Special Issue:
Challenges and Opportunities in Glioblastoma
Gang Zhou
1. Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro-oncology 2013; 15 Suppl 2: ii1-56. Doi: 10.1093/neuonc/not151. 2. Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014; 23: 1985-1996. DOI: 10.1158/1055-9965.EPI-14-0275. 3. Korja M, Raj R, Seppa K, et al. Glioblastoma survival is improving despite increasing incidence rates: a nationwide study between 2000 and 2013 in Finland. Neuro-oncology 2019; 21: 370-379. Doi: 10.1093/neuonc/noy164. 4. Miranda-Filho A, Pineros M, Soerjomataram I, et al. Cancers of the brain and CNS: global patterns and trends in incidence. Neuro-oncology 2017; 19: 270-280. Doi: 1093/neuonc/now166. 5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 2005; 352: 987-996. Doi: 10.1056/NEJMoa043330. 6. Visser O, Ardanaz E, Botta L, et al. Survival of adults with primary malignant brain tumours in Europe; Results of the EUROCARE-5 study. European journal of cancer 2015; 51: 2231-2241. DOI: 10.1016/j.ejca.2015.07.032. 7. Davis L. Spongioblastoma Multiforme of the Brain. Ann Surg 1928; 87: 8-14. 8. Pasquier B, Pasquier D, N’Golet A, et al. Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer 1980; 45: 112-125. 9. Anzil AP. Glioblastoma multiforme with extracranial metastases in the absence of previous craniotomy. Case report. Journal of neurosurgery 1970; 33: 88-94. Doi: 10.3171/jns.1970.33.1.0088. 10. Anghileri E, Castiglione M, Nunziata R, et al. Extraneural metastases in glioblastoma patients: two cases with YKL-40-positive glioblastomas and a meta-analysis of the literature. Neurosurgical review 2016; 39: 37-45; discussion 45-36. Doi: 10.1007/s10143-015-0656-9. 11. Schweitzer T, Vince GH, Herbold C, et al. Extraneural metastases of primary brain tumors. Journal of neuro-oncology 2001; 53: 107-114. DOI: 10.1023/a:1012245115209. 12. Hoffman HJ and Duffner PK. Extraneural metastases of central nervous system tumors. Cancer 1985; 56: 1778-1782. DOI: 10.1002/1097-0142(19851001)56:7+<1778::aid-cncr2820561309>3.0.co;2-i. 13. Figueroa P, Lupton JR, Remington T, et al. Cutaneous metastasis from an intracranial glioblastoma multiforme. Journal of the American Academy of Dermatology 2002; 46: 297-300. DOI: 10.1067/mjd.2002.104966. 14. Lun M, Lok E, Gautam S, et al. The natural history of extracranial metastasis from glioblastoma multiforme. Journal of neuro-oncology 2011; 105: 261-273. DOI: 10.1007/s11060-011-0575-8. 15. Han SR, Yoon SW, Yee GT, et al. Extraneural metastases of anaplastic oligodendroglioma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2008; 15: 946-949. Doi: 10.1016/j.jocn.2006.09.013. 16. Piccirilli M, Brunetto GM, Rocchi G, et al. Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature. Tumori 2008; 94: 40-51. Doi: 10.1177/030089160809400109. 17. Romero-Rojas AE, Diaz-Perez JA, Amaro D, et al. Glioblastoma metastasis to parotid gland and neck lymph nodes: fine-needle aspiration cytology with histopathologic correlation. Head and neck pathology 2013; 7: 409-415. Doi: 10.1007/s12105-013-0448-x. 18. Huang P, Allam A, Taghian A, et al. Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. Journal of neurosurgery 1995; 83: 308-315. Doi: 10.3171/jns.1995.83.2.0308. 