bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒02‒06
seventeen papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute
  1. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.
  2. Autonomic nerve regulation for prostate cancer: study based on the tissue transcriptional analysis.
  3. Combinatorial sympathetic and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockades inhibit the murine melanoma growth by targeting infiltrating T cells.
  4. Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer.
  5. Immunohistochemical Expression of Stanniocalcin 2 in Colorectal Cancer: A Retrospective Egyptian Study.
  6. Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.
  7. Prognostic Impact of Tumor Budding on Moroccan Colon Cancer Patients.
  8. Identification of a Subset of Stage I Colorectal Cancer Patients with High Recurrence Risk.
  9. Postoperative recurrence of gastric cancer depends on whether the chemotherapy cycle was more than 9 cycles: Based on a retrospective and observational study of follow-up within 3 years of 843 patients.
  10. Cleavage factor Im 25 as a potential biomarker for prognosis of colorectal cancer.
  11. Immunotherapeutic treatments for spinal and peripheral nerve tumors: a primer.
  12. GASTRIC CANCER WITH POSITIVE EXPRESSION OF ESTROGEN RECEPTOR ALPHA: A CASE SERIES FROM A SINGLE WESTERN CENTER.
  13. Large mediastinal schwannoma with great vessel encroachment requiring vascular reconstruction: a case report.
  14. Mediastinal tumors of peripheral nerve origin (so-called neurogenic tumors).
  15. Investigation of p16 protein expression and its association with histopathologic parameters in breast cancer.
  16. Paclitaxel in vitro reversibly sensitizes the excitability of IB4(-) and IB4(+) sensory neurons from male and female rats.
  17. Association Between Epidural Analgesia and Cancer Recurrence or Survival After Surgery for Renal Cell Carcinoma: A Propensity Weighted Analysis.
  1. Lancet Oncol. 2022 Feb;pii: S1470-2045(21)00596-9. [Epub ahead of print]23(2): e62-e74
    Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.
    Diana D Shi, Jimmy A Guo, Hannah I Hoffman, Jennifer Su, Mari Mino-Kenudson, Jaimie L Barth, Jason M Schenkel, Jay S Loeffler, Helen A Shih, Theodore S Hong, Jennifer Y Wo, Andrew J Aguirre, Tyler Jacks, Lei Zheng, Patrick Y Wen, Timothy C Wang, William L Hwang.
      With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.
    DOI:  https://doi.org/10.1016/S1470-2045(21)00596-9
  2. Transl Cancer Res. 2020 Nov;9(11): 6755-6767
    Autonomic nerve regulation for prostate cancer: study based on the tissue transcriptional analysis.
    Fang Liu, Huan Xu, Junyi Chen, Bo Yang, Lin Zhao, Jin Ji, Zhi Cao, Ji Lyu, Fubo Wang.
      Background: The whole-body energy metabolism is regulated by autonomic nerves which also play important roles in the regulation of the generation and development of different kinds of cancers. This study is to analyze the expression of autonomic nerve receptors and their relationship with the development of prostate cancer (PCa) and to further understand the central regulation of the prostate.Methods: RNA sequencing data concerning autonomic nerve receptors from paired tumor and adjacent benign tissues from 65 patients were collected. The mRNA expression and patient data were analyzed. The Cancer Genome Atlas (TCGA) data confirmed the results, and Pearson analysis, Pearson heat maps, gene heat maps, multivariate logistic regression models, receiver operating characteristic (ROC) curves and Gene Set Enrichment Analysis (GSEA) and Pearson's analysis were analyzed for correlation analysis in this study.
    Results: Reads with eight receptors associated with PCa generation were finally retained in this report. Favorable relationships were found among the different autonomic nerve regulators for the prostate. In univariate logistic regression analysis, adrenoceptor alpha 1A (ADRA1A) was the most positively correlated [OR (95% CI): 1.707 (1.209, 2.410)]; the area under the curve (AUC) in the ROC for ADRA1A was 0.866 (P<0.001). In multivariate logistic regression analysis, a predicted formulation for PCa diagnosis was evident. The GSEA results also showed the effect of autonomic nerves on cancer generation and some of the key cancer-related pathways, as well as Notch, Wnt and steroid biosynthesis pathways. Finally, five articles were reviewed to elucidate the center-autonomic nerve system-periphery circuit in the prostate.
