bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–12–04
twelve papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs.
  2. Stress exacerbates pancreatic cancer both directly and indirectly by creating an immunosuppressive environment.
  3. Melanoma metastasis to the femoral nerve: a novel case of melanoma masquerading as mononeuropathy. Illustrative case.
  4. Preoperative diagnosis of perineural invasion in patients with periampullary carcinoma by MSCT imaging: preliminary observations and clinical implications.
  5. Systematic review on outcomes of the use of adjuvant pharmacotherapy for treatment of cutaneous malignancies exhibiting perineural invasion: promising efficacy of anti-PD1 therapy.
  6. Histopathological investigation of colon liver metastases - which factors affect survival after surgery?
  7. CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis.
  8. The rising incidence of ductal adenocarcinoma and intraductal carcinoma of the prostate: Diagnostic accuracy of biopsy, MRI-visibility, and outcomes.
  9. Sporadic Neurofibroma of the Peritoneal Cavity.
  10. LZTR1 mutation mediates oncogenesis through stabilization of EGFR and AXL.
  11. Role of perioperative chemotherapy and radiotherapy for localized high-grade malignant peripheral nerve sheath tumor at the extremities and trunk wall: a population-based cohort study.
  12. Clinicopathological characteristics of carcinoma penis over 10 years in a tertiary-level oncology center in Nepal: a retrospective study of 380 cases.
  1. Front Endocrinol (Lausanne). 2022 ;13 1029210
    Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs.
    Ana Cristina García-Gaytán, Andy Hernández-Abrego, Mauricio Díaz-Muñoz, Isabel Méndez.
      Glutamate is one of the most abundant amino acids in the blood. Besides its role as a neurotransmitter in the brain, it is a key substrate in several metabolic pathways and a primary messenger that acts through its receptors outside the central nervous system (CNS). The two main types of glutamate receptors, ionotropic and metabotropic, are well characterized in CNS and have been recently analyzed for their roles in non-neural organs. Glutamate receptor expression may be particularly important for tumor growth in organs with high concentrations of glutamate and might also influence the propensity of such tumors to set metastases in glutamate-rich organs, such as the liver. The study of glutamate transporters has also acquired relevance in the physiology and pathologies outside the CNS, especially in the field of cancer research. In this review, we address the recent findings about the expression of glutamatergic system components, such as receptors and transporters, their role in the physiology and pathology of cancer in non-neural organs, and their possible use as biomarkers and therapeutic targets.
    Keywords:  cancer; excitatory amino acid transporter (EAAT); glutamate/cystine antiporter (xCT); ionotropic glutamate receptor (iGluR); metabotropic glutamate receptor (mGluR); non-neural organs
    DOI:  https://doi.org/10.3389/fendo.2022.1029210
  2. J Hepatobiliary Pancreat Sci. 2022 Dec 01.
    Stress exacerbates pancreatic cancer both directly and indirectly by creating an immunosuppressive environment.
    Takahiro Ikeda, Tomohiko Adachi, Takayuki Tanaka, Daisuke Miyamoto, Hajime Imamura, Hajime Matsushima, Kazuo Yamamoto, Masaaki Hidaka, Kengo Kanetaka, Susumu Eguchi.
       BACKGROUND/PURPOSE: Sympathetic nerve stimulation by stress exacerbates various solid tumors, including pancreatic cancer (PCa). The relationship between cancer and immunity has been suggested; however, there is limited information about the effects of nerve stimulation on immunity and cancer. We aimed to investigate the involvement of sympathetic nerve stimulation in immune cells and its effects on PCa using a restraint stress mouse model.
    METHODS: In the in vitro experiment, the mouse-derived PCa cell line (LTPA) was cultured in a noradrenalin-supplemented medium. In the in vivo experiment, mice were divided into non-stress and stress groups.
