bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2021‒10‒24
eleven papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. Adv Exp Med Biol. 2021 ;1329 271-294
      The central and autonomic nervous systems interact and converge to build up an adrenergic nerve network capable of promoting cancer. While a local adrenergic sympathetic innervation in peripheral solid tumors influences cancer and stromal cell behavior, the brain can participate to the development of cancer through an intermixed dysregulation of the sympathoadrenal system, adrenergic neurons, and the hypothalamo-pituitary-adrenal axis. A deeper understanding of the adrenergic nerve circuitry within the brain and tumors and its interactions with the microenvironment should enable elucidation of original mechanisms of cancer and novel therapeutic strategies.
    Keywords:  Adrenergic nerve circuitry; Adrenergic nerve signaling; Adrenergic neuron; Autonomic nervous system; Cancer neuroscience; Central nervous system; Hypothalamo-pituitary-adrenal axis; Sympathetic nervous system; Sympathoadrenal system; Tumor axonogenesis; Tumor microenvironment; Tumor neurogenesis
  2. Microorganisms. 2021 Oct 11. pii: 2129. [Epub ahead of print]9(10):
      The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood-brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination.
    Keywords:  carcinogenesis; gut–brain axis; immunity; metabolites; microbiota; neurogenesis; neurotransmitters
  3. Ann Palliat Med. 2021 Oct 18. pii: apm-21-2256. [Epub ahead of print]
      The infiltration and invasion of nerve trunks, nerve roots, and cranial nerves by lymphomatous malignant cells is defined as "neurolymphomatosis". It is mainly caused by lymphoma cells directly infiltrating the peripheral nerves, with a low incidence. Neurolymphomatosis is a rare condition of neoplastic endoneurial invasion, which is primary or secondary to non-Hodgkin's lymphoma and leukemia. We describe a case of primary peripheral neurolymphomatosis of multifocal involvement in a 77-year-old male patient. He presented with left lower limb pain and was diagnosed with CD20+ diffuse large B cell lymphoma (DLBCL). Magnetic resonance imaging (MRI), fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) computed tomography (CT), and nerve biopsy contributed to the diagnosis. Genomic profiling, programmed death ligand-1 (PD-L1) expression and tumor mutational burden (TMB) were also assessed. CDKN2A/CDKN2B deletions have been identified. PD-L1 expression assessed by 28-8 antibody was 1% positivity, and TMB of the sample was 11.6 muts/Mb. The patient responded well to rituximab combined with chemotherapy, however, he died after 3 cycles of chemotherapy due to severe lung infection and subsequent complication of respiratory failure. Here we report the clinical, radiological, pathological and molecular findings of the patient affected by multifocal neurolymphomatosis without systemic involvement of other organs.
    Keywords:  Neurolymphomatosis; case report; lymphoma; next generation sequencing (NGS); peripheral nerve
  4. J Clin Neurosci. 2021 Nov;pii: S0967-5868(21)00478-1. [Epub ahead of print]93 106-111
      BACKGROUND AND AIMS: Multinodular/plexiform schwannomas and neurofibromas of major nerves are rare: before surgery, differential diagnosis among these two uncommon variants is challenging. For both forms, surgical removal is recommended in case of progressive growth and worsening of neurological symptoms. Surgery has a higher risk of neurological damage than conventional schwannomas or neurofibromas. In literature, a comparison among these rare tumors is usually limited to the pathological aspect while specific surgical and clinical management indications are lacking. Cutaneous tumors of both forms arising from terminal peripheral nerves' branches might be treated by plastic surgeons while tumors of major nerves remain under neurosurgical competence. Here we report our recent neurosurgical experience on the matter, to furnish useful suggestions for the management of these tumors.METHOD: We analyzed the clinical, radiological, and pathological data in a consecutive case series of plexiform/multinodular nerve tumors operated at our institution in the last five years.
    RESULTS: In our series, neurofibroma type of plexiform tumors was more frequent than schwannoma type: two sporadic plexiform-multinodular schwannomas (patients 1, and 5) and three multinodular/plexiform Neurofibromatosis familial (Neurofibromatosis 1 / NF-1) (patients 2, 3, and 4). Surgery was complex when major nerves were involved. The early outcome appeared mostly related to the pre-surgical neurological conditions and histological grading.
    INTERPRETATION: Although sharing some features, multinodular-plexiform schwannomas and neurofibromas have consistent differences from the clinical, surgical and pathological points of view.
    Keywords:  Multinodular/plexiform tumors; Neurofibroma; Peripheral nerves; Schwannoma; Surgical removal
  5. Front Oncol. 2021 ;11 728583
      Background: Perineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.Methods: In our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.
    Results: We found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.
    Conclusion: Our results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.
