Articoli di riviste sul tema "GB recurrence"
Segui questo link per vedere altri tipi di pubblicazioni sul tema: GB recurrence.
Cita una fonte nei formati APA, MLA, Chicago, Harvard e in molti altri stili
Vedi i top-50 articoli di riviste per l'attività di ricerca sul tema "GB recurrence".
Accanto a ogni fonte nell'elenco di riferimenti c'è un pulsante "Aggiungi alla bibliografia". Premilo e genereremo automaticamente la citazione bibliografica dell'opera scelta nello stile citazionale di cui hai bisogno: APA, MLA, Harvard, Chicago, Vancouver ecc.
Puoi anche scaricare il testo completo della pubblicazione scientifica nel formato .pdf e leggere online l'abstract (il sommario) dell'opera se è presente nei metadati.
Vedi gli articoli di riviste di molte aree scientifiche e compila una bibliografia corretta.
1
Stadlbauer, Andreas, Ilker Eyüpoglu, Michael Buchfelder, Arnd Dörfler, Max Zimmermann, Gertraud Heinz e Stefan Oberndorfer. "Vascular architecture mapping for early detection of glioblastoma recurrence". Neurosurgical Focus 47, n. 6 (dicembre 2019): E14. http://dx.doi.org/10.3171/2019.9.focus19613.
Testo completoAbstract (sommario):
OBJECTIVETreatment failure and inevitable tumor recurrence are the main reasons for the poor prognosis of glioblastoma (GB). Gross-total resection at repeat craniotomy for GB recurrence improves patient overall survival but requires early and reliable detection. It is known, however, that even advanced MRI approaches have limited diagnostic performance for distinguishing tumor progression from pseudoprogression. The novel MRI technique of vascular architectural mapping (VAM) provides deeper insight into tumor microvascularity and neovascularization. In this study the authors evaluated the usefulness of VAM for the monitoring of GB patients and quantitatively analyzed the features of neovascularization of early- and progressed-stage GB recurrence.METHODSIn total, a group of 115 GB patients who received overall 374 follow-up MRI examinations after standard treatment were retrospectively evaluated in this study. The clinical routine MRI (cMRI) protocol at 3 Tesla was extended with the authors’ experimental VAM approach, requiring 2 minutes of extra time for data acquisition. Custom-made MATLAB software was used for calculation of imaging biomarker maps of macrovascular perfusion from perfusion cMRI as well as of microvascular perfusion and architecture from VAM data. Additionally, cMRI data were analyzed by two board-certified radiologists in consensus. Statistical procedures included receiver operating characteristic (ROC) analysis to determine diagnostic performances for GB recurrence detection.RESULTSOverall, cMRI showed GB recurrence in 89 patients, and in 28 of these patients recurrence was detected earlier with VAM data, by 1 (20 patients) or 2 (8 patients) follow-up examinations, than with cMRI data. The mean time difference between recurrence detection with VAM and cMRI data was 147 days. During this time period the mean tumor volume increased significantly (p < 0.001) from 9.7 to 26.8 cm3. Quantitative analysis of imaging biomarkers demonstrated microvascular but no macrovascular hyperperfusion in early GB recurrence. Therefore, ROC analysis revealed superior diagnostic performance for VAM compared with cMRI.CONCLUSIONSThis study demonstrated that the targeted assessment of microvascular features using the VAM technique provided valuable information about early neovascularization activity in recurrent GB that is complementary to perfusion cMRI and may be helpful for earlier and more precise monitoring of patients suffering from GB. This VAM approach is compatible with existing cMRI protocols. Prospective clinical trials are necessary to investigate the clinical usefulness and potential benefit of increased overall survival with the use of VAM in patients with recurrent GB.
2
Stadlbauer, Andreas, Stefan Oberndorfer, Max Zimmermann, Bertold Renner, Michael Buchfelder, Gertraud Heinz, Arnd Doerfler, Andrea Kleindienst e Karl Roessler. "Physiologic MR imaging of the tumor microenvironment revealed switching of metabolic phenotype upon recurrence of glioblastoma in humans". Journal of Cerebral Blood Flow & Metabolism 40, n. 3 (7 febbraio 2019): 528–38. http://dx.doi.org/10.1177/0271678x19827885.
Testo completoAbstract (sommario):
Treating recurrent glioblastoma (GB) is one of the challenges in modern neurooncology. Hypoxia, neovascularization, and energy metabolism are of crucial importance for therapy failure and recurrence. Twenty-one patients with initially untreated GB who developed recurrence were examined with a novel MRI approach for noninvasive visualization of the tumor microenvironment (TME). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of five different TME compartments: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation, and glycolysis. Volume percentages of these TME compartments were compared between untreated and recurrent GB. At initial diagnosis, all 21 GB showed either the features of a glycolytic dominant phenotype with a high percentage of functional neovasculature (N = 12) or those of a necrotic/hypoxic dominant phenotype with a high percentage of defective tumor neovasculature (N = 9). At recurrence, all 21 GB revealed switching of the initial metabolic phenotype: either from the glycolytic to the necrotic/hypoxic dominant phenotype or vice-versa. A necrotic/hypoxic phenotype at recurrence was associated with a higher rate of multifocality of the recurrent lesions. Our MRI approach may be helpful for a better understanding of treatment-induced metabolic phenotype switching and for future studies developing targeted therapeutic strategies for recurrent GB.
3
Lessi, F., M. Morelli, P. Aretini, M. Menicagli, S. Franceschi, F. Pasqualetti, C. Gambacciani, A. Di Stefano, O. Santonocito e C. M. Mazzanti. "P14.01.B Isolation and characterization of circulating tumor cells in a glioblastoma case with recurrence at distance and correlation with tumor mutational status". Neuro-Oncology 24, Supplement_2 (1 settembre 2022): ii82. http://dx.doi.org/10.1093/neuonc/noac174.286.
Testo completoAbstract (sommario):
Abstract Background Circulating Tumor Cells (CTCs) are considered to be one of the important causes of tumor recurrence and distant metastasis. For many years, glioblastoma (GB) was thought to be restricted to the brain. Nevertheless, a growing body of evidence indicates that, like many other cancers, hematogenic dissemination is a reality. The absence of a procedural uniformity in literature prompted us to develop an innovative and sensitive method to obtain CTCs in GB. Our aim is to define the genetic background of single CTCs compared with the primary GB tumor and its recurrence to assess whether or not their presence in the peripheral circulation correlates with GB migration and dissemination. Material and Methods CTCs were enriched from whole blood of one patient with recurrent GB with Parsortix Cell Separation System and analysed on DEPArray system. After that, CTCs Copy Number Aberrations (CNAs) and sequencing analysis was performed to compare CTCs genetic background with the same patient’s primary and recurrence tissues, analysed by NextSeq 500 (whole exome sequencing). Results We obtained 211 mutations in common between primary and recurrence tumor. Among these, three somatic mutations (c.430 G>A in PRKCB gene, c.815 C>T in TBX1 gene and c.1554 T>G in COG5 gene) were selected to investigate their presence in recurrence CTCs. Almost all of the sorted CTCs (9/13) had at least one of the mutations tested. Conclusion In confirmation of the hypothesis, the CTCs detected in the patient's blood were actually cancer cells deriving from GB tumor.
4
Beppu, Takaaki, Yuichi Sato, Toshiaki Sasaki, Kazunori Terasaki e Kuniaki Ogasawara. "NI-19 Use of 11C-methionine PET for decision of discontinuation of adjuvant chemotherapy with temozolomide". Neuro-Oncology Advances 2, Supplement_3 (1 novembre 2020): ii14. http://dx.doi.org/10.1093/noajnl/vdaa143.062.
Testo completoAbstract (sommario):
Abstract Background: The aim was to clarify whether positron emission tomography with 11C-methyl-L-methionine (met-PET) is useful to decide on discontinuation of TMZ-adjuvant therapy in patients with residual diffuse astrocytic tumor. Methods: Subjects were 44 patients with residual tumor comprising 17 with IDH1-mutant diffuse astrocytoma (DA), 13 with IDH1-mutant anaplastic astrocytoma (AA), and 14 with IDH1-wild glioblastoma (GB). All patients received TMZ-adjuvant chemotherapy (median, 12 courses), and whether to discontinue or continue TMZ-adjuvant chemotherapy was decided on the basis of the tumor-to-normal ratio in standardized uptake value from met-PET (T/N); patients with T/N < 1.6 immediately discontinued TMZ, and patients with T/N > 1.6 were either to continued or discontinued TMZ. Progression-free survival (PFS) was compared between patients with T/N > 1.6 and T/N < 1.6 in each tumor type. Median observation period was 434 days after met-PET scanning. Results: The number of patient who underwent recurrence was 10 in DA, 7 in AA, and 11 in GB. All patients showing T/N > 1.6 underwent tumor recurrence. PFS was significantly longer in patients with T/N < 1.6 than T/N > 1.6 in DA and AA (p < 0.01 in both types), but was no significant difference between 2 groups in GB (p = 0.06). Sixteen of 17 patients (94%) in DA and AA showed recurrence from residual tumor, whereas 4 of 11 patients (36%) in GB showed recurrent tumor at remote regions which were different from residual tumor. Conclusions: The present study suggested that met-PET is beneficial to decide to discontinue adjuvant chemotherapy with TMZ in patients with residual tumors of DA and AA, but not useful for patients with GB. Reasons for unsuccessful results in GB might have been small sample size, failure of establishing the cut off value in T/N, recurrences at remote regions where not be assessed by met-PET.
5
Pettiwala, Aafrin M., Cathy Pichol-Thievend, Oceane Anezo, Guillaume Bourmeau, Remi Montagne, Anne-Marie Lyne, Pierre-Olivier Guichet Guichet et al. "TMIC-76. GLIOBLASTOMA VESSEL CO-OPTION OCCURS AS A RESISTANCE MECHANISM TO CHEMORADIATION VIA INDUCTION OF A NOVEL CELL STATE". Neuro-Oncology 25, Supplement_5 (1 novembre 2023): v295. http://dx.doi.org/10.1093/neuonc/noad179.1141.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime-including resection, chemo-radiation, its recurrence rate is more than 90%. Recurrence is mostly caused by highly resistant and invasive cells that spread from tumor bulk and are not removed by resection. To develop an effective therapeutic approach, we need to better understand underlying molecular and cellular mechanism driving therapy resistance and invasion in GB. To dynamically track the changes post-therapy and chemoradiation-resistant cells, we employed multiple bulk and single cell transcriptomics, phosphoproteome, in vitro and in vivo real time imaging, organotypic cultures, functional analysis, digital pathology and spatial transcriptomics on patient material and preclinical models of GB. We demonstrated that the chemoradiation and brain vasculature induce a transition to invasive functional cell state, which we rename as VC-Resist. Better cell survival, G2M arrest, senescence/stemness pathway induction, makes this GB state much more resistant. Notably, these GB cells are highly vessel co-opting allowing homing to perivascular niche, which in turn increases their transition to this cell state. Molecularly, the transition to VC-Resist cell state takes place through FGF-FGFR1 signaling that leads to activation of DNA damage repair, YAP and Rho pathways. These findings demonstrate that the perivascular niche and GB cell plasticity jointly generates a vicious loop that leads to resistance and brain infiltration during GB recurrence.
