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PURPOSE: The introduction of immunotherapy in pleural mesothelioma (PM) has highlighted the need for effective outcome predictors. This study explores the role of [18F]FDG PET/CT in predicting outcomes in PM treated with immunotherapy. METHODS: Patients from the NIPU trial, receiving ipilimumab and nivolumab +/- telomerase vaccine in second-line, were included. [18F]FDG PET/CT was obtained at baseline (n = 100) and at week-5 (n = 76). Metabolic tumour volume (MTV) and peak standardised uptake value (SUVpeak) were evaluated in relation to survival outcomes. Wilcoxon rank-sum test was used to assess differences in MTV, total lesion glycolysis (TLG), maximum standardised uptake value (SUVmax) and SUVpeak between patients exhibiting an objective response, defined as either partial response or complete response according to the modified Response Criteria in Solid Tumours (mRECIST) and immune RECIST (iRECIST), and non-responders, defined as either stable disease or progressive disease as their best overall response. RESULTS: Univariate Cox regression revealed significant associations of MTV with OS (HR 1.36, CI: 1.14, 1.62, p < 0.001) and PFS (HR 1.18, CI: 1.03, 1.34, p = 0.02), while multivariate analysis showed a significant association with OS only (HR 1.35, CI: 1.09, 1.68, p = 0.007). While SUVpeak was not significantly associated with OS or PFS in univariate analyses, it was significantly associated with OS in multivariate analysis (HR 0.43, CI: 0.23, 0.80, p = 0.008). Objective responders had significant reductions in TLG, SUVmax and SUVpeak at week-5. CONCLUSION: MTV provides prognostic value in PM treated with immunotherapy. High SUVpeak was not associated with inferior outcomes, which could be attributed to the distinct mechanisms of immunotherapy. Early reductions in PET metrics correlated with treatment response. STUDY REGISTRATION: The NIPU trial (NCT04300244) is registered at clinicaltrials.gov. https://classic. CLINICALTRIALS: gov/ct2/show/NCT04300244?cond=Pleural+Mesothelioma&cntry=NO&draw=2&rank=4.
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Immunotherapy is a rapidly evolving field, with many models attempting to describe its impact on the immune system, especially when paired with radiotherapy. Tumor response to this combination involves a complex spatiotemporal dynamic which makes either clinical or pre-clinical in vivo investigation across the resulting extensive solution space extremely difficult. In this review, several in silico models of the interaction between radiotherapy, immunotherapy, and the patient's immune system are examined. The study included only mathematical models published in English that investigated the effects of radiotherapy on the immune system, or the effect of immuno-radiotherapy with immune checkpoint inhibitors. The findings indicate that treatment efficacy was predicted to improve when both radiotherapy and immunotherapy were administered, compared to radiotherapy or immunotherapy alone. However, the models do not agree on the optimal schedule and fractionation of radiotherapy and immunotherapy. This corresponds to relevant clinical trials, which report an improved treatment efficacy with combination therapy, however, the optimal scheduling varies between clinical trials. This discrepancy between the models can be attributed to the variation in model approach and the specific cancer types modeled, making the determination of the optimum general treatment schedule and model challenging. Further research needs to be conducted with similar data sets to evaluate the best model and treatment schedule for a specific cancer type and stage.
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Hypersensitivity reactions to anticancer drugs include treatment-limiting toxicity. Standard drug desensitisation offers temporary tolerance and hence requires repetition. We used omalizumab, an anti-immunoglobulin E antibody, to overcome immediate and delayed hypersensitivity reactions to various anticancer drugs. Seven of the eight patients in the current study successfully resumed the desired anticancer drug regimen without standard desensitisation. No safety issues from omalizumab were observed.
