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BACKGROUND: Tucatinib (TUC), a HER2-directed tyrosine kinase inhibitor, is the first targeted drug demonstrating intracranial efficacy and significantly prolonged survival in metastatic HER2-positive breast cancer (BC) patients with brain metastases. Current treatments for brain metastases often include radiotherapy, but little is known about the effects of combination treatment with TUC. Therefore, we examined the combined effects of irradiation and TUC in human HER2-overexpressing BC, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC) cell lines. For the latter two, a standard therapy successfully targeting HER2 is yet to be established. METHODS: Nine HER2-overexpressing (BC: BT474, ZR7530, HCC1954; CRC: LS411N, DLD1, COLO201; NSCLC: DV90, NCI-H1781) and three control cell lines (BC: MCF7, HCC38; NSCLC: NCI-H2030) were examined. WST-1 assay (metabolic activity), BrdU ELISA (proliferation), γH2AX assay (DNA double-strand breaks (DSB), Annexin V assay (apoptosis), and clonogenic assay (clonogenicity) were performed after treatment with TUC and/or irradiation (IR). The relevance of the treatment sequence was analyzed exemplarily. RESULTS: In BC, combinatorial treatment with TUC and IR significantly decreased metabolic activity, cell proliferation, clonogenicity and enhanced apoptotis compared to IR alone, whereby cell line-specific differences occurred. In the PI3KCA-mutated HCC1954 cell line, addition of alpelisib (ALP) further decreased clonogenicity. TUC delayed the repair of IR-induced DNA damage but did not induce DSB itself. Investigation of treatment sequence indicated a benefit of IR before TUC versus IR after TUC. Also in CRC and NSCLC, the combination led to a stronger inhibition of metabolic activity, proliferation, and clonogenic survival (only in NSCLC) than IR alone, whereby about 10-fold higher concentrations of TUC had to be applied than in BC to induce significant changes. CONCLUSION: Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.
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Radiation therapy (RT) plays a fundamental role in the treatment of malignant and benign brain tumors. Current state-of-the-art photon- and proton-based RT combines more conformal dose distribution of target volumes and accurate dose delivery while limiting the adverse radiation effects. PubMed was systematically searched from from 2000 to October 2023 to identify studies reporting outcomes related to treatment of central nervous system (CNS)/skull base tumors with PT in adults. Several studies have demonstrated that proton therapy (PT) provides a reduced dose to healthy brain parenchyma compared with photon-based (xRT) radiation techniques. However, whether dosimetric advantages translate into superior clinical outcomes for different adult brain tumors remains an open question. This review aims at critically reviewing the recent studies on PT in adult patients with brain tumors, including glioma, meningiomas, and chordomas, to explore its potential benefits compared with xRT.
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Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.
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Objective: Despite the lack of prospective evidence for the perioperative use of dexamethasone in meningioma surgery, its use is well established in the daily routine of several centers. The present study evaluates the effect of dexamethasone on postoperative complications, peritumoral T2/FLAIR hyperintensity, and progression-free survival in patients with supratentorial meningiomas undergoing resection. Methods: A total of 148 patients who underwent resection of a primary sporadic supratentorial meningioma at the authors' institution between 2018 and 2020 were included in this retrospective cohort. Safety criteria were side effects of dexamethasone (e.g. hyperglycemia), surgical morbidities, length of stay, and mortality. The individual Karnofsky Performance Scales (KPS) were evaluated regarding the individual development and the delta of KPS at 3- and 12-months compared to baseline KPS was calculated. Longitudinal assessment of the peritumoral T2-/FLAIR hyperintensity changes was performed. Results: The use of both pre- and postoperative dexamethasone did not influence the incidence rates of wound infections, infarctions, postoperative seizures, pulmonary embolism, postoperative hemorrhage, mortality, length of stay, new-onset hyperglycemia and new neurological deficits. Perioperative Dexamethasone use was associated with an improved Karnofsky performance development at 3- (delta of KPS 3.3 vs. -1.9, p=0.001) and 12-months (delta of KPS 3.8 vs. -1.1, p=0.008) compared to the preoperative Karnofsky performance status. Multivariable analysis revealed that perioperative dexamethasone use enhances the KPS improvement (OR: 3.65, 95% CI: 1.01-13.18, p=0.048). Persistent peritumoral T2/FLAIR hyperintensity changes were observed in 35 cases of 70 patients with available follow-up images and a baseline edema (50.0%). Perioperative dexamethasone use enhanced the reduction of the preoperative peritumoral T2-/FLAIR hyperintensity changes (mean reduction of maximum diameter: 1.8 cm vs. 1.1 cm, p=0.023). Perioperative dexamethasone use was independently associated with a lower risk for persistent peritumoral T2-/FLAIR hyperintensity changes (OR: 3.77, 95% CI: 1.05-13.54, p=0.042) The perioperative use of dexamethasone did not influence the progression-free survival time in Simpson grade I or II resected WHO grade 1 meningiomas (log-rank test: p=0.27). Conclusion: Perioperative dexamethasone use seems to be safe in surgery for primary supratentorial meningiomas. Dexamethasone use might enhance the functionality by reducing postoperative peritumoral T2-/FLAIR hyperintensities. These findings highlight the need for prospective data.
