bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2023–06–11
nine papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple myeloma induced bone pain in mice and human.
  2. Quantification of perineural invasion in pancreatic ductal adenocarcinoma: proposal of a severity score system.
  3. Analysis of influencing factors of nerve invasion in locally advanced gastric cancer.
  4. A nomogram for individually predicting the overall survival in colonic adenocarcinoma patients presenting with perineural invasion: a population study based on SEER database.
  5. Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.
  6. Malignant melanotic nerve sheath tumor with PRKAR1A, KMT2C, and GNAQ mutations.
  7. EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.
  8. Differentiation of retroperitoneal paragangliomas and schwannomas based on computed tomography radiomics.
  9. An unusual finding after adrenal surgery: a case series of adrenal schwannomas.
  1. J Neurosci. 2023 Jun 07. pii: JN-RM-0404-23. [Epub ahead of print]
    Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple myeloma induced bone pain in mice and human.
    Marta Diaz-delCastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard.
      Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin-gene related protein (CGRP+) and growth associated protein 43 (GAP43+) fibres occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signalling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP.Significance statement:Multiple myeloma is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0404-23.2023
  2. Virchows Arch. 2023 Jun 08.
    Quantification of perineural invasion in pancreatic ductal adenocarcinoma: proposal of a severity score system.
    Marco Schiavo Lena, Giulia Gasparini, Stefano Crippa, Giulio Belfiori, Francesca Aleotti, Francesca Di Salvo, Miriam Redegalli, Maria Giulia Cangi, Carla Taveggia, Massimo Falconi, Claudio Doglioni.
      Perineural invasion (PNI) is a common feature in pancreatic ductal adenocarcinoma (PDAC) and correlates with an aggressive tumor behavior already at early stages of disease. PNI is currently considered as a "present vs. absent" feature, and a severity score system has not yet been established. The aim of the present study was thus to develop and validate a score system for PNI and to correlate it with other prognostic features. In this monocentric retrospective study, 356 consecutive PDAC patients (61.8% upfront surgery patients, 38.2% received neoadjuvant therapy) were analyzed. PNI was scored as follows: 0: absent; 1: the presence of neoplasia along nerves < 3 mm in caliber; and 2: neoplastic infiltration of nerve fibers ≥ 3 mm and/or massive perineural infiltration and/or the presence of necrosis of the infiltrated nerve bundle. For every PNI grade, the correlation with other pathological features, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed. Uni- and multivariate analysis for DFS and DSS were also performed. PNI was found in 72.5% of the patients. Relevant trends between PNI score and tumor differentiation grade, lymph node metastases, vascular invasion, and surgical margins status were found. The latter was the only parameter statistically correlated with the proposed score. The agreement between pathologists was substantial (Cohen's K 0.61). PNI severity score significantly correlated also with decreased DFS and DSS at univariate analysis (p < 0.001). At multivariate analysis, only the presence of lymph node metastases was an independent predictor of DFS (HR 2.235 p < 0.001). Lymph node metastases (HR 2.902, p < 0.001) and tumor differentiation grade (HR 1.677, p = 0.002) were independent predictors of DSS. Our newly developed PNI score correlates with other features of PDAC aggressiveness and proved to have a prognostic role though less robust than lymph nodes metastases and tumor differentiation grade. A prospective validation is needed.
    Keywords:  Pancreatic ductal adenocarcinoma; Perineural invasion; Prognosis; Recurrence; Score system
    DOI:  https://doi.org/10.1007/s00428-023-03574-x
  3. Abdom Radiol (NY). 2023 Jun 08.
    Analysis of influencing factors of nerve invasion in locally advanced gastric cancer.
    Xiu-Chun Ren, Pan Liang.
       OBJECTIVES: Accurate preoperative diagnosis of locally advanced gastric cancer (GC) with nerve invasion is very important for guiding the clinical formulation of a reasonable treatment plan, improving treatment efficacy, and improving prognosis. The present study sought to analyze and evaluate the clinicopathological features of locally advanced GC, and to explore the risk factors associated with the state of nerve invasion.