19. Zustovich F, Della Puppa A, Scienza R, et al. Metastatic oligodendrogliomas: a review of the literature and case report. Acta neurochirurgica 2008; 150: 699-702; discussion 702-693. DOI: 10.1007/s00701-008-1507-z. 20. Tuettenberg J, Grobholz R, Korn T, et al. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. Journal of cancer research and clinical oncology 2005; 131: 31-40. Doi: 10.1007/s00432-004-0620-5. 21. Taha M, Ahmad A, Wharton S, et al. Extra-cranial metastasis of glioblastoma multiforme presenting as acute parotitis. British journal of neurosurgery 2005; 19: 348-351. DOI: 10.1080/02688690500305506. 22. Kraft M, Lang F, Braunschweig R, et al. Parotid gland metastasis from glioblastoma multiforme: a case report and review of the literature. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies 2008; 265: 709-711. DOI: 10.1007/s00405-007-0499-2. 23. Frank S, Kuhn SA, Brodhun M, et al. Metastatic glioblastoma cells use common pathways via blood and lymphatic vessels. Neurologia i neurochirurgia polska 2009; 43: 183-190. 24. Mentrikoski M, Johnson MD, Korones DN, et al. Glioblastoma multiforme in skin: a report of 2 cases and review of the literature. The American Journal of dermatopathology 2008; 30: 381-384. Doi: 10.1097/DAD.0b013e31817532c4. 25. Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma. Journal of neuro-oncology 2006; 77: 207-212. DOI: 10.1007/s11060-005-9029-5. 26. Nager GT. Gliomas involving the temporal bone clinical and pathological aspects. The Laryngoscope 1967; 77: 454-488. Doi: 10.1288/lary.1967.000770403. 27. M T, Stephenson, Corinne, Y, Shan, Bui, Marilyn. Cytological Diagnosis of Extracranial Extension of Glioblastoma to Scalp. ASCP Case Reports 2013; 41: 13140. DOI: 2.1.3466.3041. 28. McGovern PC, Lautenbach E, Brennan PJ, et al. Risk factors for postcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)-1-nitrosourea (Gliadel) wafer placement. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003; 36: 759-765. Doi: 10.1086/368082. 29. Shi M and Sanche L. Convection-Enhanced Delivery in Malignant Gliomas: A Review of Toxicity and Efficacy. Journal of oncology 2019; 2019: 9342796. Doi: 10.1155/2019/9342796. 30. Duffy PE, Graf L and Rapport MM. Identification of glial fibrillary acidic protein by the immunoperoxidase method in human brain tumors. Journal of neuropathology and experimental neurology 1977; 36: 645-652. Doi: 10.1097/00005072-197707000-00001. 31. Stoyanov GS, Petkova L, Iliev B, et al. Extracranial Glioblastoma Metastasis: A Neuropathological Case Report. Cureus 2023; 15: e35803. Doi: 10.7759/cureus.35803. 32. Ogungbo BI, Perry RH, Bozzino J, et al. Report of GBM metastasis to the parotid gland. Journal of neuro-oncology 2005; 74: 337-338. DOI: 10.1007/s11060-005-1480-9. 33. Alhoulaiby S, Abdulrahman A, Alouni G, et al. Extra-CNS metastasis of glioblastoma multiforme to cervical lymph nodes and parotid gland: A case report. Clinical case reports 2020; 8: 1672-1677. Doi: 10.1002/ccr3.2985. 34. Swinnen J, Gelin G, Fransis S, et al. Glioblastoma with extracranial parotid, lymph node, and pulmonary metastases: a case report. Radiology case reports 2019; 14: 1334-1347. Doi: 10.1016/j.radcr.2019.08.011. 35. Schwock J, Mirham L and Ghorab Z. Cytology of Extraneural Metastases of Nonhematolymphoid Primary Central Nervous System Tumors: Six Cases with Histopathological Correlation and Literature Update. Acta cytologica 2021; 65: 529-540. Doi: 10.1159/000517480.