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Antineoplásicos , Hipersensibilidad a las Drogas , Omalizumab , Humanos , Omalizumab/uso terapéutico , Omalizumab/efectos adversos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/diagnóstico , Persona de Mediana Edad , Femenino , Antineoplásicos/efectos adversos , Masculino , Anciano , Antialérgicos/uso terapéutico , Adulto , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: We aimed to define levels of unmet supportive care needs in people with primary brain tumor and to reach expert consensus on feasibility of addressing patients' needs in clinical practice. METHODS: We conducted secondary analysis of a prospective cohort study of people diagnosed with high-grade glioma (n = 116) who completed the Supportive Care Needs Survey-Short Form during adjuvant chemoradiation therapy. Participants were allocated to 1 of 3 categories: no need ("no need" for help on all items), low need ("low need" for help on at least 1 item, but no "moderate" or "high" need), or moderate/high need (at least 1 "moderate" or "high" need indicated). Clinical capacity to respond to the proportion of patients needing to be prioritized was assessed. RESULTS: Overall, 13% (n = 5) were categorized as no need, 23% (n = 27) low need, and 64% (n = 74) moderate/high need. At least 1 moderate/high need was reported in the physical and daily living domain (42%) and the psychological (34%) domain. In recognition of health system capacity, the moderate/high need category was modified to distinguish between moderate need ("moderate" need indicated for at least 1 item but "high" need was not selected for any item) and high need (at least 1 "high" need indicated). Results revealed 24% (n = 28) moderate need and 40% (n = 46) high need. Those categorized as high need indicated needing assistance navigating the health system and information. CONCLUSIONS: Using four step allocations resulted in 40% of patients indicating high need. Categories may facilitate appropriate triaging and guide stepped models of healthcare delivery.
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Neoplasias Encefálicas , Glioma , Necesidades y Demandas de Servicios de Salud , Evaluación de Necesidades , Humanos , Glioma/terapia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/psicología , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Adulto , Quimioradioterapia Adyuvante , Actividades Cotidianas , Estudios de Factibilidad , Encuestas y CuestionariosRESUMEN
INTRODUCTION: The eighth edition of the TNM classification of pleural mesothelioma (PM) saw substantial changes in T and N components and stage groupings. The International Association for the Study of Lung Cancer collected data into a multinational database to further refine this classification. This ninth edition proposal incorporates changes proposed in the clinical (c)T component but not the pathologic T component, to include size criteria, and further refines TNM stage groupings for PM. METHODS: Data were submitted through electronic data capture or batch transfer from institutional databases. Survival was measured from diagnosis date. Candidate stage groups were developed using a recursive partitioning and amalgamation algorithm applied to all cM0 cases for clinical stage and subsequently for pathologic stage. Cox models were developed to estimate survival for each stage group. RESULTS: Of 3598 submitted cases, 2192 were analyzable for overall clinical stage and 445 for overall pathologic stage. Recursive partitioning and amalgamation generated survival tree on overall survival outcomes restricted to cM0, with newly proposed (ninth edition) cT and cN component-derived optimal stage groupings of stage I (T1N0), II (T1N1; T2N0), IIIA (T1N2; T2N1/2; any T3), IIIB (any T4), and IV (any M1). Although cT and pathologic T descriptors are different in the ninth edition, aligning pathologic stage groupings with clinical stage produced better discrimination than did retaining eighth edition pathologic stage groupings. CONCLUSIONS: To our knowledge, this revision of the clinical TNM classification for PM is the first to incorporate the measurement-based proposed changes in cT category. The pathologic TNM aligns with clinical TNM.
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INTRODUCTION: The International Association for the Study of Lung Cancer developed an international database to inform potential revisions in the ninth edition of the TNM classification of diffuse pleural mesothelioma (PM). This study analyzed the clinical and pathologic N categories to determine whether revisions were indicated relative to the eighth edition staging system. METHODS: Of 7338 PM cases diagnosed from 2013 to 2022 and 3598 met all inclusion criteria for planned analyses. Data on 2836 patients without metastases were included in this study. Overall survival (OS) was measured from date of diagnosis. Patients were included regardless of whether they received neoadjuvant treatment. For the pathologic N analysis, patients who underwent resection (extrapleural pneumonectomy or pleurectomy/decortication) were included. N subgroups were analyzed and OS assessed by the Kaplan-Meier method. RESULTS: The existing eighth edition N categories were performed adequately in the ninth edition data set. A median OS advantage was noted for clinical and pathologic N0 versus N1 patients: 23.2 versus 18.5 and 33.8 versus 25.0 months, respectively. Patients with resected pN0 had a 3-year OS of 48%. No difference in OS was noted for single- versus multiple-station nodal metastases. The number of nodal stations sampled at the time of resection was not associated with a difference in OS. CONCLUSIONS: Data regarding clinical and pathologic N categories corroborate those used in the eighth edition. No changes in the N categories are recommended in the ninth edition of PM staging system.