    Conclusions: Central regulation plays an important role in the development of PCa, presenting the opportunity to treat the disease, and additional studies are warranted.
    Keywords:  Autonomic nerve; parasympathetic nervous system (PSNS); prostate cancer (PCa); sympathetic nervous system (SNS)
    DOI:  https://doi.org/10.21037/tcr-20-2053
  3. Transl Cancer Res. 2021 Feb;10(2): 899-913
    Combinatorial sympathetic and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockades inhibit the murine melanoma growth by targeting infiltrating T cells.
    Bin Wang, Zhifang Xu, Nuchsupha Sunthamala, Tomonori Yaguchi, Jin Huang, Yutaka Kawakami, Yinan Gong, Huiling Tang, Shanshan Li, Yi Guo, Yongming Guo, Masahisa Jinushi.
      Background: Failure of the proliferation and infiltration of tumor-specific T cells in tumor site has been considered as one of important reasons induce the inefficiencies of immune checkpoint therapies in advanced cancers. Therefore, we aimed to demonstrate how combinatorial sympathetic and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade affects the tumor growth of melanoma-bearing mice and potential mechanisms.Methods: Tumor growth was measured and the infiltrating immune cell populations were observed with flow cytometry in B16-F10 melanoma-bearing mice treated with combined sympathetic and immune checkpoint blockade, using anti-CTLA-4 antibodies. The expression of adrenergic receptors was investigated in human peripheral blood mononuclear cells and their subpopulations, and the proliferation of T cell subsets was detected when stimulated by norepinephrine and its antagonists.
    Results: B16-F10 tumor growth was associated with infiltrating CD8+ T cells. Combinatorial sympathetic and CTLA-4 blockade inhibited tumor growth and enhanced CD8+ infiltration. Meanwhile, all β1, β2 and β3 adrenergic receptors were found to be expressed in human peripheral blood mononuclear cells, activated T cells, monocytes, and monocyte-induced dendritic cells. β2-adrenergic receptors were expressed in most CD4+ T cells with increased expression in activated CD8+ T cells. Moreover, norepinephrine was able to prevent CD4+ T cell proliferation and β2-adrenergic receptor antagonists could reverse the inhibition of CD4+, but not CD8+ cell proliferation.
    Conclusions: We conclude that the combination of sympathetic and CTLA-4 inhibitors is more effective for inhibiting melanoma progression than a single treatment and might enhance the infiltration of T cells in the tumor site, offering a novel therapeutic approach for immune checkpoint targeting.
    Keywords:  Sympathetic nerve system; T cells; cytotoxic T-lymphocyte-associated protein 4 inhibitor (CTLA-4 inhibitor); melanoma; β2-adrenergic receptor
    DOI:  https://doi.org/10.21037/tcr-20-2738
  4. J Exp Clin Cancer Res. 2022 Feb 02. 41(1): 48
    Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer.
    Wunai Zhang, Rui He, Wenbin Yang, Yan Zhang, Qinggong Yuan, Jixin Wang, Yang Liu, Shuo Chen, Simei Zhang, Weifan Zhang, Zeen Zhu, Jing Zhang, Zheng Wang, Junhui Li.
      BACKGROUND: Perineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.METHODS: To investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08-2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.
    RESULTS: SC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.
    CONCLUSIONS: PanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a "nerve-repair like effect", induce a high level of autophagy of cancer cells, provide a "beacon" for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.
    Keywords:  Autophagy; NGF; Pancreatic cancer; Perineural invasion; Schwann cells
    DOI:  https://doi.org/10.1186/s13046-021-02198-w
  5. Iran J Pathol. 2022 ;17(1): 15-22
    Immunohistochemical Expression of Stanniocalcin 2 in Colorectal Cancer: A Retrospective Egyptian Study.