    Keywords:  EMT - epithelial to mesenchymal transformation; Honokiol (CID: 72303); SMAD2/3; pancreatic cancer; perineural invasion (PNI)
  6. J Hepatobiliary Pancreat Sci. 2021 Oct 22.
      BACKGROUND: Distal Cholangiocarcinoma (DCC) is a malignancy associated with a short survival time. In this study, we aimed to create an online nomogram calculator to predict early recurrence and long-term survival in patients with DCC after pancreaticoduodenectomy.METHODS: A total of 486 patients with DCC were included. An online nomogram calculator was developed and validated in training, internal validation and external validation cohorts, respectively.
    RESULTS: Of the 486 patients who met the inclusion criteria, we allocated 240, 120 and 126 patients to the training, internal validation and external validation cohorts, respectively. Multivariable analysis showed that preoperative CA19-9, maximum tumor diameter, perineural invasion, and tumor differentiation were significant risk factors for early recurrence in patients with DCC. Incorporating these 4 factors, the nomogram achieved good AUC values of 0.788, 0.771 and 0.723 for predicting early recurrence in the training, internal validation and external validation cohorts, respectively. Notably, this nomogram also had good power to predict overall survival. The discrimination ability of the nomogram was evaluated by dividing the predicted probabilities of early recurrence and survival into two risk groups in the training cohort (Low risk ≤ 132; High risk >132; P < 0.001). Time-dependent ROC and decision curve analysis further revealed that the nomogram provided higher diagnostic capacity and superior net benefit compared to other staging systems.
    CONCLUSION: This study developed and validated a web-based nomogram calculator that was capable of predicting early recurrence and long-term prognosis in patients with DCC after pancreaticoduodenectomy with high degrees of stability and accuracy.
    Keywords:  Distal cholangiocarcinoma; Early recurrence; Long-term prognosis; Nomogram; Pancreaticoduodenectomy
  7. Cancer Treat Rev. 2021 Oct 11. pii: S0305-7372(21)00147-X. [Epub ahead of print]101 102299
      BACKGROUND: Gastroenteropancreatic neoplasms (GEP-NENs)can potentially be cured through surgical resection, but only 42-57% achieve 5-year disease-free survival.There is a lack of consensus regarding the factorsassociated withrelapse followingresection ofGEP-NENs.METHODS: Asystematic review identified studies reporting factors associated with relapse in patients with GEP-NENs following resection of a primary tumour. Meta-analysis was performed to identify the factors prognostic for relapse-free survival (RFS)oroverall survival (OS).
    RESULTS: 63 studies comprising 13,715 patients were included; 56 studies reported on pancreatic NENs (12,418 patients), 24 reported on patients with grade 1-2 tumours (4,735 patients). Median follow-up was 44.2 months, median RFS was 32 months. Pooling of multivariable analyses of GEP-NENs (all sites and grades) found the following factors predicted worse RFS (all p values < 0.05): vascular resection performed, metastatic disease resected, grade 2 disease, grade 3 disease, tumour size > 20 mm, R1 resection, microvascular invasion, perineural invasion, Ki-67 > 5% and any lymph node positivity. In a subgroup of studies comprising exclusively of grade 1-2 GEP-NENs, R1 resection, perineural invasion, grade 2 disease, any lymph node positivity and tumour size > 20 mm predicted worse RFS (all p values < 0.05). Few OSdata were available for pooling; in univariableanalysis(entire cohort), grade 2 predicted worse OS (p = 0.007), whileR1 resectiondid not (p = 0.14).
    CONCLUSIONS: The factors prognostic for worse RFS following resection of a GEP-NEN identified in this meta-analysis could be included in post-curative treatment surveillance clinical guidelines and inform the stratification and inclusion criteria of future adjuvant trials.
    Keywords:  Gastroenteropancreatic; Neuroendocrine neoplasms; Relapse; Resection; Survival
  8. Pract Radiat Oncol. 2021 Oct 17. pii: S1879-8500(21)00281-2. [Epub ahead of print]
      PURPOSE: To investigate the impact of excluding irradiation of inguinal lymph nodes (ILNs) and external iliac lymph nodes (ELNs) during neoadjuvant (chemo)radiotherapy in a locally advanced lower rectal cancer (LALRC) with anal sphincter invasion.MATERIALS AND METHODS: A total of 214 LALRC patients with anal sphincter invasion according to pre-treatment magnetic resonance imaging who underwent neoadjuvant (chemo)radiotherapy followed by surgery between September 2010 and May 2019 were enrolled. ILNs and ELNs were clinically negative pre-treatment and were excluded from irradiation. Failure rates and patterns of ILNs and ELNs and survival were analyzed. Nomograms for predicting ILN and ELN failure risk were also constructed.