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Background: Concerning levels of stress, strain, and poorer mental health are observed in family carers of patients diagnosed with high-grade glioma (HGG). Understanding the reported unmet needs of these carers will enable future interventions to address such needs to improve their preparedness for care and well-being. In this secondary analysis, we aimed to explore: (i) what carers of people with HGG perceive could improve their preparedness to care; and (ii) what needs carers reported they required additional support with. Methods: Responses from 188 carers of patients with HGG participating in a randomized controlled trial of the Care-IS intervention were analyzed to identify reported unmet needs. Of this larger sample, 92 participants answered a qualitative question seeking to identify perceived unmet needs in carer preparedness over 12 months. These responses comprised the data for the current secondary analysis. Content analysis was used to analyze the qualitative data and observe trends across participant responses. Results: Five overarching themes were identified: carer needs, providing emotional and practical care, coping with uncertainty, coping with the consequences of illness progression, and processing and supporting end-of-life care. Notably, the content analysis identified differences in response numbers between groups in the Care-IS trial, particularly with the control group having more needs regarding illness progression and end-of-life care. Conclusions: Future interventions aimed at improving the well-being and preparedness of carers of people with HGG should consider providing better support centered on carer needs, their changed circumstances, living with uncertainty, and care transition.
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Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model. Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets. Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets. Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets.
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Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy.
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Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales , Mesotelioma , Microambiente Tumoral , Animales , Ratones , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , RNA-Seq , Análisis de Secuencia de ARN , Análisis de la Célula IndividualRESUMEN
Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRß) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCRß repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCRß repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCRß clonotypes was observed in responding tumours. Machine learning identified TCRß CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCRß signatures associated with ICT response.
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Inhibidores de Puntos de Control Inmunológico , Linfocitos Infiltrantes de Tumor , Receptores de Antígenos de Linfocitos T alfa-beta , Animales , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Ratones , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Humanos , Ratones Endogámicos C57BL , FemeninoRESUMEN
Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is however difficult and, apart from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. Experimental Design: RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n=138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. We used the DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) that is based on classification scores derived from a CNS-tumor classifier. We found that the CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with i) an upregulation of cell cycling genes; ii) a downregulation of glial differentiation genes; iii) an upregulation of embryonic development genes (e.g. HOX, PAX and TBX) and iv) an upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes.
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INTRODUCTION: The primary tumor (T) component in the eighth edition of pleural mesothelioma (PM) staging system is based on pleural involvement and extent of invasion. Quantitative assessment of pleural tumor has been found to be prognostic. We explored quantitative and qualitative metrics to develop recommendations for T descriptors in the upcoming ninth edition of the PM staging system. METHODS: The International Association for the Study of Lung Cancer prospectively collected data on patients with PM. Sum of maximum pleural thickness (Psum) was recorded. Optimal combinations of Psum and eighth edition cT descriptors were assessed using recursive binary splitting algorithm, with bootstrap resampling to correct for the adaptive nature of the splitting algorithm, and validated in the eighth edition data. Overall survival (OS) was calculated by the Kaplan-Meier method and differences in OS assessed by the log-rank test. RESULTS: Of 7338 patients submitted, 3598 were eligible for cT analysis and 1790 had Psum measurements. Recursive partitioning identified optimal cutpoints of Psum at 12 and 30 mm, which, in combination with extent of invasion, yielded four prognostic groups for OS. Fmax greater than 5 mm indicated poor prognosis. cT4 category (based on invasion) revealed similar performance to eighth edition. Three eighth edition descriptors were eliminated based on low predictive accuracy. Eighth edition pT descriptors remained valid in ninth edition analyses. CONCLUSION: Given reproducible prognostication by Psum, size criteria will be incorporated into cT1 to T3 categories in the ninth edition. Current cT4 category and all pT descriptors will be maintained, with reclassification of fissural invasion as pT2.
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PURPOSE: The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM). METHODS: In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10. RESULTS: 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9-9.8) in arm A and 4.7 months (95%CI 3.9-7.0) in arm B (HR 1.01, 80%CI 0.75-1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7-15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0-6.8) in arm A and 2.9 months (95%CI 2.4-5.5) in arm B (HR 0.60, 80%CI 0.45-0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35-4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8-22.9), the OS was 15.4 months (95%CI 11.1-22.6) in arm A and 11.1 months (95%CI 8.8-18.1) in arm B, (HR 0.73, 80%CI 0.53-1.0, P = 0.197). CONCLUSION: The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Telomerasa , Humanos , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/etiologíaRESUMEN
BACKGROUND: Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy. METHODS: We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models. RESULTS: The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines. CONCLUSIONS: Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.