6
Lee, Jae-Myeong, Bong-Wan Kim, Wook Hwan Kim, Hee-Jung Wang e Myung Wook Kim. "Clinical Implication of Bile Spillage in Patients Undergoing Laparoscopic Cholecystectomy for Gallbladder Cancer". American Surgeon 77, n. 6 (giugno 2011): 697–701. http://dx.doi.org/10.1177/000313481107700623.
Testo completoAbstract (sommario):
We determined the influence of bile spillage on recurrence and survival during laparoscopic cholecystectomy (LC) for gallbladder (GB) cancer. Among the 136 patients with GB cancer treated at Ajou University Hospital between 1994 and 2007, 28 underwent LC alone. We compared patients without bile spillage (bile spillage [-] group, n = 16) with patients who had bile spillage (bile spillage [+] group, n = 12). There was no statistical difference in stage between the groups. In the bile spillage (-) group, all patients underwent curative resection and there were two patients with locoregional recurrences and three patients with systemic recurrences. In the bile spillage (+) group, five patients underwent R1 resection and one patient underwent R2 resection and all eight recurrent patients had systemic recurrences. The disease-free survival and overall survival were shorter in the bile spillage (+) group (disease-free survival, 71.4 vs 20.9 months; P = 0.028; overall survival, 72.6 vs 25.8 months; P = 0.014). Bile spillage is likely to be an association with an incomplete resection and systemic recurrences. When GB cancer is suspected during LC, conversion to open surgery for preventing bile spillage and achieving curative resection should be considered.
7
Belokon, S. V., I. A. Gulidov, D. V. Gogolin, K. E. Medvedeva, S. A. Ivanov e A. D. Kaprin. "Re-irradiation combined with bevacizumab in the treatment of glioblastoma recurrence". Siberian journal of oncology 23, n. 1 (21 marzo 2024): 142–54. http://dx.doi.org/10.21294/1814-4861-2024-23-1-142-154.
Testo completoAbstract (sommario):
Background. Glioblastoma (GB) remains an aggressive disease with a poor prognosis. despite a comprehensive approach to the treatment of the primary disease, recurrence is almost inevitable. There is still no standard of care for GB recurrence, and many guidelines recommend treating these patients within clinical trials. There are various treatment options available. They include surgery, radiation therapy, systemic or regional chemotherapy or targeted therapy, various immunotherapy strategies, low- and medium-frequency electric fields, and their combinations. The combination of two non-invasive techniques: re-irradiation and systemic targeted therapy remains the most commonly used approach in this group of patients, the potential of which has not been fully realized. The aim of the study was to analyze the literature data on the use of the combination of re-irradiation with bevacizumab as a therapeutic option in patients with GB. Material and Methods. Literature search was performed using Medline, Cochrane Library, E-library, Scopus, PubMed and Google Scholar databases. Results. The current state of the problem was determined, the data available to date on the use of repeated radiotherapy with competitive and/or adjuvant bevacizumab in the treatment of GB recurrence were summarized and analyzed, different regimens of this approach were compared, and the prospects and possible ways of solving the existing problems of this therapeutic option were described. Conclusion. Re-irradiation with concomitant administration of bevacizumab may provide safer treatment of GB recurrence, including large-volume glioblastoma, with acceptable toxicity, in particular radiation necrosis, especially when an appropriate fractionation schedule is used.
8
Cianci, Francesca, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta e Michele Mazzanti. "Abstract 2092: Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure". Cancer Research 84, n. 6_Supplement (22 marzo 2024): 2092. http://dx.doi.org/10.1158/1538-7445.am2024-2092.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) is the most aggressive type of brain tumor, and current treatments are generally ineffective in preventing recurrence. Tumor Treating Fields (TTFields) are an innovative treatment that has been shown to improve patients' life expectancy in the last two decades. TTFields therapy has an antitumoral effect that involves different mechanisms and is an optional add-on to standard maintenance temozolomide. Although TTFields therapy initially slows tumor progression, it does not prevent tumor relapse in most patients. In the present investigation, we run a genomic and proteomic analysis of surgical material from 10 patients treated with TTFields. GB tissues were obtained from the primary tumor mass and from a second surgery after tumor relapse. All the patients, in addition to brain tumor standard therapies, were treated with TTFields for eighteen hours a day, the time span of treatment application was dependent on GB recurrence. Control samples were obtained from primary and secondary surgeries of 5 patients treated with standard therapy alone. The GB tissue extracts were analyzed with an RNAseq routine, and the results from the secondary surgery were compared with the data obtained from tumor specimens of the primary surgery. A common feature of transcripts among all the patients was the alterations of several pathways promoting the increase of intracellular oxidation and cell cycle regulation. In parallel with the analysis of patient specimens, we developed an in vitro GB cell relapse model. This was instrumental in investigating the beneficial contribution of TTFields action during tumor relapse, but also in uncovering the limitation of this therapeutic procedure. GB primary cultures obtained from patients' surgery were exposed for up to 12 days with 200 kHz TTFields stimulation using the inovitro™ system. After 12 days of continuous TTFields application, GB cells showed an average depolarization of the resting membrane potential, increasing oxidation, and acidification of the cytoplasm. Genomic analysis of treated cells compared with wild-type primary culture, denoted an increase of tumor stem cell markers, activation of several metabolic pathways, and upregulation of different ion channel protein transcripts. Our final goal is to identify specific molecular features enhanced by TTFields treatment to be used as a parallel therapy to fight GB recurrence. Citation Format: Francesca Cianci, Guido Rey, Dietmar Krex, Davide Ceresa, Paolo Malatesta, Michele Mazzanti. Genomic and proteomic analysis of glioblastoma recurrences during TTFields exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2092.
9
Simionescu, Natalia, Miruna Nemecz, Anca-Roxana Petrovici, Ioan Sebastian Nechifor, Razvan-Cristian Buga, Marius Gabriel Dabija, Lucian Eva e Adriana Georgescu. "Microvesicles and Microvesicle-Associated microRNAs Reflect Glioblastoma Regression: Microvesicle-Associated miR-625-5p Has Biomarker Potential". International Journal of Molecular Sciences 23, n. 15 (29 luglio 2022): 8398. http://dx.doi.org/10.3390/ijms23158398.
Testo completoAbstract (sommario):
Glioblastoma (GB) is the most aggressive and recurrent form of brain cancer in adults. We hypothesized that the identification of biomarkers such as certain microRNAs (miRNAs) and the circulating microvesicles (MVs) that transport them could be key to establishing GB progression, recurrence and therapeutic response. For this purpose, circulating MVs were isolated from the plasma of GB patients (before and after surgery) and of healthy subjects and characterized by flow cytometry. OpenArray profiling and the individual quantification of selected miRNAs in plasma and MVs was performed, followed by target genes’ prediction and in silico survival analysis. It was found that MVs’ parameters (number, EGFRvIII and EpCAM) decreased after the surgical resection of GB tumors, but the inter-patient variability was high. The expression of miR-106b-5p, miR-486-3p, miR-766-3p and miR-30d-5p in GB patients’ MVs was restored to control-like levels after surgery: miR-106b-5p, miR-486-3p and miR-766-3p were upregulated, while miR-30d-5p levels were downregulated after surgical resection. MiR-625-5p was only identified in MVs isolated from GB patients before surgery and was not detected in plasma. Target prediction and pathway analysis showed that the selected miRNAs regulate genes involved in cancer pathways, including glioma. In conclusion, miR-625-5p shows potential as a biomarker for GB regression or recurrence, but further in-depth studies are needed.
10
Nakao, Sayumi, Michio Itabashi, Mamiko Ubukata, Yoshiko Bamba, Tomoichiro Hirosawa, Shimpei Ogawa, Shingo Kameoka e Kenichi Sugihara. "Age-specific prognostic factors in patients treated surgically for pulmonary metastases of colorectal cancer: A multi-institutional cumulative follow-up study." Journal of Clinical Oncology 33, n. 3_suppl (20 gennaio 2015): 773. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.773.
Testo completoAbstract (sommario):
773 Background: The aim of this study was to investigate the age-specific prognostic factors for overall survival (OS) and disease-free interval (DFI) after pulmonary metastasectomy for colorectal cancer (CRC). Methods: We performed a retrospective analysis of 1,179 patients who underwent lung resection for colorectal metastases from 2001 to 2012 in 109 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum study group. The patients were divided into three groups by the age at pulmonary resection: Group A (GA) comprised of 396 patients who underwent lung resection under the age of 60 years old; Group B (GB) comprised of 604 patients who underwent lung resection between the ages of 61 and 74 years old; Group C (GC) comprised of 179 patients who underwent lung resection over the age of 75 years old. We used the Cox proportional hazard regression to identify independent prognostic factors for OS and DFI. Results: Median OS times after pulmonary resection were 45 months, 43 months, and 43 months for GA, GB, and GC, respectively. Two-year and 5-year overall survival rates were 73% and 54% for GA, 77% and 63% for GB, and 82% and 68% for GC, respectively. The independent unfavorable prognostic factors were recurrence after pulmonary resection (p<0.0001) in GA, detection of liver metastases before lung resection (p=0.0126), a high level of carcinoembryonic antigen (p=0.0003), and recurrence after pulmonary resection (p<0.0001) in GB, and recurrence after pulmonary resection (p<0.0001) in GC. Median DFI times were 11 months in all groups. The independent unfavorable prognostic factor was a removal of mediastinal lymph node (p=0.0335) in GB. Conclusions: Elder patients (GC) showed nearly the same OS rate compared with non-elder patients (GB), while younger patients (GA) showed poor OS rate. Recurrence after pulmonary resection revealed to be a poor prognostic factor in all groups.
11
Pichol-Thievend, C., O. Anezo, A. M. Pettiwala, G. Bourmeau, R. Montagne, A. Lyne, P. Guichet et al. "OS07.5.A GLIOBLASTOMA VESSEL CO-OPTION AND TRANSITION TO A RESISTANT CELL STATE ARE INDUCED BY CHEMORADIATION". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii18. http://dx.doi.org/10.1093/neuonc/noad137.052.
