bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒02‒27
fourteen papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2112840119. [Epub ahead of print]119(9):
      Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.
    Keywords:  adipose tissue; browning; cancer cachexia; immunometabolism; macrophage
  2. Brain Behav Immun Health. 2022 May;21 100428
      Disruption of circadian rhythms occurs in rotating shift-work, jetlag, and in individuals with irregular sleep schedules. Circadian disruption is known to alter inflammatory responses and impair immune function. However, there is limited understanding of how circadian disruption modulates cancer-induced inflammation. Inflammation is a hallmark of cancer and is linked to worse prognosis and impaired brain function in cancer patients. Here, we investigated the effect of circadian disruption on cancer-induced inflammation in an orthotopic breast cancer model. Using a validated chronic jetlag protocol that advances the light-cycle by 8 ​h every 2 days to disrupt circadian rhythms, we found that circadian disruption alters cancer-induced inflammation in a tissue-specific manner, increasing inflammation in the body and brain while decreasing inflammation within the tumor tissue. Circadian disruption did not affect inflammation in mice without tumors, suggesting that the impact of circadian disruption may be particularly detrimental in the context of underlying inflammatory conditions, such as cancer. Importantly, circadian disruption did not affect tumor burden, suggesting that increased inflammation was not a result of increased cancer progression. Overall, these findings identify the importance of healthy circadian rhythms for limiting cancer-induced inflammation.
    Keywords:  4T1 breast Cancer; Chronic jetlag; Circadian rhythms; Clock genes; Cytokines; Metastasis; Neuroinflammation
  3. J Biochem. 2022 Feb 22. pii: mvac017. [Epub ahead of print]
      There is growing evidence that disruption of our 24-hour clock increases our risk for acquiring several diseases and disorders. One of these diseases is cancer. While the mechanistic links between circadian clock disruption and cancer initiation or progression are an active area of study, significantly more work needs to be done to understand the molecular substrates involved. Of particular complexity remains the functions of the clock in individual cells during the process of transformation (cancer initiation) vs. the functions of the clock in tumor-surrounding stroma in the process of tumor progression or metastasis. Indeed, the nexus of cellular circadian dynamics, metabolism, and carcinogenesis is drawing more attention, and many new studies are now highlighting the critical role of circadian rhythms and clock proteins in cancer prevention. In this brief review, we cover some of the basic mechanisms reported to link circadian disruption and cancer at the level of gene expression and metabolism. We also review some of the human studies addressing circadian disruption and cancer incidence as well as some controlled laboratory studies connecting the two in pre-clinical models. Finally, we discuss the tremendous opportunity to use circadian approaches for future prevention and treatment in the context of cancer in specific organs.
  4. J Oncol. 2022 ;2022 1058667
      The tumor microenvironment (TME), which is composed of various cell components and signaling molecules, plays an important role in the occurrence and progression of tumors and has become the central issue of current cancer research. In recent years, as a part of the TME, the peripheral nervous system (PNS) has attracted increasing attention. Moreover, emerging evidence shows that Schwann cells (SCs), which are the most important glial cells in the PNS, are not simply spectators in the TME. In this review article, we focused on the up-to-date research progress on SCs in the TME and introduced our point of view. In detail, we described that under two main tumor-nerve interaction patterns, perineural invasion (PNI) and tumor innervation, SCs were reprogrammed and acted as important participants. We also investigated the newest mechanisms between the interactions of SCs and tumor cells. In addition, SCs can have profound impacts on other cellular components in the TME, such as immune cells and cancer-associated fibroblasts (CAFs), involving immune regulation, tumor-related pain, and nerve remodeling. Overall, these innovative statements can expand the scope of the TME, help fully understand the significant role of SCs in the tumor-nerve-immune axis, and propose enlightenments to innovate antitumor therapeutic methods and future research.