    Hala M El Hanbuli, Rehab S Galal, Mohammed F Darweesh, Mohamed H Elmahdi.
      Background & Objective: Colorectal cancer is the third most common cause of cancer death worldwide. Stanniocalcin 2 (STC2) is a glycoprotein hormone over-expressed in many human cancers where it regulates tumor progression and invasion. Evaluating its expression in colorectal cancer and its relation with different clinicopathological parameters can provide valuable information about its role in colorectal cancer progression and behavior.Methods: This retrospective study was conducted on tissue samples of colorectal cancer. The STC2 immunohistochemical expression was detected and evaluated in 60 cases of colorectal cancer tissue samples of formalin-fixed and paraffin-embedded blocks. Then statistical analysis was performed to assess the relationship between its expression level and several clinicopathological parameters in the studied cases.
    Results: Statistically significant associations were found between the high level of STC2 immunohistochemical expression and histological tumor grade (P<0.001), tumor depth of invasion (T stage) (P=0.004), lymph node metastasis (N stage) (P=0.001), tumor Dukes' stage (P<0.001), the presence of lymphovascular invasion (P<0.001), and perineural invasion (P<0.001).
    Conclusion: STC2 over-expression in colorectal cancer may be associated with more aggressive tumor behavior including increased tumor invasion, higher histological grade, higher rate of nodal metastasis and increased incidence of lymphovascular and perineural invasions. These data suggest a potential role for STC2 as a predictive biomarker for tumor behavior in colorectal cancer patients.
    Keywords:  Colorectal cancer; Immunohistochemical expression; Stanniocalcin 2 (STC2)
    DOI:  https://doi.org/10.30699/IJP.2021-.521799.2559
  6. Asia Pac J Clin Oncol. 2022 Jan 30.
    Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.
    Derrick Ho Wai Siu, Arwa Ali, Angelina Tjokrowidjaja, Madhawa De Silva, Joanna Lee, Philip R Clingan, Morteza Aghmesheh, Daniel Brungs, Cristina Mapagu, David Goldstein, Siobhan O'Neill, Winston S Liauw, Katrin M Sjoquist, David Thomas, Nick Pavlakis, Stephen J Clarke, Connie Diakos, Lorraine A Chantrill.
      BACKGROUND: Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context.AIM: To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival.
    METHODS: We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018.
    RESULTS: Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01).
    CONCLUSION: The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.
    Keywords:  BRAF colorectal cancer; KRAS; early onset; young adults
    DOI:  https://doi.org/10.1111/ajco.13745
  7. Int J Surg Oncol. 2022 ;2022 9334570
    Prognostic Impact of Tumor Budding on Moroccan Colon Cancer Patients.
    Fatima El Agy, Sanae El Bardai, Laila Bouguenouch, Nada Lahmidani, Mohammed El Abkari, El Bachir Benjelloun, Abdelmalek Ousadden, Khalid Mazaz, ImaneToughrai, Sidi Adil Ibrahimi, Zineb Benbrahim, Laila Chbani.
      Background: Tumor budding is now emerging as one of the robust and promising histological factors that play an important role in colon cancer. In this study, we aimed to investigate the association between tumor budding and tumor clinicopathological factors, tumor molecular signature, and patient survival for the first time in a Moroccan population.Methods: We collected data of 100 patients operated from colon adenocarcinoma. Tumor budding was assessed on HES slides, according to the International Tumor Budding Consensus Conference 2016 recommendations. The expression of MMR proteins was performed by immunohistochemistry. KRAS and NRAS mutations testing was performed by Sanger sequencing and pyrosequencing.