Testo completoAbstract (sommario):
Abstract BACKGROUND Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime, including resection of the tumor, radiation, and chemotherapy, the recurrence rate is more than 90%. Recurrence is mostly caused by the regrowth of highly invasive and resistant cells that have spread from the tumor bulk and are not removed by resection. To develop an effective therapeutic approach, we need to better understand the underlying molecular and cellular mechanisms of GB chemoradiation resistance and tumor spreading. MATERIAL AND METHODS To dynamically follow the changes occurring in GB post-therapy and investigate its relationship with vascular microenvironment, we employed multiple bulk and single-cell RNA-Seq analyses, phosphoproteome, in vitro and in vivo real-time imaging, organotypic cultures and functional assays, digital pathology, and spatial transcriptomics on patient material or preclinical models of GB. RESULTS We demonstrated that chemoradiation and the brain vasculature induce a transition to a functional cell state, which we named VC-Resist. This cell state is midway through the transcriptomic axis between proneural and mesenchymal GB cells and is closer to the AC/MES-like state. Better cell survival, G2M-arrest, activation of senescence/stemness pathways make this GB cell state more resistant to therapy. Notably, these persister GB cells are highly vessel co-opting, allowing homing to the perivascular niche, which, in turn, increases their transition to this cell state and resistance to therapy. Molecularly, the transition to the VC-Resist cell state is driven by FGF-FGFR1 signaling, which leads to the activation of DNA damage repair and YAP1 pathways. CONCLUSION These findings demonstrate that the perivascular niche and GB cell plasticity jointly generate a vicious loop that leads to resistance to therapy and brain infiltration during GB recurrence. SUPPORT This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 (Grant Agreement No. 805225), the INSERM-CNRS ATIP-Avenir grant, the NanoTheRad grant from Paris-Saclay University, Fondation ARC pour la recherche sur le cancer, Campus France and Canceropole Ile-de-France (2022-1-EMERG-06-ICR-1).
12
Tan, David, Imogen Roth, Agadha Wickremesekera, Paul Davis, Andrew Kaye, Theo Mantamadiotis, Stanley Stylli e Swee Tan. "Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-Angiotensin System". Cells 8, n. 11 (31 ottobre 2019): 1364. http://dx.doi.org/10.3390/cells8111364.
Testo completoAbstract (sommario):
Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection and adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs can be identified by embryonic stem cell markers, express components of the renin-angiotensin system (RAS) and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB patients rarely develop distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the RAS to improve overall symptom-free survival and maintain quality of life.
13
Centonze, Giovanni, Alessandro Mangogna, Tiziana Salviato, Beatrice Belmonte, Laura Cattaneo, Melissa Anna Teresa Monica, Giovanna Garzone et al. "Gastroblastoma in Adulthood—A Rarity among Rare Cancers—A Case Report and Review of the Literature". Case Reports in Pathology 2019 (28 novembre 2019): 1–6. http://dx.doi.org/10.1155/2019/4084196.
Testo completoAbstract (sommario):
Gastroblastoma (GB) is a rare gastric epithelial-mesenchymal neoplasm, first described by Miettinen et al. So far, all reported cases described the tumor in children or young adults, and similarities with other childhood blastomas have been postulated. We report a case of GB in a 43-year-old patient with long follow up and no recurrence up to 100 months after surgery. So far, this is the second case of GB occurring in the adult age >40-year-old. Hence, GB should be considered in the differential diagnosis of microscopically comparable conditions in adults carrying a worse prognosis and different clinical approach.
14
Obrador, Elena, Paz Moreno-Murciano, María Oriol-Caballo, Rafael López-Blanch, Begoña Pineda, Julia Lara Gutiérrez-Arroyo, Alba Loras et al. "Glioblastoma Therapy: Past, Present and Future". International Journal of Molecular Sciences 25, n. 5 (21 febbraio 2024): 2529. http://dx.doi.org/10.3390/ijms25052529.
Testo completoAbstract (sommario):
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood–brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
15
Chirica, Costin, Danisia Haba, Elena Cojocaru, Andreea Isabela Mazga, Lucian Eva, Bogdan Ionut Dobrovat, Sabina Ioana Chirica, Ioana Stirban, Andreea Rotundu e Maria Magdalena Leon. "One Step Forward—The Current Role of Artificial Intelligence in Glioblastoma Imaging". Life 13, n. 7 (14 luglio 2023): 1561. http://dx.doi.org/10.3390/life13071561.
Testo completoAbstract (sommario):
Artificial intelligence (AI) is rapidly integrating into diagnostic methods across many branches of medicine. Significant progress has been made in tumor assessment using AI algorithms, and research is underway on how image manipulation can provide information with diagnostic, prognostic and treatment impacts. Glioblastoma (GB) remains the most common primary malignant brain tumor, with a median survival of 15 months. This paper presents literature data on GB imaging and the contribution of AI to the characterization and tracking of GB, as well as recurrence. Furthermore, from an imaging point of view, the differential diagnosis of these tumors can be problematic. How can an AI algorithm help with differential diagnosis? The integration of clinical, radiomics and molecular markers via AI holds great potential as a tool for enhancing patient outcomes by distinguishing brain tumors from mimicking lesions, classifying and grading tumors, and evaluating them before and after treatment. Additionally, AI can aid in differentiating between tumor recurrence and post-treatment alterations, which can be challenging with conventional imaging methods. Overall, the integration of AI into GB imaging has the potential to significantly improve patient outcomes by enabling more accurate diagnosis, precise treatment planning and better monitoring of treatment response.
16
O’Rawe, Michael, Ethan J. Kilmister, Theo Mantamadiotis, Andrew H. Kaye, Swee T. Tan e Agadha C. Wickremesekera. "The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma". Cancers 13, n. 16 (9 agosto 2021): 4004. http://dx.doi.org/10.3390/cancers13164004.
Testo completoAbstract (sommario):
Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB.
17
Hamza, Mohamed Ali, Jacob Mandel, Charles A. Conrad, Mark R. Gilbert, W. K. Alfred Yung, Vinay K. Puduvalli e John Frederick De Groot. "Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 2042. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2042.
Testo completoAbstract (sommario):
2042 Background: Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma (GB). Differences in outcome between early versus delayed BEV treatment of recurrent GB are not well defined. We examined the relationship between the time of start of BEV treatment and outcomes in patients with recurrent GB. Methods: In this retrospective chart review derived from our longitudinal database, we identified patients with recurrent GB between 2001 and 2011, who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of BEV start. Early BEV was defined as start of BEV treatment at first recurrence, while delayed BEV was defined as start of treatment at second recurrence or later. Results: A total of 298 patients with recurrent GB who received BEV were identified, of whom 149 patients received early BEV, 134 patients received delayed BEV, and 15 patients who were excluded because they received BEV upfront. There were no significant differences in the age, sex, performance status and extent of resection between patients treated with early BEV and those treated with delayed BEV. The median time from diagnosis to first recurrence was more than 6 months (mos.) for both groups (6.5 mos. for early BEV and 7.6 mos. for delayed BEV, p = 0.01). The median time from diagnosis to start of BEV was 7.9 mos. for patients with early BEV and 15.6 mos. for patients with delayed BEV (p<0.001). There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.73 mos. vs. 4.33 mos., p = 0.07). Patients who were treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 mos. vs. 19.7 mos., p = 0.0002). Conclusions: In patients with recurrent GB, there was no significant difference in PFS between early and delayed BEV; however, patients treated with delayed BEV have longer OS when compared to those treated with early BEV. These results indicate that delaying treatment with BEV is not detrimental and may be associated with a favorable survival outcome.
18
Chédeville, Agathe L., e Patricia A. Madureira. "The Role of Hypoxia in Glioblastoma Radiotherapy Resistance". Cancers 13, n. 3 (1 febbraio 2021): 542. http://dx.doi.org/10.3390/cancers13030542.
Testo completoAbstract (sommario):
Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O2 partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future.
19
Stephenson, Connor, Daniel G. McDonald, Milad Yazdani, Shikhar Mehrotra, Cynthia A. Welsh, Libby Kosnik Infinger, William A. Vandergrift et al. "NIMG-78. DEVELOPMENT OF A PRECLINICAL GLIOBLASTOMA MURINE MODEL FOR THE ASSESSMENT OF RADIATION NECROSIS USING DIFFUSION KURTOSIS IMAGING". Neuro-Oncology 24, Supplement_7 (1 novembre 2022): vii183. http://dx.doi.org/10.1093/neuonc/noac209.696.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) patients often present with either radiation-induced necrosis (RN) or develop tumor recurrence (TR). Radiologically, differentiating between these two disease states is particularly difficult, especially utilizing traditional MRI techniques. Accurately distinguishing these separate states is important, as failure to do so can ultimately lead to unnecessary surgical intervention or early cessation of appropriate radiation therapy. Currently, distinction between these pathologies is made using best clinical judgement by the neuro-oncology team. Therefore, there is a need for developing novel non-invasive techniques that can reliably distinguish between radiation necrosis and tumor recurrence. Primary data was collected utilizing orthotopically transplanted GL261 mouse GB cells in a C57BL/6 mouse. Tumor induction was verified by MRI after two weeks. RN and TR were initiated using an aggressive radiation dose fractionation (12 Gy or 60 Gy). This was completed using a 4 mm radiation cone such that one portion of the tumor received 100% dose of 12 Gy or 60 Gy fraction which is sufficient to cause RN, whereas the tumor edge received only 50% of the dose, allowing for tumor recurrence. Our data demonstrated mice tumor recurrence and radiation necrosis on MRI imaging. Axial T2-weighted MRI and DKI sequence at 2 weeks following implantation demonstrated edema compatible with tumor recurrence. One week later, the T2-weighted MRI and DKI sequences demonstrated continued tumor progression. In a separate mouse with orthotopic glioblastoma implantation with high dose (60 Gy) radiation treatment, T2 imaging and DKI demonstrated areas of tumor and suspected central radiation necrosis. DKI imaging biomarkers was compared by liquid biopsy, H&E staining, and Immunohistochemistry (IHC) analysis of sacrificed mice. Our H&E staining results showed typical pathological features of GB and RN, and TR in each case. This result demonstrated that our proposed model for radiation induction was effective at achieving its goal.
20
Antipina, N., A. Belyashova, G. Pavlova, A. Nikolaeva, E. Savchenko, A. Ovechkina, D. Shamadykova e A. Golanov. "P02.02 Modeling of response to irradiation in recurrence glioblastoma’s cells culture". Neuro-Oncology 23, Supplement_2 (1 settembre 2021): ii17. http://dx.doi.org/10.1093/neuonc/noab180.055.
Testo completoAbstract (sommario):
Abstract BACKGROUND Radiosensitivity of glioblastoma (GB) cells of local relapses may be markedly different from the primary tumor. Optimal doses and regimes of re-irradiation GB recurrence is not determined yet. MATERIAL AND METHODS GO1 primary GB cell culture was obtained during removal of a recurrent tumor after combined treatment, including irradiation of the surgical bed. Сell’s culture was irradiated by photon beams with energy 6 MeV and dose rate 600 MU/min. Irradiation performed in 1, 3 and 5 fractions, by 10 different doses for each regime. The dose range was determined experimentally for one fraction (5–250 Gy); for other regimes it was calculated according to the biological equivalent dose conception (3 fractions: 5–450 Gy, 5 fractions: 5–550 Gy). The proliferative activity of cells was investigate by MTT test. The results were normalized to the control. Dose-effect curves were plotted for each irradiation regime.The experimental data were approximated by calculated curves obtained by selecting the optimal parameters of the LQ-model and it’s modification. RESULTS Irradiation of GO1 by 1 fraction with the dose 5–250 Gy, causes a slow decrease in proliferative activity, which reaches a minimum value of 23% at 150 Gy and then remains constant. After irradiation by 3 fractions, proliferative activity of the GO1 gradually decrease only at a total dose over 120 Gy and reaches 37% after 450 Gy. When GO1 was irradiated in 5 fractions, a similar dose-effect curve was obtained, gradual decrease was observed to a value of 52% in the range of 250–500 Gy. Thus, the experimental dose-effect curves for irradiation of recurrence GB cells for 3 and 5 fractions have the appreciable “shoulder”, which could be explained by increased radioresistance. When approximating the experimental data by fitting the parameters of the LQ-model, the use of α/β = 8 provided the slope of the curve, close to the experimental data. For reflecting the “shoulder” an additional summand was introduced into the mathematical expression for the number of proliferating cells - a 105 Gy for 3 fractions and 255 Gy for 5 fractions. CONCLUSION Modified LQ-model could be used for an adequate mathematical description of the effectiveness of fractionated irradiation in relapsed GB culture cells in vitro. It’s necessary to introduce a summand into the formula that determines the formation of a “shoulder” on the dose-effect curve for this. The research was supported financially by RFBR (Project No. 18-29-01061).