  5. Neurol Sci. 2022 Feb 23.
      Though metastasis and malignant infiltration of the peripheral nervous system is relatively rare, physicians should have a familiarity with their presentations to allow for prompt diagnosis and initiation of treatment. This article will review the clinical presentations, diagnostic evaluation, and treatment of neoplastic involvement of the cranial nerves, nerve roots, peripheral nerves, and muscle. Due to the proximity of the neural structure traversing the skull base, metastasis to this region results in distinctive syndromes, most often associated with breast, lung, and prostate cancer. Metastatic involvement of the nerve roots is uncommon, apart from leptomeningeal carcinomatosis and bony metastasis with resultant nerve root damage, and is characterized by significant pain, weakness, and numbness of an extremity. Neoplasms may metastasize or infiltrate the brachial and lumbosacral plexuses resulting in progressive and painful sensory and motor deficits. Differentiating neoplastic involvement from radiation-induced injury is of paramount importance as it dictates treatment and prognosis. Neurolymphomatosis, due to malignant lymphocytic infiltration of the cranial nerves, nerve roots, plexuses, and peripheral nerves, deserves special attention given its myriad presentations, often mimicking acquired demyelinating neuropathies.
    Keywords:  Cauda equina; Metastasis; Neurolymphomatosis; Plexopathy; Skull base
  6. Dis Colon Rectum. 2022 Feb 21.
      BACKGROUND: The diagnostic implications of lymphatic invasion, venous invasion, perineural invasion, and tumor budding in rectal cancer treated with neoadjuvant chemoradiotherapy are unknown.OBJECTIVE: This study was designed to identify the prognostic impact of lymphatic invasion, venous invasion, perineural invasion, and tumor budding in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.
    DESIGN: This study was a retrospective cohort study.
    SETTINGS: This study was conducted at the Samsung Medical Center. Grouping was performed based on lymphatic invasion, venous invasion, perineural invasion, and tumor budding status: no-risk group with 0 factors (n = 299), low-risk group with any 1 factor (n = 131), intermediate-risk group with any 2 factors (n = 75), and a high-risk group with 3 or 4 risk factors (n = 32).
    PATIENTS: A total of 537 patients who underwent neoadjuvant chemoradiotherapy, followed by radical operation for locally advanced rectal cancer from January 2010 to December 2015 were included.
    MAIN OUTCOME MEASURES: The main outcome measures were disease-free survival and overall survival.
    RESULTS: The median follow-up period was 77 months, and the 5-year disease-free survival and the 5-year overall survival varied significantly between the groups in stage III (p < 0.001, p < 0.001). The 5-year disease-free survival in stage I differed between the no-risk group and the intermediate-risk group (p=0.026). In stage II, the 5-year disease-free survival and 5-year overall survival differed between the no-risk group and intermediate-risk group p = 0.010, p = 0.045). In multivariable analysis, risk grouping was an independent prognostic factor for both disease-free survival (p < 0.001) and overall survival (p < 0.001).
    LIMITATION: The inherent limitations are associated with the retrospective single center study design.
    CONCLUSION: Lymphatic invasion, venous invasion, perineural invasion, and tumor budding are strong prognostic factors for disease-free survival and overall survival in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Therefore, adjuvant chemotherapy is strongly recommended in patients with positive lymphatic invasion, venous invasion, perineural invasion, and tumor budding. See Video Abstract at
  7. Abdom Radiol (NY). 2022 Feb 26.
      PURPOSE: Perineural invasion (PNI) has been recognized as an important prognosis factor in patients with colorectal cancer (CRC). The purpose of this retrospective study was to investigate the value of 18F-FDG PET/CT-based radiomics integrating clinical information, PET/CT features, and metabolic parameters for preoperatively predicting PNI and outcome in non-metastatic CRC and establish an easy-to-use nomogram.METHODS: A total of 131 patients with non-metastatic CRC who undergo PET/CT scan were retrospectively enrolled. Univariate analysis was used to compare the differences between PNI-present and PNI-absent groups. Multivariate logistic regression was performed to select the independent predictors for PNI status. Akaike information criterion (AIC) was used to select the best prediction models for PNI status. CT radiomics signatures (RSs) and PET-RSs were selected by maximum relevance minimum redundancy (mRMR) and the least absolute shrinkage and selection operator algorithm (LASSO) regression and radiomics scores (Rad-scores) were calculated for each patient. The prediction models with or without Rad-score were established. According to the nomogram, nomogram scores (Nomo-scores) were calculated for each patient. The performance of different models was assessed with the area under the curve (AUC), specificity, and sensitivity. The clinical usefulness was assessed by decision curve (DCA). Multivariate Cox regression was used to selected independent predictors of progression-free survival (PFS).