    Results: High tumor budding grade (BUD 3) was found to be significantly associated with adverse clinicopathological features including older age (P=0.03), presence of perineural invasion (P=0.02), presence of vascular invasion (P=0.05), distant metastases (P < 0.001), advanced TNM stage (P=0.001), the occurrence of relapse (P=0.04), and the high number of deceased cases (P=0.02). Interestingly, we found that tumors with high-grade tumor budding were more likely to be microsatellite stable (MSS) (P=0.005) and harbor more KRAS mutations (P=0.02). Tumors with high-grade tumor budding were strongly associated with KRAS G12D mutation (P=0.007). In all stages, high tumor budding was correlated with poorer overall survival (P=0.04) and decreased relapse-free survival with a difference close to significance ((P=0.09). We concluded that high tumor budding was strongly associated with unfavorable clinicopathological features and special molecular biomarkers and effectively affects the overall survival of CC patients.
    Conclusions: Based on these findings and the ITBCC group recommendations, tumor budding should be taken into account along with other clinicopathologic factors in the risk assessment of colorectal cancer.
    DOI:  https://doi.org/10.1155/2022/9334570
  8. J Natl Cancer Inst. 2022 Jan 30. pii: djac023. [Epub ahead of print]
    Identification of a Subset of Stage I Colorectal Cancer Patients with High Recurrence Risk.
    Lik Hang Lee, Lindy Davis, Lourdes Ylagan, Angela R Omilian, Kristopher Attwood, Canan Firat, Jinru Shia, Philip B Paty, William G Cance.
      BACKGROUND: A challenge in early-stage colorectal cancer (CRC) is identifying biomarkers that predict an increased risk for recurrence. A potential clinically adaptable biomarker is focal adhesion kinase (FAK), a tyrosine kinase that promotes invasion and metastasis.METHODS: An initial single-institution 298 patient cohort with all stages of CRC and long-term follow-up was assessed for FAK with tissue microarrays using immunohistochemistry. FAK expression was scored and dichotomized into high and low. Subsequently, a validation cohort of 517 early-stage CRCs from a separate institution was evaluated. All statistical tests were 2-sided.
    RESULTS: FAK overexpression did not correlate with any known histologic feature and was an early event in CRC, increasing from normal colon to stage I, and stage I to II, but not different at higher stages. High FAK was associated with decreased ten-year recurrence-free survival (RFS) among stage I patients (70.2% for high FAK vs 94.1% for low, p = .02), but not among higher stages in the initial cohort. The same finding was seen in the validation cohort (73.1% for high FAK vs 93.1% for low, p = .004). Multivariate survival analysis for stage I patients showed only two statistically significant factors predicting RFS: FAK (hazard ratio [HR] = 5.27, 95% CI = 1.81-15.33, p = .002) and perineural invasion (HR = 7.38, 95% CI = 1.01-53.96, p = .049). FAK was the only statistically significant factor in multivariate analysis across RFS, overall, and disease-specific survivals.
    CONCLUSIONS: High FAK expression identified a subset of stage I CRC patients with high incidence of recurrence and reduced survival, suggesting that FAK has important prognostic value. These patients would immediately benefit from more rigorous surveillance protocols for recurrent disease.
    DOI:  https://doi.org/10.1093/jnci/djac023
  9. Medicine (Baltimore). 2022 Feb 04. 101(5): e28620
    Postoperative recurrence of gastric cancer depends on whether the chemotherapy cycle was more than 9 cycles: Based on a retrospective and observational study of follow-up within 3 years of 843 patients.
    Yifan Li, Haoliang Zhao.