21
Akhunbay-Fudge, Christopher Yusuf, Kevin Critchley, Ryan Mathew e Heiko Wurdak. "CCRG-04. AUTOMATED REAL TIME TRACKING OF GLIOBLASTOMA CELL CYCLE TRANSITIONS IN ASSEMBLOIDS LINKS G2 CELLS TO INFILTRATION". Neuro-Oncology 25, Supplement_5 (1 novembre 2023): v39. http://dx.doi.org/10.1093/neuonc/noad179.0153.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) is the most aggressive primary brain tumour in adults associated with survival rates below 5% despite treatment. Tumour repopulating residual cells in the surgical cavity resist treatment due to their molecular heterogeneity. Single-cell transcriptomic studies have linked GB heterogeneity to the cell cycle; however, it remains unclear to what extent cell cycle states affect the infiltrative capacity of GB. The “go or grow” paradigm predicts that migration and proliferation are separate spatiotemporal events. We used a brain tumour-cerebral organoid (assembloid) approach to test the migratory potential of GB cell cycle phases during assembloid infiltration. Human induced pluripotent cells were differentiated into cerebral organoids that self-assemble with spheroids of patient-derived GB cells, expressing a fluorescent cell cycle reporter (FUCCI). Utilising live-cell confocal imaging, the process of GB assembloid infiltration was captured. Resultant videos were analysed with automated image analysis capable of tracking cell cycle transitions and cellular migration in confocal microscopy planes, enabling the longitudinal quantification of GB migration and invasion. Our analysis revealed a subset of highly infiltrative GB cells, containing a significant number of cycling G2 phase cells that demonstrated a ~1.4-fold increase in directional infiltrative capacity compared to their non cycling G1 phase counterparts. To isolate and characterize the G2 migratory GB cell state, we developed a phenotypic separation assay using microenvironmental cues. Specifically, we found that these cues markedly affect GB migration routes enabling the isolation of the highly migratory GB cells for further investigation. Our results question the “go or grow” hypothesis at the level of GB cellular subpopulations. We hypothesise that the observed G2 migratory capacity of GB cells could be critical to tumour recurrence following surgery. Further research is underway to define the underlying mechanisms of G2 GB cell migration.
22
Wang, Xiaowen, Matias Bustos, Xiaoqing Zhang, Romela Ramos, Cong Tan, Yuuki Iida, Shu-Ching Chang et al. "Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors". Cancers 12, n. 5 (27 aprile 2020): 1081. http://dx.doi.org/10.3390/cancers12051081.
Testo completoAbstract (sommario):
This study examined the role of the ubiquitin E3-ligase RNF123 in modulating downstream NF-κB1 targets in glioblastoma (GB) tumor progression. Our findings revealed an oncogenic pathway (miR-155-5p-RNF123-NF-κB1-p50-SerpinE1) that may represent a new therapeutic target pathway for GB patients with isocitrate dehydrogenase 1 and 2 (IDH) WT (wild type). Mechanistically, we demonstrated that RNF123 is downregulated in IDH WT GB patients and leads to the reduction of p50 levels. RNA-sequencing, reverse-phase protein arrays, and in vitro functional assays on IDH WT GB cell lines with RNF123 overexpression showed that SerpinE1 was a downstream target that is negatively regulated by RNF123. SERPINE1 knockdown reduced the proliferation and invasion of IDH WT GB cell lines. Both SerpinE1 and miR-155-5p overexpression negatively modulated RNF123 expression. In clinical translational analysis, RNF123, SerpinE1, and miR-155-5p were all associated with poor outcomes in GB patients. Multivariable analysis in IDH WT GB patients showed that concurrent low RNF123 and high SerpinE1 was an independent prognostic factor in predicting poor overall survival (p < 0.001, hazard ratio (HR) = 2.93, 95% confidence interval (CI) 1.7–5.05), and an increased risk of recurrence (p < 0.001, relative risk (RR) = 3.56, 95% CI 1.61–7.83).
23
Lessi, Francesca, Sara Franceschi, Mariangela Morelli, Michele Menicagli, Francesco Pasqualetti, Orazio Santonocito, Carlo Gambacciani et al. "Single-Cell Molecular Characterization to Partition the Human Glioblastoma Tumor Microenvironment Genetic Background". Cells 11, n. 7 (26 marzo 2022): 1127. http://dx.doi.org/10.3390/cells11071127.
Testo completoAbstract (sommario):
Background: Glioblastoma (GB) is a devastating primary brain malignancy. The recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. The barriers to treatment include the complex interactions among the different cellular components inhabiting the tumor microenvironment. The complex heterogeneous nature of GB cells is helped by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. Methods: By using fluorescent multiple labeling and a DEPArray cell separator, we recovered several single cells or groups of single cells from populations of different origins from IDH-WT GB samples. From each GB sample, we collected astrocytes-like (GFAP+), microglia-like (IBA1+), stem-like cells (CD133+), and endothelial-like cells (CD105+) and performed Copy Number Aberration (CNA) analysis with a low sequencing depth. The same tumors were subjected to a bulk CNA analysis. Results: The tumor partition in its single components allowed single-cell molecular subtyping which revealed new aspects of the GB altered genetic background. Conclusions: Nowadays, single-cell approaches are leading to a new understanding of GB physiology and disease. Moreover, single-cell CNAs resource will permit new insights into genome heterogeneity, mutational processes, and clonal evolution in malignant tissues.
24
Attia, Noha, Mohamed Mashal, Sudhakar Pemminati, Adekunle Omole, Carolyn Edmondson, Will Jones, Priyanka Priyadarshini et al. "Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies". Cells 11, n. 1 (30 dicembre 2021): 116. http://dx.doi.org/10.3390/cells11010116.
Testo completoAbstract (sommario):
Glioblastoma (GB), an aggressive primary tumor of the central nervous system, represents about 60% of all adult primary brain tumors. It is notorious for its extremely low (~5%) 5-year survival rate which signals the unsatisfactory results of the standard protocol for GB therapy. This issue has become, over time, the impetus for the discipline of bringing novel therapeutics to the surface and challenging them so they can be improved. The cell-based approach in treating GB found its way to clinical trials thanks to a marvelous number of preclinical studies that probed various types of cells aiming to combat GB and increase the survival rate. In this review, we aimed to summarize and discuss the up-to-date preclinical studies that utilized stem cells or immune cells to treat GB. Likewise, we tried to summarize the most recent clinical trials using both cell categories to treat or prevent recurrence of GB in patients. As with any other therapeutics, cell-based therapy in GB is still hampered by many drawbacks. Therefore, we highlighted several novel techniques, such as the use of biomaterials, scaffolds, nanoparticles, or cells in the 3D context that may depict a promising future when combined with the cell-based approach.
25
Patrón, Lilian A., Helen Yeoman, Sydney Wilson, Nanyun Tang, Michael E. Berens, Vijay Gokhale e Teri C. Suzuki. "Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma". Biomedicines 12, n. 2 (9 febbraio 2024): 406. http://dx.doi.org/10.3390/biomedicines12020406.
Testo completoAbstract (sommario):
Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood–brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 μM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers.
26
Comas Antón, S., S. Moreno, M. Antelo, C. Carrato, C. Balaña, S. Castañer, A. Hernández, C. Hostalot, M. Domenech e S. Villà. "P11.30.A LONG-TERM SURVIVING GLIOBLASTOMA. CLINICAL, MOLECULAR AND SURVIVAL ANALYSES". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii80. http://dx.doi.org/10.1093/neuonc/noad137.264.
Testo completoAbstract (sommario):
Abstract BACKGROUND Glioblastoma (GB) has a poor prognosis with median overall survival of 12-14 months. According to literature, patients surviving more than two years has progressively increased since 2005 and represent approximately 18% of this population, being considered long-term survivors (LTS). The aim of this study is to retrospectively analyze GB LTS treated in our Neurooncology Unit. MATERIAL AND METHODS From December 2009 to March 2021, 49 GB LTS patients were identified in our oncology data base, representing 21,7% of GB patients electronically registered during the same period. Patients were diagnosed and treated for GB according to the current WHO CNS classification at the time of diagnosis. Clinical and molecular characteristics as well as treatment and survival data were analyzed. Classic prognostic factors were analyzed including contact with the subventricular zone (SVZ) which has been identified as prognostic factor in some previous studies. RESULTS Median age at diagnosis was 57 years (range: 30-75 years). Median overall survival (OS) and median time to first progression were 43.6 months and 20.7 months respectively, with 9 patients alive and 6 patients without recurrence at the time of analyses. Rate of patients surviving more than 3, 4, 5 and 7 years were 55,1%, 20,4%, 12,24% and 6,12% respectively. Patients received a median of 2 rescue treatments after first relapse (range: 0-6 lines), including systemic therapies, surgery and re-irradiation. Rates for gross total resection, subtotal resection and biopsy were 32,6%, 47% and 20,4% respectively. pMGMT methylated patients and lesions without SVZ contact rates were 73,5% and 42,8% respectively. IDH analyses was available for 61.22% of our GB LTS patients (90% were IDH wild type and 10% mutant IDH, which according to WHO CNS 2021 classification would actually be defined as Astrocytoma grade 4). No statistical differences for OS or time to first progression were found according to sex, age (<55 years versus ≥55 years), pMGMT methylation status; Karnofsky performance status (≤70% versus >70%) and contact or not with the SVZ. CONCLUSION Classical prognostic factors did not show statistical differences for OS and time to first recurrence in our GB LTS sample, which could be explained by the small number of patients in the sample and the absence of statistically comparable differentiated groups for some of the variables. Larger and prospective analyses of GB LTS are needed. Molecular analyses with next generation sequencing (NGS) technics and radiomics analyses could apport new information predicting GB LTS.
27
Bourmeau, G., O. Anezo, A. Ballestin, C. Pichol-Thievend, J. Reveilles e G. Seano. "OS07.7.A GLIOBLASTOMA HYBRID CELL STATE CONVEYS RESISTANCE TO CONVENTIONAL THERAPIES". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii18—ii19. http://dx.doi.org/10.1093/neuonc/noad137.054.