    RESULTS: Among all the clinical information, PET/CT features, and metabolic parameters, CEA, lymph node metastatic on PET/CT (N stage), and total lesion glycolysis (TLG) were independent predictors for PNI (p < 0.05). Six CT-RSs and 12 PET-RSs were selected as the most valuable factors to predict PNI. The Rad-score calculated with these RSs was significantly different between PNI-present and PNI-absent groups (p < 0.001). The AUC of the constructed model was 0.90 (95%CI: 0.83-0.97) in the training cohort and 0.80 (95%CI: 0.65-0.95) in the test cohort. The nomogram's predicting sensitivity was 0.84 and the specificity was 0.83 in the training cohort. The clinical model's predicting sensitivity and specificity were 0.66 and 0.85 in the training cohort, respectively. Besides, DCA showed that patients with non-metastatic CRC could get more benefit with our model. The results also indicated that N stage, PNI status, and the Nomo-score were independent predictors of PFS in patients with non-metastatic CRC.
    CONCLUSION: The nomogram, integrating clinical data, PET/CT features, metabolic parameters, and radiomics, performs well in predicting PNI status and is associated with the outcome in patients with non-metastatic CRC.
    Keywords:  Colorectal cancer; Perineural invasion; Positron emission tomography/Computed tomography; Radiomics
  8. Front Oncol. 2022 ;12 809931
      Background: Lymph node metastasis is one of the most important factors affecting the prognosis of gastric cancer patients. The purpose of this study is to develop a new scoring system to predict lymph node metastasis in gastric cancer using preoperative tests in various combinations of inflammatory factors and to assess the predictive prognosis value of the new scoring system for the postoperative gastric cancer patients.Method: This study includes 380 gastric cancer patients, 307 in the training set and 73 in the validation set. We obtain three inflammatory markers, CRA (C-reactive protein/albumin), SIRI (systemic inflammatory response index), and PLR (platelets/lymphocytes), by calculating and comparing the results of preoperative laboratory tests. By using these three indicators, a new scoring system is developed to predict lymph node metastases, assess patients' prognoses, and compare clinicopathological characteristics in different patient subgroups. A nomogram is constructed to show and assess the predictive efficacy of every index for lymph node metastasis and survival.
    Results: In the new scoring system, higher scores are associated with more advanced pathological stage (p < 0.001), perineural invasion (p < 0.001), and vascular invasion (p = 0.001). Univariate and multivariable Cox regression analyses show that perineural invasion, vascular invasion, smoking history, and high scores on the new scoring system are significant risk factors for OS and RFS. High-scoring subgroups as an independent prognostic factor could predict overall survival (OS) and relapse-free survival (RFS). High scores on the new scoring system are significantly associated with the degree of lymph node metastasis (p < 0.001). CAR and PLR play very important roles in predicting lymph node metastasis in gastric cancer. CAR is a vital major marker in the prediction of patient survival.
    Conclusions: The new scoring system can effectively predict the patients' lymph node metastasis with gastric cancer and can independently predict the prognosis of patients.