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The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.
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Aptâmeros de Nucleotídeos , Neoplasias Encefálicas , Quimiocina CXCL12 , Glioblastoma , Humanos , Glioblastoma/radioterapia , Glioblastoma/tratamento farmacológico , Aptâmeros de Nucleotídeos/administração & dosagem , Quimiocina CXCL12/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Adulto , Dose Máxima Tolerável , Qualidade de Vida , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RTâTMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood brain barrier. METHODS: EORTC 1709/CCTG CE.8 was a multicenter, randomized, controlled, open label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RTâTMZ with patients receiving only standard treatment in the whole population, and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada and the US. A total of 749 patients (99.9% of planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs 16.5 months; HR=1.04; p=0.64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR=0.97; p=0.67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs 15.1 months, HR=1.13; p=0.27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
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PURPOSE: The decision-making process regarding cancer treatment is emotionally challenging for patients and families, harboring the risk of decision regret. We aimed to explore prevalence and determinants of decision regret following radiotherapy. METHODS: This cross-sectional observational study was conducted at a tertiary cancer center to assess decision regret following radiotherapy. The study employed the German version of the Ottawa Decision Regret Scale (DRS) which was validated in the study population. Decision regret was categorized as absent (0 points), mild (1-25 points), and strong (> 25 points). Various psychosocial outcome measures were collected using validated questionnaires to identify factors that may be associated with decision regret. RESULTS: Out of 320 eligible patients, 212 participated, with 207 completing the DRS. Median age at start of radiotherapy was 64 years [interquartile range (IQR), 56-72], genders were balanced (105 female, 102 male), and the most common cancer types were breast (n = 84; 41%), prostate (n = 57; 28%), and head-and-neck cancer (n = 19; 9%). Radiotherapy was applied with curative intention in 188 patients (91%). Median time between last radiotherapy fraction and questionnaire completion was 23 months (IQR, 1-38). DRS comprehensibility was rated as good or very good by 98% (196 of 201) of patients. Decision regret was reported by 43% (n = 90) as absent, 38% (n = 78) as mild, and 18% (n = 38) as strong. In the multiple regression analysis, poor Eastern Cooperative Oncology Group performance status, low social support, and dissatisfaction with care were independent risk factors for higher decision regret after radiotherapy. CONCLUSIONS: The German version of the DRS could be used to assess decision regret in a diverse cohort of cancer patients undergoing radiotherapy. Decision regret was prevalent in a considerable proportion of patients. Further studies are necessary to validate these findings and obtain causal factors associated with decision regret after radiotherapy.
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Tomada de Decisões , Neoplasias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Emoções , Neoplasias/radioterapia , Fatores de Risco , IdosoRESUMO
Homozygous CDKN2A/B deletion has been associated with an increased risk of recurrence in meningiomas. However, the evidence is confined to a limited number of studies, and the importance of heterozygous CDKN2A/B deletions remains insufficiently investigated. Hence, the present meta-analysis reconstructs individual patient data (IPD) and reconstructs the probabilities of progression-free survival (PFS) stratified by CDKN2A/B status. IPD of PFS rates were extracted from published Kaplan-Meier plots using the R package IPDfromKM in R studio (RStudio, Boston, MA, USA). Reconstructed Kaplan-Meier Plots of the pooled IPD data were created. One-stage and two-stage meta-analyses were performed. Hazard ratios (HR) were used as effective measures. Of 181 records screened, four articles with 2521 participants were included. The prevalence of homozygous CDKN2A/B deletions in the included studies was 0.049 (95% CI 0.040-0.057), with higher tumor grades associated with a significantly greater proportion of CDKN2A/B deletions. The reconstructed PFS curves for the pooled cohort showed that the median PFS time of patients with a CDKN2A/B wild-type status, heterozygous or homozygous CDKN2A/B deletion was 180.0 (95% CI 145.7-214.3), 26.1 (95% CI 23.3-29.0), and 11.00 (95% CI 8.6-13.3) months, respectively (p < 0.0001). Both hetero- or homozygous CDKN2A/B deletions were significantly associated with shortened time to meningioma progression. One-stage meta-analysis showed that hetero- (HR: 5.5, 95% CI 4.0-7.6, p < 0.00001) and homozygous CDKN2A/B deletions (HR: 8.4, 95% CI 6.4-11.0, p < 0.00001) are significantly associated with shortened time to meningioma progression. Multivariable Cox regression analysis of progression in a subgroup with available covariates (age, sex, WHO grade, and TERT status) and also two-stage meta-analysis confirmed and validated the results of the one-stage analysis that both heterozygous and homozygous CDKN2A/B deletions are of prognostic importance. Further large-scale studies of WHO grade 2 and 3 meningiomas are needed to validate the importance of heterozygous CDKN2A/B deletions with consideration of established factors.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/genética , Meningioma/patologia , Prognóstico , Intervalo Livre de Progressão , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genéticaRESUMO