    RESULTS: LTPA proliferated significantly more when cultured in a noradrenalin-supplemented medium than in a normal medium. Flow cytometry analysis of blood immune cells revealed a significant decrease in B cells, T cells, and macrophages and a significant increase in myeloid-derived suppressor cells (MDSCs) in the stress group. Furthermore, a significant increase in blood noradrenaline levels was observed in the stress group (p<0.01). In the PCa mice model, immune cells in the blood showed a similar trend, and the stress group had a poor prognosis. Furthermore, immunostaining at the tumor site showed that there was a lower number of B and T cells in the stress group. In addition, MDSCs were present at the tumor margins.
    CONCLUSION: These results suggest that sympathetic nerve stimulation is not only directly involved in PCa growth but also exacerbates PCa by creating an immunosuppressive environment in the blood and tumor tissue.
    Keywords:  catecholamines; immunosuppression; pancreatic cancer; stress
    DOI:  https://doi.org/10.1002/jhbp.1295
  3. J Neurosurg Case Lessons. 2022 Nov 28. pii: CASE22414. [Epub ahead of print]4(22):
    Melanoma metastasis to the femoral nerve: a novel case of melanoma masquerading as mononeuropathy. Illustrative case.
    Jaime R Guerrero, Khaled M Taghlabi, Sara A Meyer, Lokeshwar S Bhenderu, Saeed S Sadrameli, Clive I Shkedy, Amir H Faraji, Robert C Rostomily.
       BACKGROUND: Metastatic cancer may involve the central and peripheral nervous system, usually in the late stages of disease. At this point, most patients have been diagnosed and treated for widespread systemic disease. Rarely is the involvement of the peripheral nervous system the presenting manifestation of malignancy. One reason for this is a proposed "blood-nerve barrier" that renders the nerve sheath a relatively privileged site for metastases.
    OBSERVATIONS: The authors presented a novel case of metastatic melanoma presenting as intractable leg pain and numbness. Further workup revealed concurrent disease in the brain and breast, prompting urgent treatment with radiation and targeted immunotherapy.
    LESSONS: This case highlights the rare presentation of metastatic melanoma as a mononeuropathy. Although neurological complications of metastases tend to occur in later stages of disease after initial diagnosis and treatment, one must remember to consider malignancy in the initial differential diagnosis of mononeuropathy.
    Keywords:  cancer; central nervous system; melanoma; metastasis; nerve metastasis; peripheral nervous system
    DOI:  https://doi.org/10.3171/CASE22414
  4. Abdom Radiol (NY). 2022 Nov 27.
    Preoperative diagnosis of perineural invasion in patients with periampullary carcinoma by MSCT imaging: preliminary observations and clinical implications.
    Chen Zhang, Lixue Wang, Zhuozhao Zheng, Jingjing Yao, Li He, Jie Li.
       PURPOSE: The aim of this study was to investigate the value of multi-slice computed tomography (MSCT) in preoperatively diagnosing perineural invasion (PNI) of periampullary carcinoma (PAC).
    METHODS: Of 81 patients pathologically diagnosed as PAC, 73 patients were included. Their clinical documents and preoperative upper abdominal enhanced MSCT images were retrospectively reviewed to analyse clinical characteristics and MSCT features. MSCT features included tumor size, classification of fat tissue around celiac trunk and superior mesenteric artery. Chi-square test, Mann-Whitney U test or Fisher's exact test were used to compare the differences between PNI group and Non-PNI group. ROC analysis was performed to evaluate diagnostic efficiency for PAC PNI.
    RESULTS: There were significant differences in some clinical characteristics and MSCT features. PAC PNI patients had significantly higher CA19-9 levels, higher CEA levels, larger tumor size and higher classification of fat tissue around celiac trunk than Non-PNI patients (All P values < 0.05). In univariate analysis, tumor size had the highest AUC as 0.806, fat tissue around celiac trunk and CEA had the highest specificity as 100% (P < 0.001). In multivariate analysis, classification of fat tissue around celiac trunk incorporated with tumor size, CA19-9, CEA, age and sex, showed the highest AUC as 0.939, with specificity of 95.0% and sensitivity of 90.4% (P < 0.001).