Testo completoAbstract (sommario):
Abstract BACKGROUND Glioblastoma (GB) is a deadly disease and no therapeutic improvements have been made in the last 20 years. High phenotypic plasticity has been recognized as a major obstacle to the efficient treatment of GB. Single-cell sequencing revealed the coexistence of four different cell states within the same tumor. The transition from one subtype (or state) to another, such as from proneural (PN) to mesenchymal (MES), has been suggested as a mechanism for resistance to therapies. However, there is no prognostic value of the current GB states for patients, meaning that mechanisms of resistance may not lie in hardwire identities but in the transition from one subtype to another. Therefore, we investigated the role of the hybrid cell states in GB resistance to therapy. MATERIAL AND METHODS To dynamically follow spatiotemporal changes in GB plasticity in real time, we transduced patient-derived GB cells (patient-derived cell lines with different mutational and phenotypic landscapes) using two specific GB-subtype fluorescent synthetic genetic tracing cassettes. To follow the hybrid cell state dynamics and features, we functionally and transcriptionally investigated GB cells labeled with activated reporters for both the PN and MES subtypes. Using a combination of cytofluorimetry, live imaging, preclinical models, bulk and single-cell RNA-sequencing, we visualized the single-cell GB plasticity and studied the changes in the hybrid state subpopulation proportion over time and under therapeutic stress. RESULTS We discovered that the PN/MES hybrid state (GB-hybrid) has a definite molecular and phenotypic identity and that it is strongly induced after conventional therapies. The GB-hybrid cell state is highly resistant to therapy and more proliferative. Importantly, when implanted in mice the GB-hybrid cells were more aggressive than the rest of the cells, which is consistent with the marked prognostic power for the GB-hybrid geneset signature when tested in the TCGA database. Mechanistically, we showed that GB-hybrid cells were characterized by broad chromatin remodeling, an important increase in overall mRNA quantity per cell and intensification of the nuclear import/export machinery. CONCLUSION Here, we present a novel GB transition cell state between PN and MES subtypes/states. The GB-hybrid is at the same time highly proliferative and resistant to therapy, making it an interesting target to slow down GB recurrence after therapy.
28
Morelli, M., F. Lessi, M. Giacomarra, A. Marranci, M. Menicagli, O. S. Santonocito, P. Aretini et al. "P17.16.B INVESTIGATION OF REGORAFENIB TUMOR SENSITIVITY AND UNDERLYING TREATMENT INDUCED MOLECULAR MECHANISMS IN GLIOBLASTOMA RECURRENT TUMORS". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii120—ii121. http://dx.doi.org/10.1093/neuonc/noad137.406.
Testo completoAbstract (sommario):
Abstract BACKGROUND Glioblastoma (GB) is the most aggressive brain malignant tumor with a highly unfavorable prognosis. Maximal surgery resection, temozolomide chemotherapy (TMZ), and radiotherapy (RT), currently remain the best treatment option. Recently the phase II REGOMA clinical trial, has shown that regorafenib (REGO), a multikinase inhibitor that targets angiogenic, stromal and oncogenic tyrosine kinase receptors, significantly improves survival in GB patients.The aim of this study was to investigate Regorafenib tumor sensitivity and underlying molecular mechanisms in GB recurrent tumors leveraging on an ex vivo drug response functional precision medicine approach, that we have developed recently consisting of an in vitro vital patient-derived GB 3D organoid model and NAD(P)H Fluorescence Lifetime Imaging (FLIM). MATERIAL AND METHODS In-vitro 3D GB organoids were derived from 17 patients’ resected recurrent GB tumors. For 5 of these we had the matched primary tumor, and for other 3 we collected also the tumor peripheral portion. Totally, we obtained 25 samples. After 3 days from culture, organoids were treated with TMZ and REGO and drug response, using NAD(P)H FLIM, was assessed in the following 72 hours to stratify tumors in Sensitive (S) and Non Sensitive (NS). Whole-exome was performed on 14 tissue samples, comprising 5 primary/recurrence tumor pairs and whole-transcriptome on 11 recurrent samples before and after treatment. RESULTS Stratification of tumor cases in S and NS groups was performed both for TMZ and REGO treatment. We found 32% (n=8) and 76% (n= 19) of TMZ and REGO S tumors, respectively. Interestingly there was never a TMZ S case that was NS to REGO. Heterogeneity was found in the TMZ and REGO responsiveness for the tumor core/peripheral pair portions and in the primary/recurrence tumors pairs. It is noteworthy that all primary tumors were responsive to REGO.The drug-responsive stratification performed using our approach was also well reflected at the molecular level, as shown from transcriptome and exome RESULTS , where differently expressed genes and mutated genes were found in S versus NS tumors. CONCLUSION GB recurrent tumors resulted more responsive to REGO when compared to TMZ treatment, as expected. Thanks to our functional precision medicine approach, we were able to study the molecular alterations occurring due to the treatment, discovering biomarkers of sensitivity or resistance.
29
Lin, Chao-Qun, e Lu-Kui Chen. "Effect of differential hypoxia-related gene expression on glioblastoma". Journal of International Medical Research 49, n. 5 (maggio 2021): 030006052110137. http://dx.doi.org/10.1177/03000605211013774.
Testo completoAbstract (sommario):
Objective Glioblastoma (GB) is a refractory malignancy with a high rate of recurrence and treatment resistance. Hypoxia-related genes are promising prognostic indicators for GB, so we herein developed a reliable hypoxia-related gene risk scoring model to predict the prognosis of patients with GB. Method Gene expression profiles and corresponding clinicopathological features of patients with GB were obtained from the Cancer Genome Atlas (TCGA; n = 160) and Gene Expression Omnibus (GEO) GSE7696 (n = 80) databases. Univariate and multivariate Cox regression analyses of differentially expressed hypoxia-related genes were performed using R 3.5.1 software. Result Fourteen prognosis-related genes were identified and used to construct a risk signature. Patients with high-risk scores had significantly lower overall survival (OS) than those with low-risk scores. The median risk score was used as a critical value and for OS prediction in an independent external verification GSE7696 cohort. Risk score was not significantly affected by clinical-related factors. We also developed a prediction nomogram based on the TCGA training set to predict survival rates, and included six independent prognostic parameters in the TCGA prediction model. Conclusion We determined a reliable hypoxia-related gene risk scoring model for predicting the prognosis of patients with GB.
30
Zimmer, Niklas, Emily R. Trzeciak, Andreas Müller, Philipp Licht, Bettina Sprang, Petra Leukel, Volker Mailänder et al. "Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients". Cancers 15, n. 24 (5 dicembre 2023): 5711. http://dx.doi.org/10.3390/cancers15245711.
Testo completoAbstract (sommario):
Glioblastoma (GB) is notoriously resistant to therapy. GB genesis and progression are driven by glioblastoma stem-like cells (GSCs). One goal for improving treatment efficacy and patient outcomes is targeting GSCs. Currently, there are no universal markers for GSCs. Glycoprotein A repetitions predominant (GARP), an anti-inflammatory protein expressed by activated regulatory T cells, was identified as a possible marker for GSCs. This study evaluated GARP for the detection of human GSCs utilizing a multidimensional experimental design that replicated several features of GB: (1) intratumoral heterogeneity, (2) cellular hierarchy (GSCs with varied degrees of self-renewal and differentiation), and (3) longitudinal GSC evolution during GB recurrence (GSCs from patient-matched newly diagnosed and recurrent GB). Our results indicate that GARP is expressed by GSCs across various cellular states and disease stages. GSCs with an increased GARP expression had reduced self-renewal but no alterations in proliferative capacity or differentiation commitment. Rather, GARP correlated inversely with the expression of GFAP and PDGFR-α, markers of astrocyte or oligodendrocyte differentiation. GARP had an abnormal nuclear localization (GARPNU+) in GSCs and was negatively associated with patient survival. The uniformity of GARP/GARPNU+ expression across different types of GSCs suggests a potential use of GARP as a marker to identify GSCs.
31
Cardoso, Ana M., Catarina M. Morais, Frederico Pena, Tânia Marante, Pedro P. Cunha, Amália S. Jurado e Maria C. Pedroso de Lima. "Differentiation of glioblastoma stem cells promoted by miR-128 or miR-302a overexpression enhances senescence-associated cytotoxicity of axitinib". Human Molecular Genetics 30, n. 3-4 (12 gennaio 2021): 160–71. http://dx.doi.org/10.1093/hmg/ddab011.
Testo completoAbstract (sommario):
Abstract Despite the intense global efforts towards an effective treatment of glioblastoma (GB), current therapeutic options are unsatisfactory with a median survival time of 12–15 months after diagnosis, which has not improved significantly over more than a decade. The high tumoral heterogeneity confers resistance to therapies, which has hindered a successful clinical outcome, GB remaining among the deadliest cancers. A hallmark of GB is its high recurrence rate, which has been attributed to the presence of a small subpopulation of tumor cells called GB stem-like cells (GSC). In the present work, the efficacy of a multimodal strategy combining microRNA (miRNA) modulation with new generation multitargeted tyrosine kinase inhibitors (imatinib and axitinib) was investigated aiming at tackling this subpopulation of GB cells. MiR-128 and miR-302a were selected as attractive therapeutic candidates on the basis of previous findings reporting that reestablishment of their decreased expression levels in GSC resulted in cell differentiation, which could represent a possible strategy to sensitize GSC to chemotherapy. Our results show that overexpression of miR-128 or miR-302a induced GSC differentiation, which enhanced senescence mediated by axitinib treatment, thus further impairing GSC proliferation. We also provided evidence for the capacity of GSC to efficiently internalize functionalized stable nucleic acid lipid particles, previously developed and successfully applied in our laboratory to target GB. Taken together, our findings will be important in the future design of a GB-targeted multimodal miRNA-based gene therapy, combining overexpression of miR-128 or miR-302a with axitinib treatment, endowed with the ability to overcome drug resistance.
32
Lucas Calduch, A., M. Macià Garau, S. Villà Freixa, G. Plans Ahicart, C. Mesía Barroso, C. Majós Torró, A. Pons Escoda et al. "P17.09.B REIRRADIATION AS A SALVAGE THERAPY FOR LOCAL GLIOBLASTOMA RECURRENCE". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii118—ii119. http://dx.doi.org/10.1093/neuonc/noad137.399.