    Keywords:  gastric cancer; lymph node metastasis; new scoring system; prognosis; surgery
  9. Front Oncol. 2022 ;12 839621
      Objectives: This study aims to develop and evaluate multiparametric MRI (MP-MRI)-based radiomic models as a noninvasive diagnostic method to predict several biological characteristics of prostate cancer.Methods: A total of 252 patients were retrospectively included who underwent radical prostatectomy and MP-MRI examinations. The prediction characteristics of this study were as follows: Ki67, S100, extracapsular extension (ECE), perineural invasion (PNI), and surgical margin (SM). Patients were divided into training cohorts and validation cohorts in the ratio of 4:1 for each group. After lesion segmentation manually, radiomic features were extracted from MP-MRI images and some clinical factors were also included. Max relevance min redundancy (mRMR) and recursive feature elimination (RFE) based on random forest (RF) were adopted to select features. Six classifiers were included (SVM, KNN, RF, decision tree, logistic regression, XGBOOST) to find the best diagnostic performance among them. The diagnostic efficiency of the construction models was evaluated by ROC curves and quantified by AUC.
    Results: RF performed best among the six classifiers for the four groups according to AUC values (Ki67 = 0.87, S100 = 0.80, ECE = 0.85, PNI = 0.82). The performance of SVM was relatively the best for SM (AUC = 0.77). The number and importance of DCE features ranked first in the models of each group. The combined models of MP-MRI and clinical characteristics showed no significant difference compared with MP-MRI models according to Delong's tests.
    Conclusions: Radiomics models based on MP-MRI have the potential to predict biological characteristics and are expected to be a noninvasive method to evaluate the risk stratification of prostate cancer.
    Keywords:  biological characteristics; magnetic resonance imaging; prostate cancer; radiomics; risk stratification
  10. J Am Coll Surg. 2022 Jan 01. 234(1): 48-53
      BACKGROUND: We hypothesized that pancreatic and periampullary adenocarcinoma recurrence after surgical resection may be affected by the shedding of malignant epithelial cells during surgical dissection and that this may have implications for disease recurrence and survival.STUDY DESIGN: In this ongoing, investigator-initiated prospective randomized controlled trial, patients with pancreatic and periampullary adenocarcinoma were randomized intraoperatively, postresection into 3 study arms: peritoneal lavage using 10 L normal saline or distilled water, or control group with no lavage. Peritoneal fluid was sampled for cytologic analysis (cytospin, cellblock, immunohistochemistry-Ber-EP4 antibody) at 4 stages: (1) abdominal entry pre-dissection, (2) resection bed after tumor extirpation, (3) ex vivo resected specimen, and (4) resection bed postlavage.
    RESULTS: Between April 2016 and May 2018, 193 patients who underwent randomization for the study also underwent the described cytologic sampling. Of these, 167 patients (86.5%) were ultimately found to have pancreatic or periampullary adenocarcinoma. Before dissection (1) on cytospin analysis, 4.9% were positive, which rose to 10.2% intraoperatively (2), 16.7% ex vivo (3), and decreased to 4.3% (4) after lavage. Lymph node metastasis, margin involvement, and perineural invasion did not correlate with locoregional recurrence (LR). Tumor cells in the ex vivo cytospin (3) correlated with LR (odds ratio 3.8 [95% CI 1.6 to 9.2], p = 0.005) and LR disease-free survival (p = 0.007). Cox regression analysis revealed ex vivo cytospin positivity to be strongly associated with poorer LR disease-free survival (hazard ratio 2.26 [95% CI 1.16 to 4.42], p = 0.017).
    CONCLUSIONS: Cytologic sampling from ex vivo specimen irrigation after surgical resection of pancreatic and periampullary adenocarcinoma may have implications for LR, survival, and treatment, suggesting a possible cancer cell shedding phenotype.
  11. J Cancer Res Clin Oncol. 2022 Feb 23.
      PURPOSE: Angiopoietin-like 4 (ANGPTL4) was recently shown to be associated with cancer progression but little is known about its contribution to cancer metabolism. The purpose of this study was to elucidate the role of ANGPTL4 in glucose metabolism in colorectal cancer (CRC).METHODS: Immunohistochemical staining of CRC specimens classified 84 patients into two groups according to ANGPTL4 expression. Clinicopathological characteristics, gene mutation status obtained by next-generation sequencing, and fluorodeoxyglucose (FDG) uptake measured by positron emission tomography/computed tomography (PET/CT) were compared between the two groups. Furthermore, the impact of ANGPTL4 expression on cancer metabolism was investigated by a subcutaneous xenograft mouse model using the ANGPTL4 knockout CRC cell line, and glucose transporter (GLUT) expression was evaluated.