Tao L Wan
1. Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro-oncology 2013; 15 Suppl 2: ii1-56. Doi: 10.1093/neuonc/not151. 2. Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2014; 23: 1985-1996. DOI: 10.1158/1055-9965.EPI-14-0275. 3. Korja M, Raj R, Seppa K, et al. Glioblastoma survival is improving despite increasing incidence rates: a nationwide study between 2000 and 2013 in Finland. Neuro-oncology 2019; 21: 370-379. Doi: 10.1093/neuonc/noy164. 4. Miranda-Filho A, Pineros M, Soerjomataram I, et al. Cancers of the brain and CNS: global patterns and trends in incidence. Neuro-oncology 2017; 19: 270-280. Doi: 1093/neuonc/now166. 5. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 2005; 352: 987-996. Doi: 10.1056/NEJMoa043330. 6. Visser O, Ardanaz E, Botta L, et al. Survival of adults with primary malignant brain tumours in Europe; Results of the EUROCARE-5 study. European journal of cancer 2015; 51: 2231-2241. DOI: 10.1016/j.ejca.2015.07.032. 7. Davis L. Spongioblastoma Multiforme of the Brain. Ann Surg 1928; 87: 8-14. 8. Pasquier B, Pasquier D, N’Golet A, et al. Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer 1980; 45: 112-125. 9. Anzil AP. Glioblastoma multiforme with extracranial metastases in the absence of previous craniotomy. Case report. Journal of neurosurgery 1970; 33: 88-94. Doi: 10.3171/jns.1970.33.1.0088. 10. Anghileri E, Castiglione M, Nunziata R, et al. Extraneural metastases in glioblastoma patients: two cases with YKL-40-positive glioblastomas and a meta-analysis of the literature. Neurosurgical review 2016; 39: 37-45; discussion 45-36. Doi: 10.1007/s10143-015-0656-9. 11. Schweitzer T, Vince GH, Herbold C, et al. Extraneural metastases of primary brain tumors. Journal of neuro-oncology 2001; 53: 107-114. DOI: 10.1023/a:1012245115209. 12. Hoffman HJ and Duffner PK. Extraneural metastases of central nervous system tumors. Cancer 1985; 56: 1778-1782. DOI: 10.1002/1097-0142(19851001)56:7+<1778::aid-cncr2820561309>3.0.co;2-i. 13. Figueroa P, Lupton JR, Remington T, et al. Cutaneous metastasis from an intracranial glioblastoma multiforme. Journal of the American Academy of Dermatology 2002; 46: 297-300. DOI: 10.1067/mjd.2002.104966. 14. Lun M, Lok E, Gautam S, et al. The natural history of extracranial metastasis from glioblastoma multiforme. Journal of neuro-oncology 2011; 105: 261-273. DOI: 10.1007/s11060-011-0575-8. 15. Han SR, Yoon SW, Yee GT, et al. Extraneural metastases of anaplastic oligodendroglioma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2008; 15: 946-949. Doi: 10.1016/j.jocn.2006.09.013. 16. Piccirilli M, Brunetto GM, Rocchi G, et al. Extra central nervous system metastases from cerebral glioblastoma multiforme in elderly patients. Clinico-pathological remarks on our series of seven cases and critical review of the literature. Tumori 2008; 94: 40-51. Doi: 10.1177/030089160809400109. 17. Romero-Rojas AE, Diaz-Perez JA, Amaro D, et al. Glioblastoma metastasis to parotid gland and neck lymph nodes: fine-needle aspiration cytology with histopathologic correlation. Head and neck pathology 2013; 7: 409-415. Doi: 10.1007/s12105-013-0448-x. 18. Huang P, Allam A, Taghian A, et al. Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice. Journal of neurosurgery 1995; 83: 308-315. Doi: 10.3171/jns.1995.83.2.0308. 19. Zustovich F, Della Puppa A, Scienza R, et al. Metastatic oligodendrogliomas: a review of the literature and case report. Acta neurochirurgica 2008; 150: 699-702; discussion 702-693. DOI: 10.1007/s00701-008-1507-z. 20. Tuettenberg J, Grobholz R, Korn T, et al. Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. Journal of cancer research and clinical oncology 2005; 131: 31-40. Doi: 10.1007/s00432-004-0620-5. 21. Taha M, Ahmad A, Wharton S, et al. Extra-cranial metastasis of glioblastoma multiforme presenting as acute parotitis. British journal of neurosurgery 2005; 19: 348-351. DOI: 10.1080/02688690500305506. 22. Kraft M, Lang F, Braunschweig R, et al. Parotid gland metastasis from glioblastoma multiforme: a case report and review of the literature. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies 2008; 265: 709-711. DOI: 10.1007/s00405-007-0499-2. 