    CONCLUSION: PAC PNI could be diagnosed preoperatively by evaluating abdominal enhanced MSCT images with high accuracy, combined with serum tumor marker could be more helpful.
    Keywords:  Multi-slice computed tomography; Periampullary carcinoma; Perineural invasion; Preoperative diagnosis
    DOI:  https://doi.org/10.1007/s00261-022-03752-6
  5. Arch Dermatol Res. 2022 Nov 29.
    Systematic review on outcomes of the use of adjuvant pharmacotherapy for treatment of cutaneous malignancies exhibiting perineural invasion: promising efficacy of anti-PD1 therapy.
    Madiha Khan, Dimitra Xenopoulou, Amor Khachemoune.
      There is a paucity of the literature regarding the utility of pharmacotherapy in the management of cutaneous malignancies exhibiting perineural invasion (PNI). We aimed to systematically review the literature to provide an overview of the effectiveness of pharmacotherapy in treating cases of skin cancers with PNI in which first line therapy (MMS ± radiotherapy) is insufficient or contraindicated. A systematic review of PubMed and Wiley Online Library, from 1990 to July 14, 2022, identified all cases of cutaneous malignancies with PNI treated with pharmacotherapy with or without prior surgery/ radiotherapy. A total of 121 patients were included over 17 studies. The mean patient age was 72 (range, 26-94). The most commonly treated cutaneous malignancy was squamous cell carcinoma (n = 92). The most utilized chemotherapy was cisplatin (n = 46). However, anti-PD1 therapy had the best overall result with 61% of patients having complete local response (CLR) or stable disease. Three articles did not report specific patient outcomes, and all studies were either case reports or retrospective chart reviews. Our review shows the efficacy of anti-PD1 therapy particularly in conjunction with surgery and RT. Although chemotherapy does have beneficial outcomes based on anecdotal evidence in select cases, more powerful research in the form of randomized clinical trials is imperative to obtain a more comprehensive understanding of its utility.
    Keywords:  Adjunctive pharmacotherapy for cutaneous malignancies; Anti-PD1 therapy; Chemotherapy; Outcomes of chemotherapy in perineural invasion; PNI; Perineural invasion; Skin cancer treatment
    DOI:  https://doi.org/10.1007/s00403-022-02482-5
  6. Scand J Gastroenterol. 2022 Nov 28. 1-7
    Histopathological investigation of colon liver metastases - which factors affect survival after surgery?
    William Torén, Agata Sasor, Daniel Ansari, Roland Andersson.
       INTRODUCTION: Novel therapeutic options have improved prognosis for patients with colonic liver metastases (CLM) over the last decades. Despite this, the challenge to select and stratify patients for optimal treatment regimen persists. This study aimed to evaluate established and novel histopathological features and investigate the impact on overall survival (OS) and recurrence in patients undergoing surgery for CLM.
    METHODS: Two hundred and sixty patients who underwent resection of CLM with curative intent 2006-2017 were included in the study. Clinicopathological characteristics were retrieved from patient medical records. The following histopathological parameters were investigated: vascular/lymphatic invasion, perineural invasion, tumor regression grade (TRG), tumor growth pattern, pseudocapsule and acellular mucin. Histopathological traits were correlated to OS.
    RESULTS: Vascular and lymphatic invasion, as well as perineural invasion, significantly correlated with an adverse prognosis hazard ratio (HR) = 1.7, 95% confidence interval (CI) 1.23-2.40 and HR = 1.7, 95% CI 1.20-2.51, respectively. Results retrieved from the study could not propose any novel explorative histopathological features (TRG, tumor growth pattern, pseudocapsule and acellular mucin) to be of significant value as comes correlation with patient OS.
    DISCUSSION: Classical histopathological characteristics of previously reported influence on survival were confirmed, while more novel factors that has been proposed, like tumor growth pattern, tumor regression and grade and presence of a pseudocapsule, were not. Further studies are thus needed to identify better ways of understanding the impact of tumor microenvironment and tumor biology on patient outcome and not at least for stratification and improved treatment response.
