 3-fold in cancer patients compared to the general population. There is a scarcity of research focusing on the biological brain changes caused by the cancer due to the assumption that psychological symptoms are solely caused by the stress of a cancer diagnosis. Recent clinical evidence indicates that declines in cognition and increases in mood symptoms occur prior to an individual receiving a cancer diagnosis, suggesting that the cancer itself may play a role in mediating biological brain change. Furthermore, the presence of a tumour may change the brain response to environmental stressors unrelated to a cancer diagnosis. Using a syngeneic, orthotopic mouse model of breast cancer, we compared the impact of mammary tumours and chronic restraint stress on microglial and astrocytic activation throughout stress-relevant neurocircuitry. We also examined whether changes in microglial and astrocytic activation overlapped with changes in chronic neuronal activity. We show that cancer and chronic restraint stress activates microglia to the same magnitude in the same subcortical brain regions, and that this activation correlates with stress coping behaviours. The findings suggest that in some cancer patients, microglia may be activated in brain regions involved in interpreting and responding to psychological distress before they are aware of their diagnosis. In contrast, cancer reduced astrocyte reactivity in two cortical brain regions where there were no clear changes in response to chronic restraint stress. Taken together, it is likely that interventions that aim to improve anxiety and stress in cancer patients by targeting glial responses to cancer would need to be cell-specific; reducing microglial activation and/or stimulating astrocytic activation.

Keywords:  Anxiety; Astrocytes; Breast cancer; Microglia; Neuroinflammation; Stress

DOI:  https://doi.org/10.1016/j.psyneuen.2022.105938
J Obstet Gynaecol Res. 2022 Sep 29.

Patterns and predictors of site-specific recurrence in cervical cancer after radical hysterectomy.

Tatsuya Kato, Chisa Shimada, Fumi Kato, Hiromi Okada-Kanno, Mahito Takeda, Daisuke Endo, Kei Ihira, Takashi Mitamura, Yosuke Konno, Noriaki Sakuragi, Hidemichi Watari.

   AIM: This study examines patterns and predictors of site-specific recurrence to explore the causes of local recurrence of cervical cancer.
METHODS: Radical hysterectomy was performed in 121 patients (stage IB-IIB). Nerve-sparing was performed whenever possible. The first recurrence in local, regional, and distant areas was examined. We investigated the possibility of nerve involvement in local recurrence, focusing on paravaginal tissues containing the pelvic plexus. We provide Supporting Information on local recurrence in the paravaginal area.
RESULTS: Local recurrence was an independent event from regional or distant recurrence. Local recurrence was seen only in high-risk patients, while regional and distant recurrences were not or less related to the risk category. The independent risk factors by logistic regression for local, regional, and distant recurrence were parametrial invasion, vaginal invasion, and lymph node metastasis, respectively. Local recurrence showed a comparable or more significant negative impact on survival than distant recurrence. Among seven patients with local recurrences, five had a recurrence in the paravagina. The rate of paravaginal recurrence was one in 76 early-stage and four in 45 locally advanced diseases. Four sites of paravaginal recurrence occurred on the nerve-sparing side and two on the non-nerve-sparing side. Supporting Information demonstrated histological evidence of perineural spread into the pelvic plexus and perineural invasion of the primary tumor.
CONCLUSIONS: A high percentage of local recurrences are in paravaginal tissue containing the pelvic plexus. The causal association of nerve-sparing surgery and perineural invasion with local recurrence needs to be investigated in large prospective studies.

Keywords:  local recurrence; nerve-sparing; perineural invasion; radical hysterectomy

DOI:  https://doi.org/10.1111/jog.15432
Pathology. 2022 Sep 08. pii: S0031-3025(22)00250-1. [Epub ahead of print]

Low HES-1 and positive DLL4 expression predicts poor prognosis of colorectal cancers.

Gilhyang Kim, Jiyoon Jung, Jeong Won Kim, Joo Young Kim.