    RESULTS: There were significantly more cases of T3/4 tumours (94.3% vs. 57.1%, P < 0.001) and perineural invasion (42.9% vs. 22.4%, P = 0.046) in the ANGPTL4-high group than in the low group. Genetic exploration revealed a higher frequency of KRAS mutation (54.3% vs. 22.4%, P = 0.003) in the ANGPTL4-high tumours. All the FDG uptake parameters were significantly higher in ANGPTL4-high tumours. In vivo analysis showed a significant reduction in tumour size due to ANGPTL4 knockout with lower expression of GLUT1 and GLUT3, and suppression of AKT phosphorylation.
    CONCLUSION: ANGPTL4 regulates the expression of GLUTs by activating the PI3K-AKT pathway and thereby promoting glucose metabolism in CRC. These findings establish a new functional role of ANGPTL4 in cancer progression and lay the foundation for developing a novel therapeutic target.
    Keywords:  Angiopoietin-like 4; Cancer progression; Colorectal cancer; Glucose metabolism; KRAS mutation
  12. J Neurosurg. 2022 Feb 25. pii: 2021.12.JNS211882. [Epub ahead of print] 1-10
      OBJECTIVE: Perineural spread of breast cancer to the brachial plexus can lead to pain, sensory alterations, and upper-extremity weakness. Although rare, perineural spread is an often-misdiagnosed long-term complication following breast cancer diagnosis. The objective of this study was to critically review the clinical, radiological, and pathological findings of biopsy-proven perineural spread of breast cancer to the brachial plexus.METHODS: This is a retrospective study from a single institution in which a total of 19 patients with brachial plexus involvement from perineural spread of breast cancer who underwent fascicular biopsy between 1999 and 2021 were identified. Clinical, radiographic, and pathological data were retrospectively collected. Descriptive statistics were calculated for the cohort.
    RESULTS: The mean age of patients at the time of diagnosis of breast cancer perineural spread was 60.6 ± 11.5 years. The diagnosis of brachial plexopathy due to perineural spread was on average 12 years after the primary diagnosis of breast cancer. There was also a delay in diagnosis due to the rarity of this disease, with a mean time from initial symptom onset to diagnosis of perineural spread of 25 ± 30 months. All patients at the time of presentation had upper-extremity weakness and pain. Nearly all patients demonstrated T2 signal change and nodular so-called sugar-coating contrast enhancement on brachial plexus MRI. Similarly, all patients who underwent PET/MRI or PET/CT had increased FDG uptake in the involved brachial plexus. Breast cancer perineural spread has an overall poor prognosis, with 16 of 19 patients dying within 5.9 ± 3.0 years after diagnosis of perineural spread.
    CONCLUSIONS: Perineural spread should be considered in patients with a history of breast cancer, even 10 years after primary diagnosis, especially in patients who present with arm pain, weakness, and/or sensory changes. Further diagnostic workup with electrodiagnostic studies; brachial plexus MRI, PET/CT, or PET/MRI; and possibly nerve biopsy is warranted to ensure accurate diagnosis.
    Keywords:  brachial plexopathy; breast cancer; oncology; perineural spread; peripheral nerve
  13. Biomed Res Int. 2022 ;2022 2204745
      Introduction: The concept of selective neck dissection (SND) in locally advanced oral cancers is emerging. Contemporary studies support the feasibility of SND in selected node-positive oral cancers with early primaries. Nevertheless, the suitability of SND in clinically node-positive (cN+) oral cancers with advanced primaries (T3/T4) is unknown.Aim: This study explores if patients with cN+ advanced primaries were suitable candidates for SND by spotting the involved lymph node distribution in various stations of the neck. Secondary objectives were to check if predictive clinicopathological factors for metastases to the neck in general also apply for lymph node metastases to levels IV and V.