    Keywords:  Colonic liver metastases; histopathology; prognosis; survival after surgery; tumor biology
    DOI:  https://doi.org/10.1080/00365521.2022.2151319
  7. Pathol Res Pract. 2022 Dec;pii: S0344-0338(22)00464-2. [Epub ahead of print]240 154220
    CD47 mediates the progression of colorectal cancer by inducing tumor cell apoptosis and angiogenesis.
    Hyung-Hoon Oh, Young-Lan Park, Sun-Young Park, Eun Myung, Chan-Muk Im, Hyung-Joo Yu, Bora Han, Yoon-Jin Seo, Ki-Hyun Kim, Dae-Seong Myung, Sung-Bum Cho, Wan-Sik Lee, Daeho Park, Young-Eun Joo.
      CD47 is an immunoregulatory protein that is found on the cell surface and plays significant roles in cellular functions such as proliferation, apoptosis, migration, and immune homeostasis. CD47 is overexpressed in various human cancers and is associated with tumor development, progression, and poor prognosis. In this study, we analyzed the expression of CD47 to determine whether it affected the oncogenic behavior of colorectal cancer (CRC) and investigated the prognostic value of CD47 expression in patients with CRC. We investigated 468 patients with CRC who underwent curative surgery and examined the expression of CD47 in tumor and lymph node tissues by performing RT-PCR and immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined via a TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. CD47 expression was increased in human CRC tumors and metastatic lymph nodes compared with normal colorectal mucosa and non-metastatic lymph node tissues. CD47 expression was significantly associated with perineural invasion, lymphovascular invasion, cell differentiation, cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The mean apoptotic index and microvessel density value of CD47-positive tumors were significantly higher than those of CD47-negative tumors. However, no significant difference was observed between CD47 expression and Ki-67 labeling index or lymphatic vessel density. These results indicate that CD47 mediated the progression of CRC by inducing tumor cell apoptosis and angiogenesis.
    Keywords:  Angiogenesis; Apoptosis; CD47; Colon Neoplasm; Prognosis
    DOI:  https://doi.org/10.1016/j.prp.2022.154220
  8. Urol Oncol. 2023 Jan;pii: S1078-1439(22)00353-2. [Epub ahead of print]41(1): 48.e11-48.e18
    The rising incidence of ductal adenocarcinoma and intraductal carcinoma of the prostate: Diagnostic accuracy of biopsy, MRI-visibility, and outcomes.
    Gaurav Pahouja, Hiten D Patel, Shalin Desai, Goran Rac, Teresa Cheng, Yudai Okabe, Alexander Gorbonos, Marcus L Quek, Robert C Flanigan, Maria M Picken, Gopal N Gupta.
       INTRODUCTION: Ductal adenocarcinoma (DA) and intraductal carcinoma (IDC) of the prostate are associated with higher stage disease at radical prostatectomy (RP). We evaluated diagnostic accuracy of biopsy, MRI-visibility, and outcomes for patients undergoing RP with DA/IDC histology compared to pure acinar adenocarcinoma (AA) of the prostate.
    MATERIALS AND METHODS: A retrospective cohort study of men receiving RP between 2014 and 2021 revealing AA, DA, or IDC on final pathology was conducted. Multivariable logistic regression and Cox proportional hazards regression models were employed.
    RESULTS: A total of 609 patients were included with 103 found to have DA/IDC. Patients with DA/IDC were older and had higher PSA, biopsy grade group (GG), RP GG, and other pathologic findings (extraprostatic extension, lymphovascular invasion, perineural invasion, pN stage) compared to AA patients (all P < 0.05). On multivariable analysis, higher age, RP GG, and pT3a were associated with DA/IDC on RP (all P < 0.05). Sensitivity and specificity of biopsy compared to RP for diagnosis of DA/IDC was 29.1% (16.7% DA, 27.8% IDC) and 96.6% (99.3% DA, 96.6% IDC), respectively. In a subset of 281 men receiving MRI, PI-RADS distribution was similar for patients with DA/IDC vs. AA (90.7% vs. 80.7% with PI-RADS 4-5 lesions, P = 0.23) with slightly higher biopsy sensitivity (41.9%). DA/IDC was associated with worse BCR (HR = 1.77, P = 0.02) but not biopsy DA/IDC (P = 0.90).