Testo completoAbstract (sommario):
Abstract BACKGROUND There is a lack of successful strategies to treat glioblastoma (GB) recurrences. Reirradiation is one of them, but it only can be considered in a few patients with localized relapses. This review aims to analyse the role of reirradiation in this setting and the management difficulties associated with this strategy. MATERIAL AND METHODS We have retrospectively reviewed the outcome of GB patients treated with surgery and the standard Stupp regimen, that have received stereotactic radiotherapy (RT) at the time of a local in-field relapse in our centre, during the period from 2005 to 2022. RESULTS 44 patients have been identified. The recurrence occurred at a median time of 9.7 months (m) after the end of the first RT. It was the first relapse in 89% of patients, and RT was given exclusively in 47.7% of cases. In the remaining patients, RT was combined with other treatments. The median maximum diameter of the relapse was 13.5 mm. Treatment schemes were mainly two: 35 Gy in 3.5 Gy daily fractions (52%) and 20 Gy in 5 Gy daily fractions (39%). Acute toxicity was mild, with worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 m, radiological responses were observed in 40% of patients, with a remarkable number of distant progressions in less than 6m (32.5%). The median time to progression was 4.8 m, being longer for patients treated at first relapse, females and with a Karnofsky index (KI) >70. The diameter of the relapse showed a tendency to impact in time to progression, but no differences for RT dose, RT scheme or type of strategy (exclusive RT vs combined) have been detected. The median overall survival after reirradiation was 14.9 m. Related prognostic factors were KI >70, size of the relapse (maximum diameter <25 mm) and reirradiation given at first relapse. Radiological changes after reirradiation were commonly observed (47% of patients); differentiating them from true local progression was often difficult. CONCLUSION Reirradiation is a feasible and safe therapeutic option to treat localized GB relapses, able to control the disease for a few months in selected patients, especially those with first recurrences and small lesions. Further studies must be performed to improve the radiological evaluation in these patients and to determine the optimal combination with other treatment modalities.
33
Clavreul, Anne, Lila Autier, Jean-Michel Lemée, Paule Augereau, Gwénaëlle Soulard, Luc Bauchet, Dominique Figarella-Branger, Philippe Menei e FGB Network. "Management of Recurrent Glioblastomas: What Can We Learn from the French Glioblastoma Biobank?" Cancers 14, n. 22 (9 novembre 2022): 5510. http://dx.doi.org/10.3390/cancers14225510.
Testo completoAbstract (sommario):
Safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) is universally accepted as the first-line treatment for glioblastoma (GB), but no standard of care has yet been defined for managing recurrent GB (rGB). We used the French GB biobank (FGB) to evaluate the second-line options currently used, with a view to defining the optimal approach and future directions in GB research. We retrospectively analyzed data for 338 patients with de novo isocitrate dehydrogenase (IDH)-wildtype GB recurring after TMZ chemoradiotherapy. Cox proportional hazards models and Kaplan–Meier analyses were used to investigate survival outcomes. Median overall survival after first surgery (OS1) was 19.8 months (95% CI: 18.5–22.0) and median OS after first progression (OS2) was 9.9 months (95% CI: 8.8–10.8). Two second-line options were noted for rGB patients in the FGB: supportive care and treatments, with systemic treatment being the treatment most frequently used. The supportive care option was independently associated with a shorter OS2 (p < 0.001). None of the systemic treatment regimens was unequivocally better than the others for rGB patients. An analysis of survival outcomes based on time to first recurrence (TFR) after chemoradiotherapy indicated that survival was best for patients with a long TFR (≥18 months; median OS1: 44.3 months (95% CI: 41.7–56.4) and median OS2: 13.0 months (95% CI: 11.2–17.7), but that such patients constituted only a small proportion of the total patient population (13.0%). This better survival appeared to be more strongly associated with response to first-line treatment than with response to second-line treatment, indicating that the recurring tumors were more aggressive and/or resistant than the initial tumors in these patients. In the face of high rates of treatment failure for GB, the establishment of well-designed large cohorts of primary and rGB samples, with the help of biobanks, such as the FGB, taking into account the TFR and survival outcomes of GB patients, is urgently required for solid comparative biological analyses to drive the discovery of novel prognostic and/or therapeutic clinical markers for GB.
34
Vilarino, Noelia, Neus Martinez-Bosch, Carmen Balana, Francesc Alameda, Anna Estival, Estela Pineda, Sonia del Barco et al. "Galectin-1 (Gal-1) expression as a prognostic factor in patients with newly diagnosed glioblastoma (GB) treated with Stupp regimen (GLIOCAT study)." Journal of Clinical Oncology 35, n. 15_suppl (20 maggio 2017): e13526-e13526. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13526.
Testo completoAbstract (sommario):
e13526 Background: Gal-1 is a β-galactoside binding protein that plays an important role in cancer, promoting cell invasion, proliferation, migration, angiogenesis and evasion of the immune response. Gal-1 is involved in glioma progression and is related to tumor grade and poor clinical outcome. Gal-1 has been implicated in resistance to chemotherapy and as a potential mediator of resistance to anti-VEGF therapy. The aim of our study was to evaluate the prognostic significance of Gal-1 in a homogenous cohort of GB patients and to analyze its potential predictive value of response to bevacizumab at recurrence. Methods: A substudy of GLIOCAT, a multicenter study of newly diagnosed GB patients treated with standard Stupp regimen (previously reported). GLIOCAT enrolled 432 patients between 2005-2014. Tissue was available from 243 cases, from which a tissue microarray (TMA) was constructed. Gal-1 expression in tissue from initial surgery was analyzed by immunohistochemistry. Results were evaluated by three reviewers and quantified by H-score. Expression levels were correlated with clinical outcome, known GB prognostic factors and response to bevacizumab. Results: We defined a cut off for Gal-1 H-Score of >60 (cytoplasm) and >25 (nucleus). HighcytoplasmicGal-1 expression significantly correlated with worse OS and with a trend for shorter PFS. In the multivariate analysis KPS, age, MGMT methylation status and, extent of resection but not Gal-1 expression were independent prognostic factors for survival. Of 92 patients who received bevacizumab at recurrence, only 54 were included in the TMA, and only 1 had low Gal-1 expression. We couldn’t find any relationship with OS or PFS in this population. Conclusions: Gal-1 expression may represent a prognostic factor for GB patients treated with standard therapy. [Table: see text]
35
Lee, Sang Hun, Yong Mi Seol e Dong Uk Kim. "Preoperative risk factors related to relapse-free survival after R0 resection of gallbladder cancer." Journal of Clinical Oncology 42, n. 3_suppl (20 gennaio 2024): 566. http://dx.doi.org/10.1200/jco.2024.42.3_suppl.566.
Testo completoAbstract (sommario):
566 Background: Gallbladder (GB) cancer shows high prevalence in South Korea, and tends to be fatal. In surgically fit patients, radical resection aiming R0 margin combined with lymphadenectomy is the mainstay of curative-intent therapy. In spite of R0 resection, however, high recurrence rate is observed in GB cancer, demanding a need to find out risk factors related to recurrence after surgery. Methods: This is a single center, retrospective cohort study conducted on 148 patients with GB cancer who underwent R0 resection between January 1st, 2014 and December 31st, 2019. Several variables were analyzed with statistical tools to identify risk factors related to prognosis. Relapse free survival (RFS), defined as time from treatment of disease to any event, was analyzed with Cox regression analysis. Results: Based on statistical analysis, risk factors related to RFS were age over 65 (hazard ratio [HR] 3.82, 95% confidence interval [CI] 1.71 – 8.56, p= .001), glycated hemoglobin (HbA1c) level more than 6.5% (HR 2.72, 95% CI 1.31 – 5.66, p=0.007), surgical T stage more than T3 (HR 5.60, 95% CI 3.05 – 10.25, p<0.001), surgical N stage more than N1 (HR 4.07, 95% CI 2.25 – 7.36, p<0.001), pathologic differentiation of moderate or poor differentiation (HR 2.80, 95% CI 1.46 – 5.37, p=0.002), reversed albumin-globulin ratio (HR 0.16, 95% CI 0.06 – 0.40, p<0.001), and high gamma glutamyl peptidase (GGT) level (HR 1.00, 95% CI 1.00 – 1.00, p<0.001). Conclusions: Advanced pathologic stage and high inflammatory marker levels, reflecting high tumor burden, were related with poor surgical outcome. Interestingly, high HbA1c level was related to reduced RFS as well. In conclusion, active screening for early detection, reducing inflammatory conditions, and managing diabetes might enhance RFS after R0 resection of GB cancer. [Table: see text]
36
Bynoe, Margaret S. "Glioblastoma usurps host extracellular adenosine to circumvent host anti-tumor Responses". Journal of Immunology 198, n. 1_Supplement (1 maggio 2017): 76.17. http://dx.doi.org/10.4049/jimmunol.198.supp.76.17.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) is the most aggressive, fatal, and least successfully treated of all solid brain tumors due to its high capacity to proliferate and extreme chemoresistance. Treatment for GB patients is managed with multimodal therapies including surgical resection (if possible), radiotherapy and chemotherapy with temozolomide (one of the few drugs shown to have some effect). Despite this, patient survival ranges between 6–18 months. Because GB is highly infiltrative, it often invades normal brain tissue, sometimes preventing surgical resection, which inevitably leads to recurrence. Adenosine is an immune suppressive signaling molecule that is generated by the enzymatic action of CD73. I tested the hypothesis that GB usurps host extracellular adenosine to circumvent host anti-tumor mechanisms by down regulating macrophage/microglial cell immune responses and promote M2 instead of M1 macrophage/microglial phenotype. To test this, I isolated macrophage/microglial cells from the tumor microenvironment of mice lacking or expressing CD73. Compared to WT mice, the frequency of M1 verses M2 phenotypes showed that eighty percent of the macrophage/microglial cells present in the tumor microenvironment of CD73−/− mice exhibited an M1 phenotype, while WT mice had about 30 percent M1 phenotype.
37
Hervás-Corpión, Irati, Jorge Navarro-Calvo, Paula Martín-Climent, Marianela Iriarte-Gahete, Noelia Geribaldi-Doldán, Carmen Castro e Luis M. Valor. "Defining a Correlative Transcriptional Signature Associated with Bulk Histone H3 Acetylation Levels in Adult Glioblastomas". Cells 12, n. 3 (19 gennaio 2023): 374. http://dx.doi.org/10.3390/cells12030374.
Testo completoAbstract (sommario):
Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.
38
Sun, Xuheng, Yijun WANG e Yingbin Liu. "Construction and validation of the prognostic model for patients with gallbladder neuroendocrine neoplasm-based a nationwide retrospective registry study." Journal of Clinical Oncology 40, n. 16_suppl (1 giugno 2022): e16140-e16140. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e16140.
Testo completoAbstract (sommario):
e16140 Background: Gallbladder neuroendocrine neoplasm (GB-NEN) is an extremely rare type of gallbladder neoplasm and the prognosis of patients with GB-NENs varies widely. The focus of this study was to construct and validate a prognostic model of GB-NENs based on the data from a nationwide retrospective multicenter registry cohort. Methods: The Chinese Research Group of Gallbladder Cancer (CRGGC) study is a multicenter retrospective registry cohort study reviewing the electronic medical records from 76 tertiary and secondary hospitals across 28 provinces in China. We assembled patients with GB-NEN diagnosed between 2010 and 2017 in 24 tertiary hospitals from CRGGC study. Influential factors of recurrence free survival (RFS) and overall survival (OS) were identified using Least absolute shrinkage and selection operator (LASSO) regression and Cox predicting model was constructed for predicting RFS and OS. The prognostic model was validated both internally and externally. Performance of the model was assessed by concordance index (C-index) and calibration curves stratified by risk categories. Results: A total of 84 patients with GB-NEN was extracted from CRGGC study, among which 3 were diagnosed with GB-NEN Grade 1, 8 were diagnosed with GB-NEN Grade 2 and 35 with GB-NEN Grade 3. Of the 35 patients with GB-NEN Grade 3, 3 had poorly differentiated small-cell neuroendocrine carcinomas (SC-NECs) and 8 patients had Mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). 53 patients were included in the training group (median survival, 21.1 months; 95% confidence interval (CI), 13.8-37.6 months) and 31 patients in the validation cohort (median survival, 34.3 months; 95% CI, 9.63-58.97months). A Cox predicting model was built, including 5 variables (age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined). The C-index was 78.1 (95% CI, 63.9-92.3), with a good calibration, and these results were confirmed in the internal validation cohorts. Conclusions: We have built a clinical model for GB-NEN patients and clinical doctors for prognosis prediction based on age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined which can be easily obtained in one’s case history. It can be used to determine subgroups of patients who may have poorer prognosis and assist individualized and precise treatment for GB-NEN.