    RESULTS: The median follow-up was 53.3 months. The three-year failure rates were 3.7% for ILNs and 3.3% for ELNs. Only one patient developed isolated ILN failure, and no patient experienced isolated ELN failure. Multivariate analyses demonstrated that lower edge of tumors invaded or located below the dentate line (odds ratio [OR] 7.513, P = 0.013), high histological grade (OR 6.892, P = 0.017), and perineural invasion (OR 7.111, P = 0.023) were significantly related to ILN failure. Both perineural invasion (OR 8.923, P = 0.011) and high histological grade (OR 8.129, P = 0.011) showed a strong correlation with ELN failure. The concordance index of nomograms for predicting ILN and ELN failure risk were 0.842 and 0.880, respectively. The three-year local recurrence free survival, disease-free survival, and overall survival were 94.6% (95% confidence interval [CI], 91.3%‒97.9%), 77.7% (95% CI, 71.8%‒83.6%), and 91.9% (95% CI, 87.8%‒96.0%), respectively, for the whole cohort.
    CONCLUSIONS: Excluding ILNs and ELNs from irradiation was associated with an acceptably low failure risk for LALRC invading the anal sphincter. These findings help to refine existing guidelines for clinical target volume delineation of ILNs and ELNs during neoadjuvant (chemo)radiotherapy in rectal cancer.
    Keywords:  Anal sphincter; External iliac lymph nodes; Inguinal lymph nodes; Locally advanced lower rectal cancer; Neoadjuvant (chemo)radiotherapy
  9. J Kidney Cancer VHL. 2021 ;8(3): 19-21
      Adenoid cystic carcinoma (ACC) is a rare malignant cancer that arises from secretory glands. Slow growth, perineural invasion, and late recurrences are the main characteristics of ACC. Only few cases of kidney metastases from ACC have been reported in the literature. We report here the case of a 66-year-old female patient who presented with bilateral renal metastases from ACC of the nasal cavity, detected 14 years after treatment of primary tumor and 6 years after metastasectomy of lung metastases. Histological examination confirmed diagnosis and the patient was treated with systemic chemotherapy. Radiological evaluation showed stability of the disease. However, a progression with occurrence of metastases in other sites (lung and bones) has been observed after 7 months. She is still receiving second-line chemotherapy. To the best of our knowledge, this is the second case of kidney metastases from ACC of the nasal cavity.
    Keywords:  adenoid cystic; carcinoma; kidney; nasal cavity; renal metastases
  10. Indian J Pathol Microbiol. 2021 Oct-Dec;64(4):64(4): 693-701
      Introduction: Pancreaticobiliary subtype of Periampullary carcinoma (PAC) has a poor prognosis in comparison to the intestinal subtype. We assessed the potential of cytokeratins and mucin markers to classify the sub-types of periampullary tumors and compared them with the survival data to identify markers that may predict prognosis.Methodology: PAC tumor tissues were obtained from 94 patients undergoing Whipples Pancreaticoduodenectomy. Paraffin-embedded tissues were immunostained with cytokeratins CK7, CK20), mucins (MUC1, MUC2, MUC5Ac), and CDX2 antibodies. The survival status of patients was obtained as follow-up up to 5-years of surgery. The Receiver Operating Character Curve (ROC) analysis was used for detecting sensitivity and specificity. The survival data were analyzed using the Kaplan-Meier survival curve.
    Results: Tumors were initially categorized on the basis of histological classification as pancreaticobiliary (n = 46), intestinal (n = 35) and indeterminate (n = 13). Further, using immunohistochemical markers (MUC1, CK20, and CDX2), we gave systematic classification of IHC-PB (n = 51), IHC-Int (n = 30) and IHC-Mixed (n = 13). The interobserver analysis showed good agreement between histologic and IHC type with a kappa value of 0.554. Combined expression of CK20, MUC1 and CDX2 accurately classify the mixed type of tumor. Overall survival rate and duration were 74.4% and 44.95 ± 2.29 months. Survival analysis for subtypes reveal, pancreaticobiliary tumors have low survival (27.9 ± 1.63 months) than mixed type (35.5 ± 0.45 months) and intestinal-type (52.92 ± 2.18 months). Among these, intestinal-type have better survival. Only TNM Stage III (tumor staging as per American Joint Committee on Cancer classification) and perineural invasion have been associated with predicting poor survival in PAC patients.
    Conclusion: Our results suggest that the combined expression of MUC1, CK20 and CDX2 could serve as markers to diagnose histological inconclusive specimens as mixed subtype tumors.
    Keywords:  Immunohistochemistry; intestinal type; mixed type; pancreaticobiliary type; periampullary cancer
  11. Turk Neurosurg. 2021 Apr 17.
      AIM: Schwannomas are the most common benign tumors of the peripheral nerve. Surgery is indicated in patients with progressively increasing tumor volume, pain, paresthesia, and progressively worsening neurological deficits.CASE DESCRIPTION: This article presents the case of a 32-year-old female patient with schwannoma. The patient had swelling on the anterior aspect of her right foot for a year. Her pain increased over the past 2 months, and a positive Tinel sign was present over the swelling. Magnetic resonance imaging revealed a large schwannoma mass in the deep peroneal nerve. The patient's large schwannoma was completely excised along with its capsule.
    CONCLUSION: Schwannomas are benign tumors of the peripheral nerves that rarely exhibit malignant transformation. Treatment is considered to be curative if complete resection is achieved.