    METHODS: The clinicopathological data of 296 patients with locally advanced GC were retrospectively analyzed in our hospital from July 2011 to December 2020 who underwent radical gastrectomy. PNI is defined as a tumor close to the nerve and involving at least 33% of its circumference or tumor cells within any of the 3 layers of the nerve sheath. The patient's age, gender, tumor location, T stage, N stage, TNM stage, degree of differentiation, Lauren classification, microvascular invasion, as well as TAP, AFP, CEA, CA125, CA199, CA724, CA153, tumor thickness, longest diameter, and plain CT value, arterial phase CT value, venous phase CT value, arterial phase enhancement rate, venous phase enhancement rate were assessed.
    RESULTS: A total of 296 patients with locally advanced GC were included, and 226 (76.35%) were positive for nerve invasion. Univariate analysis showed that tumor T stage, N stage, TNM stage, Lauren classification, tumor thickness, and longest diameter were related to the state of nerve invasion (P < 0.05). Multivariate analysis showed that tumor TNM stage was an independent risk factor for nerve invasion (OR 0.393, 95%CI 0.165-0.939, P = 0.036).
    CONCLUSIONS: Tumor TNM stage is an independent risk factor for nerve invasion (+) in patients with locally advanced GC. Patients at high risk of nerve invasion should be followed closely and, if necessary, performed pathological examinations.
    Keywords:  Gastric neoplasms; Influencing factors; Nerve invasion; Tomography; X-ray computed
    DOI:  https://doi.org/10.1007/s00261-023-03970-6
  4. Front Oncol. 2023 ;13 1152931
    A nomogram for individually predicting the overall survival in colonic adenocarcinoma patients presenting with perineural invasion: a population study based on SEER database.
    Junhong Chen, Hao Zhou, Hengwei Jin, Kai Liu.
       Background: Colonic adenocarcinoma, representing the predominant histological subtype of neoplasms in the colon, is commonly denoted as colon cancer. This study endeavors to develop and validate a nomogram model designed for predicting overall survival (OS) in patients with colon cancer, specifically those presenting with perineural invasion (PNI).
    Methods: The Surveillance, Epidemiology, and End Results (SEER) database supplied pertinent data spanning from 2010 to 2015, which facilitated the randomization of patients into distinct training and validation cohorts at a 7:3 ratio. Both univariate and multivariate analyses were employed to construct a prognostic nomogram based on the training cohort. Subsequently, the nomogram's accuracy and efficacy were rigorously evaluated through the application of a concordance index (C-index), calibration plots, decision curve analysis (DCA), and receiver operating characteristic (ROC) curves.
    Results: In the training cohorts, multivariable analysis identified age, grade, T-stage, N-stage, M-stage, chemotherapy, tumor size, carcinoembryonic antigen (CEA), marital status, and insurance as independent risk factors for OS, all with P-values less than 0.05. Subsequently, a new nomogram was constructed. The C-index of this nomogram was 0.765 (95% CI: 0.755-0.775), outperforming the American Joint Committee on Cancer (AJCC) TNM staging system's C-index of 0.686 (95% CI: 0.674-0.698). Calibration plots for 3- and 5-year OS demonstrated good consistency, while DCA for 3- and 5-year OS revealed excellent clinical utility in the training cohorts. Comparable outcomes were observed in the validation cohorts. Furthermore, we developed a risk stratification system, which facilitated better differentiation among three risk groups (low, intermediate, and high) in terms of OS for all patients.
    Conclusion: In this study, we have devised a robust nomogram and risk stratification system to accurately predict OS in colon cancer patients exhibiting PNI. This innovative tool offers valuable guidance for informed clinical decision-making, thereby enhancing patient care and management in oncology practice.
    Keywords:  colonic adenocarcinoma; nomogram; overall survival; perineural invasion; predict
    DOI:  https://doi.org/10.3389/fonc.2023.1152931
  5. J Gastrointest Cancer. 2023 Jun 05.
    Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.