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Mesotelioma , Tretinoina , Humanos , Animales , Ratones , Tretinoina/farmacología , Tretinoina/uso terapéutico , Ciclofosfamida , Linfocitos T CD8-positivos , Terapia Combinada , Mesotelioma/tratamiento farmacológico , Microambiente TumoralRESUMEN
The International Association for the Study of Lung Cancer collaborated with the International Mesothelioma Interest Group to propose the first TNM stage classification system for diffuse pleural mesothelioma in 1995, accepted by the Union for International Cancer Control and the American Joint Committee on Cancer for the sixth and seventh edition stage classification manuals. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Mesothelioma Domain developed and analyzed an international registry of patients with pleural mesothelioma and updated TNM descriptors for the eighth edition of the stage classification system. To inform revisions for the forthcoming ninth edition of the TNM stage classification system, data submission was solicited for patients diagnosed between 2013 and 2022 with expanded data elements on the basis of the first project's exploratory analyses, including pleural thickness measurements, updated surgical nomenclature, and molecular markers. The resulting database consisted of a total of 3598 analyzable cases from Europe, Australia, Asia, North America, and South America, with a median age of 71 years (range: 18-99 y), 2775 (77.1%) of whom were men. With only 1310 patients (36.4%) undergoing curative-intent operations, this iteration of the database includes far more patients treated nonsurgically compared with prior. Four separate manuscripts on T, N, M, and stage groupings submitted to this journal will summarize analyses of these data and will serve collectively as the primary source of the proposed changes to the upcoming ninth edition of the pleural mesothelioma stage classification system.
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Neoplasias Pulmonares , Mesotelioma , Estadificación de Neoplasias , Neoplasias Pleurales , Humanos , Estadificación de Neoplasias/normas , Estadificación de Neoplasias/métodos , Neoplasias Pleurales/patología , Neoplasias Pleurales/clasificación , Masculino , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/clasificación , Mesotelioma/patología , Mesotelioma/clasificación , Anciano , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Adulto , Adulto Joven , Adolescente , Mesotelioma Maligno/patología , Mesotelioma Maligno/clasificación , Bases de Datos FactualesRESUMEN
Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.
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Hidrolasas , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Polietilenglicoles , Anciano , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arginina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mesotelioma/tratamiento farmacológico , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma Maligno/etiología , Neoplasias Pleurales/tratamiento farmacológicoRESUMEN
INTRODUCTION: Malignant pleural mesothelioma is difficult to prognosticate. F18-Fluorodeoxyglucose positron emission tomography (FDG PET) shows promise for response assessment but is confounded by talc pleurodesis. F18-Fluorothymidine (FLT) PET is an alternative tracer specific for proliferation. We compared the prognostic value of FDG and FLT PET and determined the influence of talc pleurodesis on these parameters. METHODS: Overall, 29 prospectively recruited patients had FLT PET, FDG PET and CT-scans performed prior to and post one chemotherapy cycle; 10 had prior talc pleurodesis. Patients were followed for overall survival. CT response was assessed using mRECIST. Radiomic features were extracted using the MiM software platform. Changes in maximum SUV (SUVmax), mean SUV (SUVmean), FDG total lesion glycolysis (TLG), FLT total lesion proliferation (TLP) and metabolic tumour volume (MTV) after one chemotherapy cycle. RESULTS: Cox univariate analysis demonstrated FDG PET radiomics were confounded by talc pleurodesis, and that percentage change in FLT MTV was predictive of overall survival. Cox multivariate analysis showed a 10% increase in FLT tumour volume corresponded with 9.5% worsened odds for overall survival (P = 0.028, HR = 1.095, 95% CI [1.010, 1.187]). No other variables were significant on multivariate analysis. CONCLUSION: This is the first prospective study showing the statistical significance of FLT PET tumour volumes for measuring mesothelioma treatment response. FLT may be better than FDG for monitoring mesothelioma treatment response, which could help optimise mesothelioma treatment regimes.