23. Frank S, Kuhn SA, Brodhun M, et al. Metastatic glioblastoma cells use common pathways via blood and lymphatic vessels. Neurologia i neurochirurgia polska 2009; 43: 183-190. 24. Mentrikoski M, Johnson MD, Korones DN, et al. Glioblastoma multiforme in skin: a report of 2 cases and review of the literature. The American Journal of dermatopathology 2008; 30: 381-384. Doi: 10.1097/DAD.0b013e31817532c4. 25. Gururangan S, McLaughlin CA, Brashears J, et al. Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma. Journal of neuro-oncology 2006; 77: 207-212. DOI: 10.1007/s11060-005-9029-5. 26. Nager GT. Gliomas involving the temporal bone clinical and pathological aspects. The Laryngoscope 1967; 77: 454-488. Doi: 10.1288/lary.1967.000770403. 27. M T, Stephenson, Corinne, Y, Shan, Bui, Marilyn. Cytological Diagnosis of Extracranial Extension of Glioblastoma to Scalp. ASCP Case Reports 2013; 41: 13140. DOI: 2.1.3466.3041. 28. McGovern PC, Lautenbach E, Brennan PJ, et al. Risk factors for postcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)-1-nitrosourea (Gliadel) wafer placement. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003; 36: 759-765. Doi: 10.1086/368082. 29. Shi M and Sanche L. Convection-Enhanced Delivery in Malignant Gliomas: A Review of Toxicity and Efficacy. Journal of oncology 2019; 2019: 9342796. Doi: 10.1155/2019/9342796. 30. Duffy PE, Graf L and Rapport MM. Identification of glial fibrillary acidic protein by the immunoperoxidase method in human brain tumors. Journal of neuropathology and experimental neurology 1977; 36: 645-652. Doi: 10.1097/00005072-197707000-00001. 31. Stoyanov GS, Petkova L, Iliev B, et al. Extracranial Glioblastoma Metastasis: A Neuropathological Case Report. Cureus 2023; 15: e35803. Doi: 10.7759/cureus.35803. 32. Ogungbo BI, Perry RH, Bozzino J, et al. Report of GBM metastasis to the parotid gland. Journal of neuro-oncology 2005; 74: 337-338. DOI: 10.1007/s11060-005-1480-9. 33. Alhoulaiby S, Abdulrahman A, Alouni G, et al. Extra-CNS metastasis of glioblastoma multiforme to cervical lymph nodes and parotid gland: A case report. Clinical case reports 2020; 8: 1672-1677. Doi: 10.1002/ccr3.2985. 34. Swinnen J, Gelin G, Fransis S, et al. Glioblastoma with extracranial parotid, lymph node, and pulmonary metastases: a case report. Radiology case reports 2019; 14: 1334-1347. Doi: 10.1016/j.radcr.2019.08.011. 35. Schwock J, Mirham L and Ghorab Z. Cytology of Extraneural Metastases of Nonhematolymphoid Primary Central Nervous System Tumors: Six Cases with Histopathological Correlation and Literature Update. Acta cytologica 2021; 65: 529-540. Doi: 10.1159/000517480.
Bing Leng
Department of Pathology, Baylor Scott & White Health, 2401 S. 31st. St. MS-01-266 Temple, TX 76508
Frank Yuan Shan
Department of Pathology, Baylor Scott & White Health, 2401 S. 31st. St. MS-01-266 Temple, TX 76508
Abstract
Glioblastoma multiforme (GBM) is a WHO grade 4 primary brain tumor with a recalcitrant and dismal prognosis and a 14-month-median survival time. The extracranial spread of GBM is so rare that historically it was not believed to spread outside of the central nervous system (CNS). Since the first extracranial spread of GBM was described in 1928, more cases have been reported. However, the mechanisms have yet to be elucidated due to the rareness of well-documented cases. Here, we reported two cases of GBM with postoperative extracranial spread and reviewed related literature.
Jack Boylan
Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA.; Center for Structural Oncology, Pennsylvania State University, University Park, PA 16802, USA.; Molecular, Cellular, and Integrative Biosciences Graduate Program, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Elizabeth Byers
Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA.; Molecular, Cellular, and Integrative Biosciences Graduate Program, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Deborah F. Kelly
Department of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802, USA.; Center for Structural Oncology, Pennsylvania State University, University Park, PA 16802, USA.