      ABSTRACT: We retrospectively reviewed the medical records of patients with pathologically confirmed gastric cancer/adenocarcinoma who underwent curative surgical resection follow-up within 3 years at Shanxi cancer hospital between 2002 and 2020. The clinicopathologic parameters explored included gender, age at surgery, vascular invasion, neural invasion, Tumor infiltration depth (T stage), N stage, TNM stage, chemotherapy, Lauren classification, maximum diameter of tumor, type of gastrectomy, tumor location and survival data.With a median follow-up of 29 months (range 0-36 months), the ratio of patients with recurrence was 26.80% (n = 226) and the death rate of patients was 45.31% (n = 382) in this period. According to the results of univariate analysis, gender (P = .014), age at surgery (P = .010), vascular invasion (P = .000), neural invasion (P = .000), T stage (P = .000), N stage (P = .000), TNM stage (P = .000), chemotherapy cycle (P = .000), lauren classification (P = .000), maximum diameter of tumor (P = .000), type of gastrectomy (P = .000) were independent risk factors of recurrence of follow-up within 3 years. From the multivariate analysis by logistic regression showed that TNM Stage (P = .002), chemotherapy cycle (P = .000) were risk factors of recurrence of follow-up within 3 years. Univariate analysis of survival by Kaplan-Meier showed that gender (P = .038), vascular invasion (P = .000), neural invasion (P = .000), maximum diameter of tumor (P = .000), Lauren classification (P = .000), T stage (P = .000), N stage (P = .000), TNM Stage (P = .000) and type of gastrectomy (P = .000) were key factors linked to overall survival of follow-up within 3 years. The results of the multivariate analysis by Cox regression were clearly presented that T Stage (P = .000), TNM stage (P = .001), maximum diameter of tumor (P = .001) were key factors of overall survival of follow-up within 3 years.TNM Stage, chemotherapy cycle were closely related to recurrence and of follow-up within 3 years. More than 9 cycles of chemotherapy was able to reduce the probability of recurrence. T Stage, TNM stage, maximum diameter of tumor were independent factors associated with overall survival of gastric cancer of follow-up within 3 years. For maximum diameter of tumor, the probability of death of more than 6 cm was 1.317 times less than 6 cm within 3 years of follow-up.
    DOI:  https://doi.org/10.1097/MD.0000000000028620
  10. Transl Cancer Res. 2021 Dec;10(12): 5267-5279
    Cleavage factor Im 25 as a potential biomarker for prognosis of colorectal cancer.
    Yubo Cai, Zequn Chen, Yutong Liang, Yuehua Liao, Yuanwei Wu, Junqiang Huang, Zhizhen Huang, Ronggang Li, Jiewei Chen.
      Background: Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear.Methods: A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer.
    Results: Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372-0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032-2.094; P=0.033) are independent prognostic factors for colorectal cancer.
    Conclusions: Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future.
    Keywords: Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25.
    DOI:  https://doi.org/10.21037/tcr-21-1441
  11. Neurosurg Focus. 2022 Feb;pii: 2021.11.FOCUS21590. [Epub ahead of print]52(2): E8
    Immunotherapeutic treatments for spinal and peripheral nerve tumors: a primer.
    Jean-Paul Bryant, Victor M Lu, Vaidya Govindarajan, Roberto J Perez-Roman, Allan D Levi.
      OBJECTIVE: Spinal and peripheral nerve tumors are a heterogeneous group of neoplasms that can be associated with significant morbidity and mortality despite the current standard of care. Immunotherapy is an emerging therapeutic option to improve the prognoses of these tumors. Therefore, the authors sought to present an updated and unifying review on the use of immunotherapy in treating tumors of the spinal cord and peripheral nerves, including a discussion on mechanism of action, drug delivery, current treatment techniques, and preclinical and clinical studies.METHODS: Current data in the literature regarding immunotherapy were collated and summarized. Targeted tumors included primary and secondary spinal tumors, as well as peripheral nerve tumors.
    RESULTS: Four primary modalities of immunotherapy (CAR T cell, monoclonal antibody, viral, and cytokine) have been reported to target spine and peripheral nerve tumors. Of the primary spinal tumors, spinal cord astrocytomas had the most preclinical evidence supporting immunotherapy success with CAR T-cell therapy targeting the H3K27M mutation, whereas spinal schwannomas and ependymomas had the most evidence reported for monoclonal antibody therapy preclinically. Of the secondary spinal tumors, primary CNS lymphomas demonstrated some clinical response to immunotherapy, whereas multiple myeloma and bone tumor experiences with immunotherapy were largely limited to concept only. Within peripheral nerve tumors, the use of immunotherapy to treat neurofibromas in the setting of syndromes has been suggested in theory, and possible immunotherapeutic targets have been identified in malignant peripheral nerve tumors. To date, there have been 2 clinical trials involving spine tumors and 2 clinical trials involving peripheral nerve tumors that have reported results, all of which are promising but require validation.