    Vikram Chaudhari, Anant Ramaswamy, Sujay Srinivas, Ajit Agarwal, Ramakrishnan Ayloor Seshadri, Vineet Talwar, Prabhat Bhargava, Shaifali Goel, Smita Kayal, Pradeep Rebala, Bharat Prajapati, Devendra Parikh, Jagdish Kothari, Ramesh M Ch, Jacob Mathew Kadamapuzha, Deeksha Kapoor, Adarsh Chaudhary, Varun Goel, Shivendra Singh, Joydeep Ghosh, Viraj Lavingia, Amit Gupta, Anbarasan Sekar, Sanjeev Misra, Jeewan Ram Vishnoi, Subhash Soni, Vaibhav Kumar Varshney, Sandeep Bairwa, Manish Bhandare, Shailesh V Shrikhande, Vikas Ostwal.
       BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs).
    METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019.
    RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)).
    CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.
    Keywords:  Adjuvant chemotherapy; India; Multicentre; Pancreatic cancer; Perineural invasion; R0 resection
    DOI:  https://doi.org/10.1007/s12029-023-00936-1
  6. Free Neuropathol. 2022 Jan;pii: 3-21. [Epub ahead of print]3
    Malignant melanotic nerve sheath tumor with PRKAR1A, KMT2C, and GNAQ mutations.
    Merryl Terry, Kristina Wakeman, Brian J Williams, Donald M Miller, Müge Sak, Zied Abdullaev, Marwil C Pacheco, Kenneth Aldape, Norman L Lehman.
      Malignant melanotic nerve sheath tumor (MMNST) is a rare and potentially aggressive lesion defined in the 2021 WHO Classification of Tumors of the Central Nervous System. MMNST demonstrate overlapping histologic and clinical features of schwannoma and melanoma. MMNST often harbor PRKAR1A mutations, especially within the Carney Complex. We present a case of aggressive MMNST of the sacral region in a 48-year-old woman. The tumor contained PRKAR1A frameshift pR352Hfs*89, KMT2C splice site c.7443-1G>T and GNAQ p.R183L missense mutations, as well as BRAF and MYC gains. Genomic DNA methylation analysis using the Illumina 850K EpicBead chip revealed that the lesion did not match an established methylation class; however, uniform manifold approximation and projection (UMAP) placed the tumor very near schwannomas. The tumor expressed PD-L1, and the patient was treated with radiation and immune checkpoint inhibitors following en bloc resection. Although she had symptomatic improvement, she suffered early disease progression with local recurrence, and distant metastases, and died 18 months after resection. It has been suggested that the presence of GNAQ mutations can differentiate leptomeningeal melanocytic neoplasms and uveal melanoma from MMNST. This case and others demonstrate that GNAQ mutations may exist in malignant nerve sheath tumors; that GNAQ and PRKAR1A mutations are not always mutually exclusive and that neither can be used to differentiate MMNST or MPNST from all melanocytic lesions.
    Keywords:  Case Report; GNAQ; KMT2C; MMNST; Malignant melanotic nerve sheath tumor; Nerve sheath tumor; PRKAR1A; Pigmented epithelioid melanocytoma; Psammomatous melanotic schwannoma
    DOI:  https://doi.org/10.17879/freeneuropathology-2022-3864
  7. Carcinogenesis. 2023 Jun 09. pii: bgad041. [Epub ahead of print]
    EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.
    Hao Yu, Xiao-Kang Qin, Kai-Wen Yin, Zi-Ming Li, En-De Ni, Jian-Ming Yang, Xun-Hua Liu, Ai-Jun Zhou, Shu-Ji Li, Tian-Ming Gao, Ying Li, Jian-Ming Li.
      EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.
    Keywords:  Colorectal cancer; EphB6; GABA; Intestinal neuron; Snap25; Tumor growth
    DOI:  https://doi.org/10.1093/carcin/bgad041
  8. Sci Rep. 2023 Jun 07. 13(1): 9253
    Differentiation of retroperitoneal paragangliomas and schwannomas based on computed tomography radiomics.
    Yuntai Cao, Zhan Wang, Jialiang Ren, Wencun Liu, Huiwen Da, Xiaotong Yang, Haihua Bao.