Abstract
Malignant brain tumors are aggressive and difficult to treat. Glioblastoma is the most common and lethal form of primary brain tumor, often found in patients with no genetic predisposition. The median life expectancy for individuals diagnosed with this condition is 6 months to 2 years and there is no known cure. New paradigms in cancer biology implicate a small subset of tumor cells in initiating and sustaining these incurable brain tumors. Here, we discuss the heterogenous nature of glioblastoma and theories behind its capacity for therapy resistance and recurrence. Within the cancer landscape, cancer stem cells are thought to be both tumor initiators and major contributors to tumor heterogeneity and therapy evasion and such cells have been identified in glioblastoma. At the cellular level, disruptions in the delicate balance between differentiation and self-renewal spur transformation and support tumor growth. While rapidly dividing cells are more sensitive to elimination by traditional treatments, glioblastoma stem cells evade these measures through slow division and reversible exit from the cell cycle. At the molecular level, glioblastoma tumor cells exploit several signaling pathways to evade conventional therapies through improved DNA repair mechanisms and a flexible state of senescence. We examine these common evasion techniques while discussing potential molecular approaches to better target these deadly tumors. Equally important, the presented information encourages the idea of augmenting conventional treatments with novel glioblastoma stem cell-directed therapies, as eliminating these harmful progenitors holds great potential to modulate tumor recurrence.
Diane D McConnell, DVM, PhD
University of Missouri
Joseph P Herbert, MD
University of Missouri
Douglas C Miller, MD, PhD N. Scott Litofsky, MD
University of Missouri
Abstract
Purpose: Of patients with glioblastoma who smoke tobacco, 16 to 28% will continue to smoke following diagnosis. Use of nicotine-containing products may enhance proliferation, migration and radioresistance and detrimentally affect treatment and prognosis of glioblastoma. The aim of this study is to identify effects of a period of nicotine exposure on efficacy of subsequent treatment with temozolomide and radiation therapy on 5 glioblastoma cell lines. We hypothesize that prior and continued nicotine exposure would reduce tumoricidal effects of temozolomide and radiation therapy.
Methods: After 5 glioblastoma cell cultures are exposed to nicotine prior to treatment with temozolomide and /or radiation, proliferation, migration, colony forming assays, and enzymatic expression of matrix metalloproteinases are assessed.
Results: Proliferation is not affected by exposure of physiologically relevant concentrations of nicotine prior to treatment with temozolomide or irradiation. Nicotine exposure has variable effects which include enhancement of migration rate, metalloproteinase expression, and colony formation for some glioblastoma cell lines subsequently treated with temozolomide and /or radiation therapy.
Conclusions: These findings suggest that continued smoking or use of other nicotine-containing products during treatment could result in increased aggressiveness and invasion of residual tumor cells causing a resistance to treatment in some glioblastoma.
Christophe Lallemand
Svar Life Science France, Villejuif, France
Rosa Ferrando-Miguel
Svar Life Science France, Villejuif, France
Franziska Di Pauli
Department of Neurology, Innsbruck University Hospital, Medizinisches Zentrum, Innsbruck, Austria.
Florian Deisenhamer
Department of Neurology, Innsbruck University Hospital, Medizinisches Zentrum, Innsbruck, Austria.
Michael G. Tovey
Svar Life Science France, Villejuif, France
Abstract
Highly sensitive reporter-gene assays have been developed that allow the precise quantification of both the direct vascular endothelial growth factor-A neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity. The use of these assays to analyzes samples from patients with ovarian cancer following four cycle of bevacizumab treatment revealed a close correlation between bevacizumab neutralizing activity and antibody dependent cellular cytotoxicity activity, and a reasonably good correlation between both activities and circulating drug levels determined using an enzyme-linked immunosorbent assay. Analysis of longitudinal samples from a small cohort of patients with glioblastoma treated with bevacizumab revealed a lower correlation between these parameters. We report herein that reanalysis of the grouped samples from the two studies using the nonparametric Spearman rank correlation coefficient revealed a surprisingly good correlation between the two facets of bevacizumab activity, and between both activities and circulating drug levels despite the different indications and treatment regimens, revealing new insights into the action of bevacizumab in neoplastic disease.