39
Todkar, Sampatti Sambhaji, e Lagdir Appasaheb Gaikwad. "Outcome of suspected H1N1 influenza cases admitted in tertiary care Govt. Hospital Solapur, Maharashtra". Indian Journal of Medical Sciences 69, n. 1 (28 marzo 2017): 6. http://dx.doi.org/10.18203/issn.0019-5359.indianjmedsci20170482.
Testo completoAbstract (sommario):
<span class="ABS_Bold-Italic" lang="en-GB">Introduction:</span><span> Influenza (H1N1) is very sensitive and newly emerged pandemic. Influenza (H1N1) pandemics are caused by new influenza viruses that have recently adapted to humans and resemble major natural disasters both in terms of recurrence and magnitude. </span><span class="ABS_Bold-Italic" lang="en-GB">Aims and Objectives:</span><span> To study the outcome and epidemiological factors of suspected H1N1 influenza cases. </span><span class="ABS_Bold-Italic" lang="en-GB">Study Design:</span><span> Hospital-based descriptive study, </span><span class="ABS_Bold-Italic" lang="en-GB">Study Period:</span><span> Study was conducted over a period of seven months from April 2009 to October 2009. </span><span class="ABS_Bold-Italic" lang="en-GB">Study Variable:</span><span> Outcome, age, sex, time, place of residence. </span><span class="ABS_Bold-Italic" lang="en-GB">Results and Discussion:</span><span> The total 110 cases of suspected H1N1 influenza were admitted in Infectious diseases ward of Government Hospital Solapur. Out of 110 total suspected cases, 91 (82.72%) were cured and discharged. Among these 91 (82.72%) suspected cases, 17 (15.45%) were laboratory confirmed for Influenza (H1N1). </span><span class="ABS_Bold-Italic" lang="en-GB">Conclusion:</span><span> In present study, maximum case fatality rate (32%) was observed in females in age group of 15-44 years as compared to male.</span>
40
Mann, Anmol, Nur Safa, Emma Martell, Wenxia Luo, Prasanta Paul, Parandoush Abbasian, Rashid Ahmed et al. "BSCI-07 ACETYL-AMANTADINE AS A DIAGNOSTIC BIOMARKER IN PATIENTS WITH GLIOBLASTOMA". Neuro-Oncology Advances 4, Supplement_1 (1 agosto 2022): i2. http://dx.doi.org/10.1093/noajnl/vdac078.007.
Testo completoAbstract (sommario):
Abstract AIM Glioblastoma (GB) is the most common malignant primary brain tumor in adults, with a prognosis as poor as 12-15 months with standard treatment. Spermidine/spermine N1-acetyltransferase (SAT1) is a rate limiting enzyme in polyamine metabolism and has been reported to be upregulated in various cancers, including GB. Amantadine is a Health Canada approved drug that is acetylated by SAT1. We established a clinical trial in GB patients to determine if plasma and urine acetyl amantadine (Ac-Am) can be used to measure SAT1 activity and whether levels correlate with their tumor burden. METHODS A clinical trial was established that is currently active and recruiting patients with GB who receive care at CancerCare Manitoba. A total of n=8 participants have been recruited thus far. Participants’ blood and urine were collected two hours after ingesting amantadine (200 mg). Levels of serum and urine Ac-Am were measured using liquid chromatography-tandem mass spectrometry. Acetyl-amantadine levels were correlated with tumour bidimensional diameter and volume measured on MRI. In addition, expression of SAT1 was examined in various cultured GB cells (both cell lines and patient-derived cells) and correlated with Ac-Am. RESULTS Preliminary results indicate that the levels of plasma Ac-Am in study participants positively correlate with their initial tumor burden (r = 0.41). While transient increases in plasma and urine Ac-Am above baseline levels were observed, the clinical significance of these findings is undergoing further analysis. SAT1 was detected in all the GB tumor cells examined. The production of Ac-Am in cultured GB cells varied as a function of SAT1 expression. SIGNIFICANCE A diagnostic biomarker, such as Ac-Am, that could effectively and reliably detect tumor progression and recurrence would be an invaluable adjunct to MRI imaging and could significantly impact the timing of appropriate treatment and reduce patients’ morbidity and mortality.
41
Sokolov, Dmitry K., Oleg B. Shevelev, Anna S. Khotskina, Alexandra Y. Tsidulko, Anastasia V. Strokotova, Galina M. Kazanskaya, Alexander M. Volkov et al. "Dexamethasone Inhibits Heparan Sulfate Biosynthetic System and Decreases Heparan Sulfate Content in Orthotopic Glioblastoma Tumors in Mice". International Journal of Molecular Sciences 24, n. 12 (16 giugno 2023): 10243. http://dx.doi.org/10.3390/ijms241210243.
Testo completoAbstract (sommario):
Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5–6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5–2-fold), the inhibition of HS biosynthetic system mainly due to the -3–3.5-fold down-regulation of N-deacetylase/N-sulfotransferases (Ndst1 and Ndst2) and sulfatase 2 (Sulf2) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes (Ext1/2, Ndst1/2, Glce, Hs2st1, Hs6st1/2), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content.
42
Kurz, Sabine K., e Matthias J. Reddehase. "Patchwork Pattern of Transcriptional Reactivation in the Lungs Indicates Sequential Checkpoints in the Transition from Murine Cytomegalovirus Latency to Recurrence". Journal of Virology 73, n. 10 (1 ottobre 1999): 8612–22. http://dx.doi.org/10.1128/jvi.73.10.8612-8622.1999.
Testo completoAbstract (sommario):
ABSTRACT The lungs are a significant organ site of murine cytomegalovirus (mCMV) latency. We have shown that activity of the major immediate-early promoter (MIEP), which drives the transcription from the ie1-ie3 transcription unit, does not inevitably initiate the productive cycle (S. K. Kurz, M. Rapp, H.-P. Steffens, N. K. A. Grzimek, S. Schmalz, and M. J. Reddehase, J. Virol. 73:482–494, 1999). Thus, even though MIEP activity governed by the MIEP-enhancer is unquestionably the first condition for recurrence, regulation of the enhancer by transcription factors is not the only mechanism controlling latency. Specifically, during latency, focal and stochastic MIEP activity in lung tissue was found to selectively generate IE1 transcripts, while transactivator-specifying IE3 transcripts were missing. This suggested a control of mCMV latency that is effectual at IE1-IE3 precursor mRNA cotranscriptional processing. Here we have used this model for studying the kinetics of reactivation and recurrence in individual lung tissue pieces after hematoablative, genotoxic treatment. Notably, reactivation was triggered, but the number of transcriptionally active foci in the lungs did not increase over time. This result is not compatible with a model of spontaneous reactivations accumulating after withdrawal of immune control. Instead, the data support the idea that reactivation is an induced event. In some pieces, focal reactivation generated IE3 transcripts but not gB transcripts, while other pieces contained foci that had proceeded to gB transcription, and only a few foci actually reached the state of virus recurrence. This finding indicates the existence of several sequentially ordered control points in the transition from mCMV latency to recurrence.
43
Chernov, Alexandr, Irina Baldueva, Tatyana Nekhaeva, Elvira Galimova, Diana Alaverdian e Olga Shamova. "The molecular mechanisms of multidrug resistance of human glioblastomas". Problems in oncology 67, n. 1 (4 marzo 2021): 20–28. http://dx.doi.org/10.37469/0507-3758-2021-67-1-20-28.
Testo completoAbstract (sommario):
In review discusses the phenomenon of drug resistance of GB in the context of the expression of ABC family transporter proteins and the processes of proliferation, angiogenesis, recurrence and death. The emphasis is on the identifying for molecular targets among growth factors, receptors, signal transduction proteins, microRNAs, transcription factors, proto-oncogenes, tumor suppressor genes and their polymorphic variants (SNPs) for the development and creation of targeted anticancer drugs.
44
Mendes, Maria, João José Sousa, Alberto Pais e Carla Vitorino. "Targeted Theranostic Nanoparticles for Brain Tumor Treatment". Pharmaceutics 10, n. 4 (9 ottobre 2018): 181. http://dx.doi.org/10.3390/pharmaceutics10040181.
Testo completoAbstract (sommario):
The poor prognosis and rapid recurrence of glioblastoma (GB) are associated to its fast-growing process and invasive nature, which make difficult the complete removal of the cancer infiltrated tissues. Additionally, GB heterogeneity within and between patients demands a patient-focused method of treatment. Thus, the implementation of nanotechnology is an attractive approach considering all anatomic issues of GB, since it will potentially improve brain drug distribution, due to the interaction between the blood–brain barrier and nanoparticles (NPs). In recent years, theranostic techniques have also been proposed and regarded as promising. NPs are advantageous for this application, due to their respective size, easy surface modification and versatility to integrate multiple functional components in one system. The design of nanoparticles focused on therapeutic and diagnostic applications has increased exponentially for the treatment of cancer. This dual approach helps to understand the location of the tumor tissue, the biodistribution of nanoparticles, the progress and efficacy of the treatment, and is highly useful for personalized medicine-based therapeutic interventions. To improve theranostic approaches, different active strategies can be used to modulate the surface of the nanotheranostic particle, including surface markers, proteins, drugs or genes, and take advantage of the characteristics of the microenvironment using stimuli responsive triggers. This review focuses on the different strategies to improve the GB treatment, describing some cell surface markers and their ligands, and reports some strategies, and their efficacy, used in the current research.
45
Ballestín, A., C. Pichol-Thievend, G. Bourmeau, B. Blanchard, A. Pettiwala, J. Reveilles, S. Leboucher, O. Anezo e G. Seano. "P10.20.B POSTOPERATIVE ISCHEMIA CAUSED BY MICROSURGICAL RESECTION PROMOTES PRONEURAL-TO-MESENCHYMAL TRANSITION IN GLIOBLASTOMA". Neuro-Oncology 25, Supplement_2 (1 settembre 2023): ii66—ii67. http://dx.doi.org/10.1093/neuonc/noad137.218.