PURPOSE: The AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort. METHODS: We evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models. RESULTS: Employing the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier. CONCLUSION: In contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Bevacizumab/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estimativa de Kaplan-Meier , PrognósticoRESUMO
BACKGROUND: Brain metastases (BM) cause relevant morbidity and mortality in cancer patients. The presence of cerebrovascular diseases can alter the tumor microenvironment, cellular proliferation and treatment resistance. However, it is largely unknown if the presence of distinct cerebrovascular risk factors may alter the prognosis of patients with BM. METHODS: Patients admitted for the radiotherapy of BM at a large tertiary cancer center were included. Patient and survival data, including cerebrovascular risk factors (diabetes mellitus (DM), smoking, arterial hypertension, peripheral arterial occlusive disease, hypercholesterolemia and smoking) were recorded. RESULTS: 203 patients were included. Patients with DM (n = 39) had significantly shorter overall survival (OS) (HR 1.75 (1.20-2.56), p = 0.003, log-rank). Other vascular comorbidities were not associated with differences in OS. DM remained prognostically significant in the multivariate Cox regression including established prognostic factors (HR 1.92 (1.20-3.06), p = 0.006). Furthermore, subgroup analyses revealed a prognostic role of DM in patients with non-small cell lung cancer, both in univariate (HR 1.68 (0.97-2.93), p = 0.066) and multivariate analysis (HR 2.73 (1.33-5.63), p = 0.006), and a trend in melanoma patients. CONCLUSION: DM is associated with reduced survival in patients with BM. Further research is necessary to better understand the molecular mechanisms and therapeutic implications of this important interaction.
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PURPOSE: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO). METHODS: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T1-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined. RESULTS: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T1-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm. CONCLUSION: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Dacarbazina/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Temozolomida/uso terapêutico , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Lomustina/uso terapêutico , Imageamento por Ressonância Magnética , Antineoplásicos Alquilantes/uso terapêuticoRESUMO
PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.
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Neoplasias Encefálicas , Glioma , Humanos , Adulto , Seguimentos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/radioterapia , Qualidade de Vida , Estudos Prospectivos , Glioma/complicações , Glioma/radioterapia , Terapia CombinadaRESUMO
Medial sphenoid wing meningiomas (MSWM) are surgically challenging skull base tumors. Irregular tumor shapes are thought to be linked to histopathology. The present study aims to investigate the impact of tumor shape on postoperative functioning, progression-free survival, and neuropathology. This monocentric study included 74 patients who underwent surgery for primary sporadic MSWM (WHO grades 1 and 2) between 2010 and 2021. Furthermore, a systematic review of the literature regarding meningioma shape and the MIB-1 index was performed. Irregular MSWM shapes were identified in 31 patients (41.9%). Multivariable analysis revealed that irregular shape was associated with postoperative cranial nerve deficits (OR: 5.75, 95% CI: 1.15-28.63, p = 0.033). In multivariable Cox regression analysis, irregular MSWM shape was independently associated with tumor progression (HR:8.0, 95% CI: 1.04-62.10, p = 0.046). Multivariable regression analysis showed that irregular shape is independently associated with an increased MIB-1 index (OR: 7.59, 95% CI: 2.04-28.25, p = 0.003). A systematic review of the literature and pooled data analysis, including the present study, showed that irregularly shaped meningiomas had an increase of 1.98 (95% CI: 1.38-2.59, p < 0.001) in the MIB-1 index. Irregular MSWM shape is independently associated with an increased risk of postoperative cranial nerve deficits and a shortened time to tumor progression. Irregular MSWM shapes might be caused by highly proliferative tumors.