Maurizio Martellini
TheranostiCentre S.r.l., Via Fregug-lia 8 – 20122 Milan (ITALY)
Massimo Sarotto
ENEA FSN-SICNUC-PSSN, C.R. Saluggia, Strada per Crescentino 41 – 13040 Saluggia (ITALY)
Ka-Ngo Leung Leung
Berkion Technology LLC, Colusa Avenue 1102 – 94707 Berkeley (CA, USA)
Giuseppe Gherardi
TheranostiCentre S.r.l., Via Fregug-lia 8 – 20122 Milan (ITALY)
Antonietta Rizzo
ENEA FSN-SICNUC-TNMT, C.R. Bologna, Via Martiri di Monte Sole 4 – 40129 Bologna (ITALY)
Giuseppe Ottaviano
ENEA FSN-SICNUC-TNMT, C.R. Bologna, Via Martiri di Monte Sole 4 – 40129 Bologna (ITALY)
Lidia Falzone
TheranostiCentre S.r.l., Via Fregug-lia 8 – 20122 Milan (ITALY)
Abstract
The glioblastoma multiforme (GBM) is the most malignant glial brain tumour with average survival time of 6÷18 months. Emerging evidence suggests that GBM cells appears to reprogram their tumour microenvironment, which is a highly heterogeneous and complex system, so that an efficient GBM radiotherapy (RT) should cover both the cells of the GBM and those of its microenvironment. Relying on a 5-year collaborative research study on the intra-operative radiotherapy (IORT) with fast neutrons – the so-called neutron-IORT (nIORT®) technique – the authors think that this objective could be achieved by using an ionizing radiation field of fast neutrons that behave in the biological tissues as a “foam field” hitting both the GBM cancer cells and the neighbouring microenvironment.
The nIORT® research activities – conducted by TheranostiCentre Srl, Berkion Technology LLC and ENEA – led to the fabrication of the first prototype of a compact neutron generator (CNG) that, through the deuterium-deuterium fusion reaction, produces neutrons of 2.45 MeV energy having: i) high linear energy transfer; ii) very high relative biological effectiveness (RBE), about 16 times higher than X-rays (and electrons) used in standard RT and IORT treatments; iii) reduced oxygen enhancement ratio, and hence resulting be very effective in cancer cells necrosis and apoptosis. The CNG is self-shielded, limited in size and weight (~120 kg) and manageable remotely by a robotic arm. A new prototype equipped by a cylindrical applicator to be inserted in the surgical cavities is currently under construction, with some technical advancements making possible its installation in an operating room dedicated to nIORT® treatments without posing any safety and environmental concern.
In this article the nIORT® potentiality was investigated in the view of the GBM treatment, but the study is however generalisable for the neutron irradiation of other brain cancer pathologies. Accurate Monte Carlo simulations, modelling the CNG equipped with a couple of cylindrical applicators of 4 and 6 cm in diameter inserted in the brain surgical cavity after craniotomy, demonstrated that the nIORT® device operated at 100 kV-10 mA DC supplies a neutron flux ~108 cm-2 s-1 and can deliver equivalent dose rates ~5 Gy (RBE)/min in the centre of the tumour bed. Thus, it could administer the clinical endpoints foreseen by the standard IORT protocols (~10-20 Gy (RBE)) in treatment times of few minutes, by providing a sort of “switching on and off neutron brachytherapy tool” without using needles of radioisotopes (e.g., 252Cf). The near isotropic neutron emission allows to irradiate the tumour bed margins, normally filled by potential quiescent cancer cells, with lower (but still significant) dose levels. This should improve the local control of the tumour through the reduction of local recurrences and metastasis in the tumour microenvironment, and at the same time to avoid adverse effects of the administered neutron radiation field on the surrounding brain central nervous system. Also, the rapid decrease in tissue depth of the dose gradient (within few centimetres) should avoid any adverse effect on normal brain tissues and the neighbouring organs.