    Methods: The present retrospective study analysed the distribution of pathologically involved lymph nodes in 134 patients and explored the interrelation of various predictive factors and cervical metastases overall and those specific to levels IV and V.
    Results: Level V was involved in 6.7% (6/83) of T4 and none of the T3 primaries. Depth of invasion (DOI), perineural invasion (PNI), and skin invasion were statistically significant predictors for nodal metastases in general on multivariate analysis.
    Conclusion: Our analysis supports the option of considering SND, sparing level V in patients with cN+ oral cancers in a subset with T3 primary and nodal stage N2 and below.
  14. Biomedicines. 2022 Feb 01. pii: 340. [Epub ahead of print]10(2):
      BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Risk prediction for tumor recurrence is important for making effective treatment decisions and for the survival outcomes of patients with CRC after surgery. Herein, we aimed to explore a prediction algorithm and the risk factors for postoperative tumor recurrence using a machine learning (ML) approach with standardized pathology reports for patients with stage II and III CRC.METHODS: Pertinent clinicopathological features were compiled from medical records and standardized pathology reports of patients with stage II and III CRC. Four ML models based on logistic regression (LR), random forest (RF), classification and regression decision trees (CARTs), and support vector machine (SVM) were applied for the development of the prediction algorithm. The area under the curve (AUC) of the ML models was determined in order to compare the prediction accuracy. Genomic studies were performed using a panel-targeted next-generation sequencing approach.
    RESULTS: A total of 1073 patients who received curative intent surgery at the National Cheng Kung University Hospital between January 2004 and January 2019 were included. Based on conventional statistical methods, chemotherapy (p = 0.003), endophytic tumor configuration (p = 0.008), TNM stage III disease (p < 0.001), pT4 (p < 0.001), pN2 (p < 0.001), increased numbers of lymph node metastases (p < 0.001), higher lymph node ratios (LNR) (p < 0.001), lymphovascular invasion (p < 0.001), perineural invasion (p < 0.001), tumor budding (p = 0.004), and neoadjuvant chemoradiotherapy (p = 0.025) were found to be correlated with the tumor recurrence of patients with stage II-III CRC. While comparing the performance of different ML models for predicting cancer recurrence, the AUCs for LR, RF, CART, and SVM were found to be 0.678, 0.639, 0.593, and 0.581, respectively. The LR model had a better accuracy value of 0.87 and a specificity value of 1 in the testing set. Two prognostic factors, age and LNR, were selected by multivariable analysis and the four ML models. In terms of age, older patients received fewer cycles of chemotherapy and radiotherapy (p < 0.001). Right-sided colon tumors (p = 0.002), larger tumor sizes (p = 0.008) and tumor volumes (p = 0.049), TNM stage II disease (p < 0.001), and advanced pT3-4 stage diseases (p = 0.04) were found to be correlated with the older age of patients. However, pN2 diseases (p = 0.005), lymph node metastasis number (p = 0.001), LNR (p = 0.004), perineural invasion (p = 0.018), and overall survival rate (p < 0.001) were found to be decreased in older patients. Furthermore, PIK3CA and DNMT3A mutations (p = 0.032 and 0.039, respectively) were more frequently found in older patients with stage II-III CRC compared to their younger counterparts.
    CONCLUSIONS: This study demonstrated that ML models have a comparable predictive power for determining cancer recurrence in patients with stage II-III CRC after surgery. Advanced age and high LNR were significant risk factors for cancer recurrence, as determined by ML algorithms and multivariable analyses. Distinctive genomic profiles may contribute to discrete clinical behaviors and survival outcomes between patients of different age groups. Studies incorporating complete molecular and genomic profiles in cancer prediction models are beneficial for patients with stage II-III CRC.
    Keywords:  age; cancer recurrence; colorectal cancer; lymph node ratio; machine learning model