    CONCLUSIONS: Sensitivity of prostate biopsy was low for detection of DA/IDC histology at RP. Patients with DA/IDC histology had unfavorable pathologic features at RP and worse BCR. Of patients with DA/IDC at RP, 90.7% were categorized as PI-RADS 4 to 5 on preoperative MRI.
    Keywords:  Ductal adenocarcinoma; Intraductal adenocarcinoma; Prostate cancer
    DOI:  https://doi.org/10.1016/j.urolonc.2022.09.025
  9. ACG Case Rep J. 2022 Nov;9(11): e00915
    Sporadic Neurofibroma of the Peritoneal Cavity.
    Rahil H Shah, Justin Forde, Kshitij Satnamdas Arora, Sean Bhalla, Sunil Amin, Shria Kumar.
      Neurofibromas are peripheral nerve sheath tumors that are typically seen in syndromic conditions such as neurofibromatosis 1. We present the case of a 26-year-old woman suffering from chronic abdominal pain for over 5 years. Prior workup showed a large retroperitoneal mass extending into the abdomen and encasing multiple major vessels. She underwent endoscopic ultrasound (EUS)-guided biopsy, which was histologically consistent with a solitary neurofibroma. There is no prior report of solitary neurofibroma of the abdomen diagnosed with the use of EUS-guided biopsy. This case highlights the utility of EUS-guided biopsy in the evaluation of intra-abdominal pathology.
    DOI:  https://doi.org/10.14309/crj.0000000000000915
  10. Cancer Discov. 2022 Nov 29. pii: CD-22-0376. [Epub ahead of print]
    LZTR1 mutation mediates oncogenesis through stabilization of EGFR and AXL.
    Aram Ko, Mohammad Hasanain, Young Taek Oh, Fulvio D'Angelo, Danika Sommer, Brulinda Frangaj, Suzanne Tran, Franck Bielle, Bianca Pollo, Rosina Paterra, Karima Mokhtari, Rajesh Kumar Soni, Matthieu Peyre, Marica Eoli, Laura Papi, Michel Kalamarides, Marc Sanson, Antonio Iavarone, Anna Lasorella.
      LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase frequently mutated in sporadic and syndromic cancer. We combined biochemical and genetic studies to identify LZTR1 substrates and interrogated their tumor-driving function in the context of LZTR1 loss-of-function mutations. Unbiased screens converged on EGFR and AXL receptor tyrosine kinases as LZTR1 interactors targeted for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated mutations of LZTR1 failed to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system caused tumors in the peripheral nervous system including schwannoma-like tumors, thus recapitulating aspects of Schwannomatosis, the prototype tumor predisposition syndrome sustained by LZTR1 germline mutations. Lztr1 and Cdkn2a deleted tumors aberrantly accumulated EGFR and AXL and exhibited specific vulnerability to EGFR and AXL co-inhibition. These findings explain tumorigenesis by LZTR1 inactivation and offer therapeutic opportunities to patients with LZTR1 mutant cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0376
  11. Jpn J Clin Oncol. 2022 Dec 02. pii: hyac178. [Epub ahead of print]
    Role of perioperative chemotherapy and radiotherapy for localized high-grade malignant peripheral nerve sheath tumor at the extremities and trunk wall: a population-based cohort study.
    Hiroshi Kobayashi, Liuzhe Zhang, Koichi Okajima, Toshihide Hirai, Yusuke Tsuda, Masachika Ikegami, Akira Kawai, Sakae Tanaka.
       BACKGROUND: Primary tumor resection is the mainstay of treatment for malignant peripheral nerve sheath tumors. However, the efficacy of perioperative chemotherapy and radiotherapy for malignant peripheral nerve sheath tumors has not been elucidated.