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Radiochemotherapy-associated leuco- or thrombocytopenia is a common complication, e.g., in head and neck cancer (HNSCC) and glioblastoma (GBM) patients, often compromising treatments and outcomes. Currently, no sufficient prophylaxis for hematological toxicities is available. The antiviral compound imidazolyl ethanamide pentandioic acid (IEPA) has been shown to induce maturation and differentiation of hematopoietic stem and progenitor cells (HSPCs), resulting in reduced chemotherapy-associated cytopenia. In order for it to be a potential prophylaxis for radiochemotherapy-related hematologic toxicity in cancer patients, the tumor-protective effects of IEPA should be precluded. In this study, we investigated the combinatorial effects of IEPA with radio- and/or chemotherapy in human HNSCC and GBM tumor cell lines and HSPCs. Treatment with IEPA was followed by irradiation (IR) or chemotherapy (ChT; cisplatin, CIS; lomustine, CCNU; temozolomide, TMZ). Metabolic activity, apoptosis, proliferation, reactive oxygen species (ROS) induction, long-term survival, differentiation capacity, cytokine release, and DNA double-strand breaks (DSBs) were measured. In tumor cells, IEPA dose-dependently diminished IR-induced ROS induction but did not affect the IR-induced changes in metabolic activity, proliferation, apoptosis, or cytokine release. In addition, IEPA showed no protective effect on the long-term survival of tumor cells after radio- or chemotherapy. In HSPCs, IEPA alone slightly enhanced CFU-GEMM and CFU-GM colony counts (2/2 donors). The IR- or ChT-induced decline of early progenitors could not be reversed by IEPA. Our data indicate that IEPA is a potential candidate for the prevention of hematologic toxicity in cancer treatment without affecting therapeutic benefits.
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Glioblastoma , Neoplasias de Cabeça e Pescoço , Humanos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Células-Tronco Hematopoéticas , Temozolomida/farmacologia , Citocinas/metabolismo , Glioblastoma/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismoRESUMO
Superficial leiomyosarcomas (LMS) are rare skin cancers (2-3% of cutaneous sarcomas) that originate from dermally located hair follicle muscles, dartos or areolar muscles (cutaneous/dermal LMS), or from vascular muscle cells of the subcutaneous adipose tissue (subcutaneous LMS). These superficial LMS are distinct from LMS of the deep soft tissues. Leiomyosarcomas are typically localized at the lower extremities, trunk or capillitium, and present as painful, erythematous to brownish nodules. Diagnosis is made by histopathology. The treatment of choice for primary LMS is complete (R0) microscopically controlled excision, with safety margins of 1 cm in dermal LMS, and 2 cm in subcutaneous LMS, if possible. Non-resectable or metastatic LMS require individual treatment decisions. After R0 resection with 1 cm safety margins, the local recurrence rate of dermal LMS is very low, and metastasis is very rare. Subcutaneous LMS, very large, or incompletely excised LMS recur and metastasize more frequently. For this reason, clinical follow-up examinations are recommended every six months for cutaneous LMS, and every three months for subcutaneous LMS within the first two years (in subcutaneous LMS including locoregional lymph node sonography). Imaging such as CT/MRI is indicated only in primary tumors with special features, recurrences, or already metastasized tumors.
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Leiomiossarcoma , Neoplasias Cutâneas , Humanos , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/cirurgia , Leiomiossarcoma/patologia , Pele/patologia , Neoplasias Cutâneas/patologia , Tela Subcutânea/patologia , Gordura SubcutâneaRESUMO
To date, gross total resection (GTR) of the contrast-enhancing area of glioblastoma (GB) is the benchmark treatment regarding surgical therapy. However, GB infiltrates beyond those margins, and most tumors recur in close proximity to the initial resection margin. It is unclear whether a supramarginal resection (SMR) enhances progression-free survival (PFS) time without increasing the incidence of postoperative surgical complications. The aim of the present meta-analysis was to investigate SMR with regard to PFS and postoperative surgical complications. We searched for eligible studies comparing SMR techniques with conventional GTR in PubMed, Cochrane Library, Web of Science, and Medline databases. From 3158 initially identified records, 11 articles met the criteria and were included in our meta-analysis. Our results illustrate significantly prolonged PFS time in SMR compared with GTR (HR: 11.16; 95% CI: 3.07-40.52, p = 0.0002). The median PFS of the SMR arm was 8.44 months (95% CI: 5.18-11.70, p < 0.00001) longer than the GTR arm. The rate of postoperative surgical complications (meningitis, intracranial hemorrhage, and CSF leaks) did not differ between the SMR group and the GTR group. SMR resulted in longer median progression-free survival without a negative postoperative surgical risk profile. Multicentric prospective randomized trials with a standardized definition of SMR and analysis of neurologic functioning and health-related quality of life are justified and needed to improve the level of evidence.
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BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.