      The purpose of this study was to differentiate the retroperitoneal paragangliomas and schwannomas using computed tomography (CT) radiomics. This study included 112 patients from two centers who pathologically confirmed retroperitoneal pheochromocytomas and schwannomas and underwent preoperative CT examinations. Radiomics features of the entire primary tumor were extracted from non-contrast enhancement (NC), arterial phase (AP) and venous phase (VP) CT images. The least absolute shrinkage and selection operator method was used to screen out key radiomics signatures. Radiomics, clinical and clinical-radiomics combined models were built to differentiate the retroperitoneal paragangliomas and schwannomas. Model performance and clinical usefulness were evaluated by receiver operating characteristic curve, calibration curve and decision curve. In addition, we compared the diagnostic accuracy of radiomics, clinical and clinical-radiomics combined models with radiologists for pheochromocytomas and schwannomas in the same set of data. Three NC, 4 AP, and 3 VP radiomics features were retained as the final radiomics signatures for differentiating the paragangliomas and schwannomas. The CT characteristics CT attenuation value of NC and the enhancement magnitude at AP and VP were found to be significantly different statistically (P < 0.05). The NC, AP, VP, Radiomics and clinical models had encouraging discriminative performance. The clinical-radiomics combined model that combined radiomics signatures and clinical characteristics showed excellent performance, with an area under curve (AUC) values were 0.984 (95% CI 0.952-1.000) in the training cohort, 0.955 (95% CI 0.864-1.000) in the internal validation cohort and 0.871 (95% CI 0.710-1.000) in the external validation cohort. The accuracy, sensitivity and specificity were 0.984, 0.970 and 1.000 in the training cohort, 0.960, 1.000 and 0.917 in the internal validation cohort and 0.917, 0.923 and 0.818 in the external validation cohort, respectively. Additionally, AP, VP, Radiomics, clinical and clinical-radiomics combined models had a higher diagnostic accuracy for pheochromocytomas and schwannomas than the two radiologists. Our study demonstrated the CT-based radiomics models has promising performance in differentiating the paragangliomas and schwannomas.
    DOI:  https://doi.org/10.1038/s41598-023-28297-6
  9. Front Surg. 2023 ;10 1175633
    An unusual finding after adrenal surgery: a case series of adrenal schwannomas.
    Mehmet Kostek, Mehmet Taner Unlu, Ozan Caliskan, Nurcihan Aygun, Yalin Iscan, Ahmet Cem Dural, Ismail Cem Sormaz, Fatih Tunca, Yasemin Giles Senyurek, Mehmet Uludag.
      Adrenal schwannomas are rare benign tumors with no specific imaging and laboratory findings to diagnose preoperatively. Due to the limited number of cases in the literature, clinical, imaging, and pathological findings are presented in this study. Case 1 is a 61-year-old woman patient who has a 31-mm mass in the right adrenal gland. This mass was nonfunctional; in imaging studies, this mass had a cystic necrotic component, and high 18-fluorodeoxyglucose (FDG) uptake was seen. There was no metaiodobenzylguanidine (MIBG) uptake. Laparoscopic transabdominal right adrenalectomy was performed, and the pathology result was consistent with adrenal schwannomas. Case 2 is a 63-year-old man patient who presented with a 38-mm mass in the left adrenal gland. This mass was nonfunctional and similar to that in Case 1; this mass had a cystic component. Laparoscopic transabdominal left adrenalectomy was performed. The diagnosis of adrenal schwannoma with degeneration was revealed. Case 3 was a 72-year-old woman patient admitted to the hospital for a 125-mm left adrenal mass. Similar to Case 1, this mass also had a cystic necrotic component in imaging studies. High FDG uptake was seen, and the patient underwent conventional adrenalectomy due to the suspicion of malignancy. After pathological evaluation, a diagnosis of adrenal schwannoma was made. A main diagnostic challenge in adrenal schwannomas is the preoperative diagnosis. These masses have no pathognomonic finding or specific hormonal function. Imaging findings of these masses may increase the suspicion of malignancy, which may affect decisions for surgery and the surgical technique.
    Keywords:  adrenal glands; adrenal schwannoma; adrenalectomy; adrenocortical carcinoma; schwannoma
    DOI:  https://doi.org/10.3389/fsurg.2023.1175633
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