    CONCLUSIONS: Immunotherapy to treat spinal and peripheral nerve tumors has become an emerging area of research and interest. A large amount of preclinical data supporting the translation of this therapy into practice, aimed at ameliorating the poor prognoses of specific tumors, have been reported. Future clinical studies for translation will focus on the optimal therapy type and administration route to best target these tumors, which often preclude total surgical resection given their proximity to the neural and vascular elements of the spine.
    Keywords:  CAR T cell; immunotherapy; peripheral nerve tumors; spine tumors; vaccines
    DOI:  https://doi.org/10.3171/2021.11.FOCUS21590
  12. Arq Bras Cir Dig. 2022 ;pii: S0102-67202021000400308. [Epub ahead of print]34(4): e1635
    GASTRIC CANCER WITH POSITIVE EXPRESSION OF ESTROGEN RECEPTOR ALPHA: A CASE SERIES FROM A SINGLE WESTERN CENTER.
    Alice Cristina Castro DA Silva, Marina Alessandra Pereira, Marcus Fernando Kodama Pertille Ramos, Leonardo Cardili, Ulysses Ribeiro, Bruno Zilberstein, Evandro Sobroza de Mello, Tiago Biachi de Castria.
      AIM: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis.METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group.
    RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups.
    CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.
    DOI:  https://doi.org/10.1590/0102-672020210002e1635
  13. Mediastinum. 2021 ;5 37
    Large mediastinal schwannoma with great vessel encroachment requiring vascular reconstruction: a case report.
    Joanne B Szewczyk, Krista Hachey, Jorge Rey, Dao M Nguyen, Nestor R Villamizar.
      The most common posterior mediastinal masses are neurogenic tumors such as peripheral nerve sheath tumors (PNST). Schwannomas, a subtype of PNST, are most often benign, well encapsulated tumors of neural crest cell origin, and are frequently incidentally found, ranging in size from small asymptomatic mediastinal tumors to large masses. Rarely, large schwannomas are discovered when symptoms develop due to compression or involvement of nearby structures leading to an array of possible sequela which can include, but not limited to, persistent cough, hemoptysis, and dysphagia. Management decisions are based off of tumor size, location, concern for underlying malignant pathology, and potential for complications related to tumor invasion of vital anatomical structures. A majority of the schwannomas undergo surgical resection, though a subset of small, asymptomatic, benign tumors on imaging or pathology may be managed with surveillance. This case report describes a large posterior mediastinal schwannoma adherent to the posterior aortic arch and encasing the left subclavian and vertebral arteries. Surgical resection required vascular resection of a segment of the left subclavian artery and graft reconstruction using polytetrafluoroethylene (PTFE). This report further highlights the importance of preoperative planning with consideration of a multidisciplinary approach in preparation for resection of large, complex posterior mediastinal masses.
    Keywords:  Posterior mediastinum; aortic arch; case report; neurogenic tumor; schwannoma
    DOI:  https://doi.org/10.21037/med-20-71
  14. Mediastinum. 2020 ;4 32
    Mediastinal tumors of peripheral nerve origin (so-called neurogenic tumors).
    Alberto M Marchevsky, Bonnie Balzer.
      The mediastinum can be the site of origin of a variety of benign and malignant tumors of peripheral nerve sheath origin. Although schwannoma is one of the most common tumors found in the posterior mediastinum, peripheral nerve sheath tumors are reported in all compartments of the mediastinum. The majority of peripheral nerve sheath tumors in the mediastinum as in other anatomic sites occur sporadically, and a subset of them, most notably neurofibromas, and to a lesser extent, schwannomas and malignant peripheral nerve sheath tumors, occur in patients with syndromes such as neurofibromatosis 1 (NF1). In this review, the characteristics of mediastinal nerve sheath tumors along with the histologic differential diagnosis are summarized. Primary emphasis is placed upon the use of morphologic criteria for establishing a definitive diagnosis with reference to photomicrographs to illustrate the classic and sometimes unusual features of this varied group of tumors. The judicious application of ancillary testing, most frequently immunohistochemistry, for separating peripheral nerve sheath tumors from each other and from their morphologic mimics is reviewed. Included in the review are the clinicopathologic features, clinical management and prognostic implications of benign and malignant mediastinal peripheral nerve sheath tumors.