Testo completoAbstract (sommario):
Abstract BACKGROUND Four glioblastoma (GB) cellular states drive the intratumoral heterogeneity of this lethal primary brain tumor and are influenced by genetics, the tumor microenvironment (TME), and response to treatment. The impact of microsurgical resection on the TME and plasticity of GB cells is unknown. Postoperative cerebral ischemic events have been described after these surgical resections, altering the proper distribution of subsequent chemo-radiotherapy treatment. Despite the aggressive standard of care, 90% of patients experience recurrence a few months after treatment and it usually begins with the regrowth of highly invasive cells that spread from the peritumoral brain resection zone. Therefore, the objective of this study was to perform morphological and transcriptomic phenotyping of residual tumor cells and TME after microsurgical resection. MATERIAL AND METHODS The GFP-transduced syngeneic GB IDH-wildtype cell lines CT2A and GL261 were orthotopically implanted in C57Bl6j mice brains. We developed a refined microsurgical resection protocol for GB in a size-matched study by carefully following the same surgical steps performed in patients. Mice were randomly divided into four groups: control (prior to surgery) and 1, 3, and 7 days post-surgery. Tumor tissues were harvested for time-resolved bulk and single-cell RNA sequencing as well as immunohistochemistry (IHC) studies. RESULTS According to our time-resolved transcriptomic and IHC analyses, microsurgical resection induced pronounced proneural-to-mesenchymal transition (PMT), chromatin remodeling, and stimulation of hypoxia-driven pathways in residual GB cells after surgery. Moreover, single-cell RNA-seq of post-resection tumors allowed us to observe significant changes in the TME relative to the immune response and vascular function in line with ischemia exposure. CONCLUSION The impact of microsurgical resection has important consequences on the phenotypic landscape of GB tumor cells and TME, which is characterized by a transient ischemic TME that induces PMT in GB cells. In addition, we developed a refined microsurgical resection model that can be useful in a wide variety of preclinical studies. Support/Disclosure: This study was supported by the Institut National du Cancer (INCa; 1154 INCa-2020-1-PLBIO-01-ICR-1) and by the Marie Skłodowska-Curie Postdoctoral Fellowship under the European Union’s programme Horizon2020 (HORIZON-MSCA-2021-PF-01, GlioSurg, Grant agreement ID: 101061921).
46
Giordano, Carolina, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano e Simona Gaudino. "Abstract 5474: Combined use of MRI and TAM analysis in GB monitoring". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 5474. http://dx.doi.org/10.1158/1538-7445.am2023-5474.
Testo completoAbstract (sommario):
Abstract Glioblastoma (GB) is the most frequent and aggressive primary brain tumor. It is a highly infiltrating tumor. Complete eradication by surgery is difficult. The probability of survival beyond two years is very low. Magnetic resonance imaging (MRI) is a routine procedure for diagnosing gliomas. However, morphological MRI often fails to identify and quantify the presence of infiltration in peritumoral non-enhanced areas, resulting in inaccuracy in the assessment of invasive margins. Up to 50% of the patients show pseudo-progression. Morphological MRI fails to distinguish the marked enhancement in the tumor bed caused by radionecrosis from actual tumor progression. Diagnosis of GB recurrence through MR morphological sequences has a sensitivity and specificity of about 68% and 77%. Such percentages rise thanks to the use of non-morphological sequences (PWI, DWI, MRS), which are used in routine tumor protocols only in large centers and interpreted by expert neuroradiologists. Biomarkers in conjunction with MRI may help improve the classification, prognosis, and treatment choice. GB is highly infiltrated with monocytic cells, tumor-associated macrophages (TAMs), that invade the peripheral blood. Our group has recently identified a splice isoform of FK506-binding protein 51 (FKBP51) as a reliable TAM marker. We found an expansion in circulating CD163/FKBP51s monocytes in a cohort of GB patients. In patients with an MRI diagnosis of complete surgical tumor removal, these monocytes dramatically decreased. In patients with an MRI diagnosis of residual tumor, most of the peripheral CD163 monocytes that in the preoperative stage were FKBP51s- had turned into FKBP51s+. CD163/FKBP51s+ monocytes helped to distinguish between radionecrosis and actual tumor progression. These results suggest that circulating CD163/FKBP51s+ monocytes are associated with GB and can be helpful in monitoring GB patients. Citation Format: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino. Combined use of MRI and TAM analysis in GB monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5474.
47
Antelo, G., I. Valduvieco, S. Comas, S. Serrano, J. Molero, C. Balañá, S. Villà, S. Moreno, M. Mollà e C. Gomà. "P11.36.A Could a transcriptome profile predict local control for glioblastoma?" Neuro-Oncology 24, Supplement_2 (1 settembre 2022): ii65. http://dx.doi.org/10.1093/neuonc/noac174.225.
Testo completoAbstract (sommario):
Abstract Background Glioblastoma (GB) is the most frequent and aggressive primary brain tumor in adults. The standard of care is surgery followed by radiotherapy in combination with temozolomide. GB molecular subtypes (Classical [CL], Mesenchimal [MES] and Proneural [PN]) have been correlated with prognosis. In the preclinical setting, CL and MES glioma stem-like initiating cells have also been shown to be more radioresistant than PN subtype. If confirmed in patients, the molecular subtype could predict the specific benefit of adjuvant treatment. The aim of this work is therefore to investigate whether GB molecular profiles are associated with treatment resistance in vivo. Material and Methods We analyzed the spatiotemporal pattern of recurrence (progression-free survival [PFS] and local control) in 37 GB patients treated with adjuvant radiotherapy (30 x 2 Gy, following EORTC contouring guidelines) plus temozolomide in the context of a multi-centric study. Relapse was defined following the RANO criteria (gadolinium enhanced area on MRI T1 sequence) and classified into 3 groups: in-field relapse (Dmean > 57 Gy), out-of-field relapse (Dmean < 48 Gy) and not-defined relapse (no follow-up MR data or marginal relapse). We used three different classification algorithms (SVM, K-Nearest Neighbor and single sample gene set enrichment analysis) for the transcriptomic classification of tumor samples, and we only assigned a molecular profile when all three classifications agreed, otherwise we called it Mixed profile. Patients with a not-defined spatial pattern of recurrence were included in the PFS analysis, but excluded from the local control analysis. Results The transcriptomic classification resulted in 14 CL, 1 MES, 9 PN and 13 Mixed. Median PFS after radiotherapy was 6 months, with a mean follow-up of 11 months. No differences in PFS were found between CL, PN and Mixed groups (the single MES case was excluded). Local control was analyzed in 24 patients (10 CL, 4 PN, 10 Mixed). Non- statistically significant differences were found between PN/Mixed and CL subtypes, with a median in-field relapse-free survival of 6.9 months (PN), 6.3 months (Mixed) and 4.7 months (CL). Conclusion Although there is no difference in PFS among GB molecular subtypes, these results suggest that the Classical subtypes seem to relapse faster inside the radiotherapy field. This would suggest a higher radioresistance compared to Proneural and Mixed subtypes, in agreement with preclinical data. Due to the low number of patients these differences are statistically non-significant, but they provide the rationale for further investigation in a larger patient cohort. Grant: Marató -TV3
48
Fan, Qing Qing, He Li e Hong Xi Yin. "Study on Optical Performance Monitoring for Fiber-Optical Link Utilizing Chaos Theory". Advanced Materials Research 571 (settembre 2012): 390–94. http://dx.doi.org/10.4028/www.scientific.net/amr.571.390.
Testo completoAbstract (sommario):
Optical-link performance monitoring (OLPM) plays a crucial role in ensuring the link performance, the channel assignment and the network reconfiguration in the high-speed and WDM optical networks. An OLPM scheme based on the chaos theory and the pattern recognition is proposed in this paper. The identification results of nonlinear regimes of 4/8/16-channel WDM links with 10 Gb/s are demonstrated through utilizing the maximum Lyapunov exponent, the recurrence plot and the two-layer perceptron.
49
Humphreys, Luke M., Paul Smith, Zhuoyao Chen, Shahd Fouad e Vincenzo D’Angiolella. "The role of E3 ubiquitin ligases in the development and progression of glioblastoma". Cell Death & Differentiation 28, n. 2 (11 gennaio 2021): 522–37. http://dx.doi.org/10.1038/s41418-020-00696-6.
Testo completoAbstract (sommario):
AbstractDespite recent advances in our understanding of the disease, glioblastoma (GB) continues to have limited treatment options and carries a dismal prognosis for patients. Efforts to stratify this heterogeneous malignancy using molecular classifiers identified frequent alterations in targetable proteins belonging to several pathways including the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signalling pathways. However, these findings have failed to improve clinical outcomes for patients. In almost all cases, GB becomes refractory to standard-of-care therapy, and recent evidence suggests that disease recurrence may be associated with a subpopulation of cells known as glioma stem cells (GSCs). Therefore, there remains a significant unmet need for novel therapeutic strategies. E3 ubiquitin ligases are a family of >700 proteins that conjugate ubiquitin to target proteins, resulting in an array of cellular responses, including DNA repair, pro-survival signalling and protein degradation. Ubiquitin modifications on target proteins are diverse, ranging from mono-ubiquitination through to the formation of polyubiquitin chains and mixed chains. The specificity in substrate tagging and chain elongation is dictated by E3 ubiquitin ligases, which have essential regulatory roles in multiple aspects of brain cancer pathogenesis. In this review, we begin by briefly summarising the histological and molecular classification of GB. We comprehensively describe the roles of E3 ubiquitin ligases in RTK and MAPK, as well as other, commonly altered, oncogenic and tumour suppressive signalling pathways in GB. We also describe the role of E3 ligases in maintaining glioma stem cell populations and their function in promoting resistance to ionizing radiation (IR) and chemotherapy. Finally, we consider how our knowledge of E3 ligase biology may be used for future therapeutic interventions in GB, including the use of blood–brain barrier permeable proteolysis targeting chimeras (PROTACs).
50
Helaine, Charly, Aurélie E. Ferré, Marine M. Leblond, Elodie A. Pérès, Myriam Bernaudin, Samuel Valable e Edwige Petit. "Angiopoietin-2 Combined with Radiochemotherapy Impedes Glioblastoma Recurrence by Acting in an Autocrine and Paracrine Manner: A Preclinical Study". Cancers 12, n. 12 (30 novembre 2020): 3585. http://dx.doi.org/10.3390/cancers12123585.
Testo completoAbstract (sommario):
(1) We wanted to assess the impact of Ang2 in RCT-induced changes in the environment of glioblastoma. (2) The effect of Ang2 overexpression in tumor cells was studied in the GL261 syngeneic immunocompetent model of GB in response to fractionated RCT. (3) We showed that RCT combined with Ang2 led to tumor clearance for the GL261-Ang2 group by acting on the tumor cells as well as on both vascular and immune compartments. (4) In vitro, Ang2 overexpression in GL261 cells exposed to RCT promoted senescence and induced robust genomic instability, leading to mitotic death. (5) Coculture experiments of GL261-Ang2 cells with RAW 264.7 cells resulted in a significant increase in macrophage migration, which was abrogated by the addition of soluble Tie2 receptor. (6) Together, these preclinical results showed that, combined with RCT, Ang2 acted in an autocrine manner by increasing GB cell senescence and in a paracrine manner by acting on the innate immune system while modulating the vascular tumor compartment. On this preclinical model, we found that an ectopic expression of Ang2 combined with RCT impedes tumor recurrence.