  Hairy and enhancer of split-1 (HES-1) is a downstream transcription factor and delta-like 4 (DLL4) is a ligand of the Notch signalling pathway. HES-1 and DLL4 expression are known to have an association with the progression and metastasis of cancers. We evaluated HES-1 and DLL4 expression and assessed their correlation with biological behaviour and prognostic significance of 327 colorectal cancers. Low HES-1 expression was identified in 210 (64.2%) cases and was significantly correlated with large tumour size, lymphovascular invasion, and distant metastasis. DLL4 was positive in 132 (40.4%) cases and significantly correlated with perineural invasion, distant metastasis, and involved resection margin. Patients with low HES-1 expression showed significantly worse overall survival than patients with high HES-1 expression [hazard ratio (HR)=3.017; 95% confidence interval (CI) 1.880-4.841; p<0.001]. The overall survival of patients with positive DLL4 expression was significantly worse than that of patients with negative DLL4 expression (HR=2.922; 95% CI 1.976-4.322; p<0.001). Furthermore, the combined HES-1lowDLL4positive expression group showed the worst overall survival compared to other groups (p<0.001) and was an independent poor prognostic factor of colorectal cancer patients. Thus, low HES-1 and positive DLL4 expression are associated with aggressive biological behaviour and can be used as prognostic factors in colorectal cancer patients.

Keywords:  Colorectal cancers; DLL4; HES-1; prognosis

DOI:  https://doi.org/10.1016/j.pathol.2022.07.008
World J Gastrointest Surg. 2022 Aug 27. 14(8): 765-777

Nomogram to predict permanent stoma in rectal cancer patients after sphincter-saving surgery.

Chih-Yu Kuo, Po-Li Wei, Chia-Che Chen, Yen-Kuang Lin, Li-Jen Kuo.

   BACKGROUND: Approximately 20 percent of patients with a tumour localized in the low rectum still encounter the possibility of requiring permanent stoma (PS), which can cause drastic changes in lifestyle and physical perceptions.
AIM: To determine the risk factors for PS and to develop a prediction model to predict the probability of PS in rectal cancer patients after sphincter-saving surgery.
METHODS: A retrospective cohort of 421 rectal cancer patients who underwent radical surgery at Taipei Medical University Hospital between January 2012 and December 2020 was included in this study. Univariate and multivariate analyses were performed to identify the independent risk factors for PS. A nomogram was developed according to the independent risk factors obtained in the multivariate analysis. The performance of the nomogram was assessed using a receiver operating characteristic curve and a calibration curve.
RESULTS: The PS rate after sphincter-saving surgery was 15.1% (59/391) in our study after a median follow-up of 47.3 mo (range 7-114 mo). Multivariate logistic regression analysis demonstrated that local recurrence, perirectal abscess, anastomosis site stenosis, perineural invasion, tumor size and operative time were independent risk factors for PS. These identified risk factors were incorporated into the nomogram, and the concordance index of this model was 0.903 (95%CI: 0.851-0.955). According to the calibration curves, the nomogram represents a perfect prediction model.
CONCLUSION: Several risk factors for PS after sphincter-saving surgery were identified. Our nomogram exhibited perfect predictive ability and will improve a physician's ability to communicate the benefits and risks of various treatment options in shared decision making.

Keywords:  Nomogram; Permanent stoma; Rectal cancer; Risk factor; Shared decision making; Sphincter-saving operation

DOI:  https://doi.org/10.4240/wjgs.v14.i8.765
J Hand Surg Glob Online. 2022 Sep;4(5): 283-287

Atypically Located Solitary Neurofibroma of the Ulnar Nerve as Inaugural Presentation of a New Genetic Variant of Neurofibromatosis Type 1: A Case Report.

Diogo Rocha Carvalho, Pedro Martins Branco, P Diana Afonso, Gonçalo Gerardo, Carolina Baptista.

  We report the case of a 34-year-old woman with hypothenar pain due to a solitary neurofibroma (NF) of the ulnar nerve, with an extrafascicular location, outside Guyon canal, with no clinical evidence of associated neurologic impairment, who was successfully treated with surgical resection. The identification of this isolated tumor led to the diagnosis of a new genetic variant of neurofibromatosis type 1 after genome sequencing. At the 1-year follow-up, the patient remains asymptomatic without recurrence or other peripheral nerve sheath tumors. A solitary NF of a deep-seated nerve is extremely rare, especially in the context of neurofibromatosis type 1. To our knowledge, there are no reports of a NF of the ulnar nerve with an extraneural location. In the presence of a solitary NF related to a deep-seated peripheral nerve, neurofibromatosis type 1 should always be excluded.

Keywords:  Hand tumor; NF-1; Neurofibromatosis; Peripheral nerve sheath tumor; Solitary neurofibroma; Ulnar nerve neurofibroma

DOI:  https://doi.org/10.1016/j.jhsg.2022.04.008