Sarah Adelaide Crawford
Cancer Biology Research Laboratory, Southern Connecticut State University
Brielle Hayward-Piatkovskyi
Department of Biological Sciences, University of Delaware
Abstract
Although many factors contribute to the low translational success of pre-clinical data into human trials, one major factor is the failure of pre-clinical models to recapitulate essential physiological components of malignant tumors. An important body of clinical research indicates that the surrounding cellular microenvironment involving stromal tissue, matrix and the resident immune system play a critical role in the genesis of brain tumors of many diverse types. The research presented in this paper specifically addresses the role of biomechanical components in the brain extracellular matrix that may play a critical role in the development and spread of central nervous system malignancies, specifically gliomas. The data suggest that unfertilized chicken egg albumen, as a novel three-dimensional culture medium, provides a biologically relevant microenvironment that can support dynamic tumor formation and growth. Chicken egg albumen supplemented culture media produced compaction effects on tumor density that varied inversely with invasion zone expansion parameters. Based on this observed relationship, a ratio was extrapolated from primary data measurements to assess more quantitatively the relationship between microtumor spheroid surface area and invasion zone diameter. The ratio of microtumor invasion zone diameter divided by microtumor surface area was calculated and designated a “Malignancy Index” based on the premise that the relationship between the peripheral invasion zone diameter relative to surface area changes reflecting changing compaction parameters of the tumor mass represents a relevant assessment of tumor invasiveness, a fundamental hallmark of malignancy.
Ana Catarina Viana Valle
Department of Research, Idis Lamasson Institute, Ribeirao Preto, Sao Paulo, Brazil.
Aloiso Cunha de Carvalho
Department of Research, Idis Lamasson Institute, Ribeirao Preto, Sao Paulo, Brazil.
Samir Wady Rahme
Department of Research, Idis Lamasson Institute, Ribeirao Preto, Sao Paulo, Brazil.
Andressa de Rezende Bastos Araujo
BioInnova Laboratory, Brasilia, Distrito Federal, Brazil.
Patrícia Furtado Malard
BioInnova Laboratory, Brasilia, Distrito Federal, Brazil.
Hilana S. Sena Brunel
BioInnova Laboratory, Brasilia, Distrito Federal, Brazil.
Abstract
Viscum album (VA), also known as Mistletoe, has various therapeutic properties, including analgesic, anti-inflammatory, and anticancer effects. It has been used for treating different types of cancer, exhibiting proven efficacy against breast cancer, glioblastoma, carcinoma, and other advanced-stage tumor types. Besides promoting improvements in the clinical condition, VA also helps reduce the side effects caused by conventional treatment, thereby offering patients a better quality of life. Hence, the objective of this study was to assess the effects of the homeopathic dilution of VA at the potency of D30 (1×10-30) (VA D30) on human mesenchymal stem cells (MSCs) and hepatocellular carcinoma cells (HepG2). The cells were grown in 75 cm² flasks until they reached approximately 80% confluence. Subsequently, they were trypsinized and plated in 96-well plates at 10,000 cells/well. After 24 hours of incubation in an oven, VA was added at 30 and 40 µL/mL concentrations. The cells were further incubated for an additional 48 hours. After the treatment, the cells underwent a cell viability test using MTT. The results indicated a decrease in HepG2 viability, while no damage to normal cells (MSCs) was detected. The findings suggest that VAD30 holds promise as a potential therapeutic agent in treating hepatocellular carcinoma due to its observed cytotoxicity towards HepG2 cells while exhibiting no adverse effects on mesenchymal stem cells at the equivalent concentration.
Priya Hays
Hays Documentation Specialists, LLC, San Mateo, CA USA
Abstract
Cancer stems cells are cells in tumors that have self-renewing capabilities and proliferation, and are partly responsible for tumor growth, metastasis and drug resistance, and have been associated with multidrug resistance and epithelial-mesenchymal transition. mRNA stemness index or mRNAsi is a machine learning tool that uses the application of algorithms to find associations between cancer stemness and tumor prognostic signatures. mRNAsi predicts gene mutation status and identifies tumor signaling pathways. Clinical tier grading is a common feature for stratifying the presenting features and symptoms of patients in several diseases. This study is a review article that summarizes studies in lung cancer, gastric cancer, hepatocellular carcinoma and glioblastoma that use mRNA stemness index machine learning tools to identify differentially expressed genes, characterize the tumor microenvironment and tumor mutational burden, and determine clinical endpoints. A prognostic signature is shown in this paper as determined by mRNAsi high and low values, and a clinical tier grading system is proposed that categorizes cancer stemness presenting characteristics. This clinical grading tier system demonstrates a relationship between cancer stemness and immune checkpoint inhibitor efficacy. This type of tiered system for cancer patients and the accompanying workflow proposed may prove useful to oncologists, and has not been performed before, and is unique in the literature.