    METHODS: This retrospective analysis based on a Japanese registry included patients with localized malignant peripheral nerve sheath tumors arising at the extremities and trunk wall. Disease-specific overall survival and local recurrence-free survival were estimated using the Kaplan-Meier method. A Cox regression model was used to identify prognostic factors. Characteristics of groups with or without chemotherapy were adjusted using propensity score matching.
    RESULTS: In total, 291 patients were included. The 5-year disease-specific overall survival rate was 70.6%. Multivariate analysis of disease-specific overall survival revealed that deep-seated tumors were a poor prognostic factor, but perioperative chemotherapy was not associated with disease-specific overall survival (hazard ratio, 0.81; 95% confidence interval, 0.45-1.43, P = 0.46). Local recurrence was observed in 55 patients (19.0%), and surgical margins (R1 and R2) were significant risk factors. Overall, perioperative chemotherapy did not prolong disease-specific overall survival (5-year disease-specific overall survival: 74.1% vs. 69.3%, P = 0.75) and had limited efficacy in the group with tumor size ≥ 5 cm, although the difference was not statistically significant (5-year disease-specific overall survival: 77.2% vs. 68.6%, respectively, P = 0.13). After adjustment by propensity score matching, perioperative chemotherapy significantly prolonged disease-specific overall survival (5-year disease-specific overall survival: 74.9% vs. 57.1%, P = 0.03), but this effect was not observed in local recurrence-free survival. In all patients, perioperative radiotherapy did not correlate with local recurrence-free survival (hazard ratio, 1.43; 95% confidence interval 0.78-2.62, P = 0.25).
    CONCLUSIONS: Perioperative chemotherapy had limited efficacy for disease-specific overall survival in patients with localized malignant peripheral nerve sheath tumors.
    Keywords:  malignant peripheral nerve sheath tumor; perioperative chemotherapy; perioperative radiotherapy
    DOI:  https://doi.org/10.1093/jjco/hyac178
  12. Int Urol Nephrol. 2022 Dec 01.
    Clinicopathological characteristics of carcinoma penis over 10 years in a tertiary-level oncology center in Nepal: a retrospective study of 380 cases.
    Prem Raj Sigdel, Navin Mahaseth, Bharat Mani Pokharel, Jeevan Thapa, Aditya Jalan, Binod Babu Gharti, Gyan Prasad Pokharel, Greta Pandey, Umesh Nepal, Nirmal Lamichhane.
       PURPOSE: This study was done to find out the clinicopathological characteristics of carcinoma penis in Nepali population and to evaluate various risk factors that predict its inguinal lymph node metastasis.
    METHODS: A retrospective cross-sectional study was carried out at the Urology Unit, Department of Surgical Oncology at BP Koirala Memorial Cancer Hospital, Bharatpur, Nepal. Case notes of biopsy-proven penile cancer, from January 2012 to December 2021, who underwent some form of surgical intervention were included.
    RESULTS: A total of 380 patients were included in the study. The mean age of the patients was 55.92 ± 13.81 years. At presentation, 78.5% had clinically node-positive disease. The most common treatment for the primary tumor was partial amputation of the penis (74.2%). Bilateral inguinal lymph node dissections were done in 370 cases. The most common histology was the usual SCC in 94.2% of cases and 69% were well differentiated. T3 was the most common staging in 49.4% cases. Pathologically nodal negative status was found in 58% cases. In univariate analysis, factors like duration of symptoms (≥ 6 months), high-risk histopathology (basaloid/sarcomatoid variant), increased T-stage, poorly differentiated tumor, and the presence of PNI or LVI were significantly associated with lymph node metastasis.
    CONCLUSIONS: Penile cancer is a common cancer in developing countries such as Nepal. The majority of the patients present late. Early recognition and prompt treatment are required to improve the overall outcome.
    Keywords:  Carcinoma penis; Inguinal lymph node dissection; Penectomy; Squamous cell carcinoma
    DOI:  https://doi.org/10.1007/s11255-022-03427-7
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