    Keywords:  Mediastinal nerve sheath tumor; malignant peripheral nerve sheath tumor; schwannoma; thoracic nerve sheath tumor
    DOI:  https://doi.org/10.21037/med-20-43
  15. Mol Biol Res Commun. 2021 Dec;10(4): 165-170
    Investigation of p16 protein expression and its association with histopathologic parameters in breast cancer.
    Siamak Naji-Haddadi, Daniel Elieh-Ali-Komi, Saeid Aghayan, Rahim Asghari, Javad Rasouli.
      We investigated the association between p16 expression and histopathologic parameters including size, neural and vascular invasion, and lymph node involvement in breast cancer. 58 specimens from patients with different grades of breast cancer were included. Hematoxylin and eosin and immunohistochemistry staining for p16 was performed. 5 patients (8.6%) had grade I, 23 (39.7%) had grade II, and 30 (51.7%) had grade III breast cancer. Assessment of the tumor size showed that 5 (8.6%) tumors had a size of ≤2cm, 29 (50%) were between 2-5 cm and 24 (41.4%) had a size of ≥5cm. Moreover, 45 (77.6%) of the included patients had axillary lymph node involvement. Investigation of association between p16 positivity with pathological parameters in three groups with positivity to p16 (1-25%, 26-75%, >75%) showed that there was no association between p16 positivity and other parameters including histologic score (p=0.44), tumor size (p=0.77), neural invasion (p=0.79), perivascular invasion (p=0.98) and the number of involved LNs (p=0.49). From the group including eight patients with >75% p16 positivity, seven (87.5%) were found with neural invasion and two (25%) with perivascular invasion. P16 positivity was not associated with size, neural and vascular invasion, and LN involvement in breast cancer.
    Keywords:  Breast cancer; Neural invasion; Nodal involvement; Vascular invasion; p16
    DOI:  https://doi.org/10.22099/mbrc.2021.41691.1671
  16. Br J Pharmacol. 2022 Jan 31.
    Paclitaxel in vitro reversibly sensitizes the excitability of IB4(-) and IB4(+) sensory neurons from male and female rats.
      
    DOI:  https://doi.org/10.1111/bph.15809
  17. Front Med (Lausanne). 2021 ;8 782336
    Association Between Epidural Analgesia and Cancer Recurrence or Survival After Surgery for Renal Cell Carcinoma: A Propensity Weighted Analysis.
    Fang-Yu Yen, Wen-Kuei Chang, Shih-Pin Lin, Tzu-Ping Lin, Kuang-Yi Chang.
      Whether epidural anesthesia and analgesia (EA) is beneficial for postoperative cancer outcomes remains controversial and we conducted this historical cohort study to evaluate the association between EA and long-term outcomes following surgery for renal cell carcinoma (RCC). We collected patients receiving RCC surgery from 2011 to 2017 and followed up them until February 2020. Patient attributes, surgical factors and pathological features were gathered through electronic medical chart review. The association between EA and recurrence-free and overall survival after surgery was evaluated using Cox regression models with inverse probability of treatment weighting (IPTW) to balance the observed covariates. The median follow-up time for the 725 included patients was 50 months (interquartile range: 25.3-66.5) and 145 of them (20%) received perioperative EA. We demonstrated EA use was associated with better recurrence-free survival [IPTW adjusted hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.49-0.83, p < 0.001] and overall survival [IPTW adjusted HR: 0.66, 95% CI: 0.49-0.89, p = 0.006] in patients receiving surgical resection for RCC. More prospective studies are needed to verify this connection between EA and superior cancer outcomes after RCC surgery.
    Keywords:  epidural analgesia; inverse probability of treatment weighting; recurrence; renal cell carcinoma; survival
    DOI:  https://doi.org/10.3389/fmed.2021.782336
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