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Mesotelioma Maligno , Mesotelioma , Humanos , Mesotelioma Maligno/diagnóstico por imagen , Pronóstico , Estudios Prospectivos , Fluorodesoxiglucosa F18 , Talco , Radiofármacos , Tomografía de Emisión de Positrones/métodos , Mesotelioma/diagnóstico por imagen , Mesotelioma/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
AIMS: Mesothelioma is a rare malignancy of the serosal membranes that is commonly related to exposure to asbestos. Despite extensive research and clinical trials, prognosis to date remains poor. Consistent, comprehensive and reproducible pathology reporting form the basis of all future interventions for an individual patient, but also ensures that meaningful data are collected to identify predictive and prognostic markers. METHODS AND RESULTS: This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the international consensus mesothelioma reporting data set. It describes the 'core' and 'non-core' elements to be included in pathology reports for mesothelioma of all sites, inclusive of clinical, macroscopic, microscopic and ancillary testing considerations. An international expert panel consisting of pathologists and a medical oncologist produced a set of data items for biopsy and resection specimens based on a critical review and discussion of current evidence, and in light of the changes in the 2021 WHO Classification of Tumours. The commentary focuses particularly upon new entities such as mesothelioma in situ and provides background on relevant and essential ancillary testing as well as implementation of the new requirement for tumour grading. CONCLUSION: We recommend widespread and consistent implementation of this data set, which will facilitate accurate reporting and enhance the consistency of data collection, improve the comparison of epidemiological data, support retrospective research and ultimately help to improve clinical outcomes. To this end, all data sets are freely available worldwide on the ICCR website (www.iccr-cancer.org/data-sets).
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Mesotelioma Maligno , Mesotelioma , Patología Clínica , Humanos , Peritoneo , Pleura , Estudios Retrospectivos , Mesotelioma/diagnóstico , Pericardio , Patología Clínica/métodosRESUMEN
Background: Inadequate knowledge and skills and a lack of confidence to provide care have been identified as major unmet needs for carers of people with brain cancer. An online intervention was developed to address the unmet needs of carers of people with high-grade glioma. Methods: Ten carers evaluated the intervention through multiple methods. Acceptability and usability were measured through online data analytics (unique page views, time on page), surveys, and interviews. Questionnaires measured potential impacts on distress (Distress Thermometer), depression, anxiety (Hospital Anxiety and Depression Scale), carer competence (Carer Competence Scale), carer preparedness (Caregiving Preparedness Scale), unmet needs (Supportive Care Needs Scale - Brain Tumor Specific for carers), usability and acceptability (USE). Results: Results suggested the intervention had high levels of usability (usability scales' means range = 5.1 to 6.7 out of 7) and acceptability (M = 76.3/100). Correlations indicated the potential to impact depression. Qualitative findings highlighted benefits of the intervention as a comprehensive reliable resource that could validate and normalize carer experiences. Interview findings guided further improvements (eg, additional carer videos, content organization). Conclusions: The study indicated high acceptability and usability of an online intervention for carers of people with high-grade glioma. This exploratory study also provided preliminary indications of a potential to decrease depression. However, a more robust, potentially longitudinal, investigation is needed with a larger and broader sample. Informed by this study, the intervention has been amended and a randomized controlled trial will further evaluate the enhanced intervention.
RESUMEN
Background: The objective of this scoping review was to describe the intervention characteristics and effectiveness of psychosocial interventions aimed at managing personality and behavior changes in people with brain tumors. A secondary objective was to explore if these interventions had an impact on outcomes for carers. Personality and behavior changes considered included aggression, apathy, paranoia, disinhibition, and emotional lability. Methods: This review was conducted following the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Searches were conducted in PsycINFO, CINAHL, Medline (Ovid), and Scopus. We synthesized studies published from 1996 to 2022 that evaluated interventions to manage brain tumor related personality and behavioral changes in adults. A data extraction tool were used based on the Joanna Briggs Institute template. Results are presented in a summary table and a narrative synthesis was conducted. Results: Three thousand and five hundred and ninety-four records were screened. Title and abstract screening resulted in 29 potentially eligible studies. Full screening excluded 24 articles and 5 interventions met the inclusion criteria. The interventions were diverse in duration, delivery modality, setting, and participation (eg, the patient individually or patient and carer). The interventions reported improvements in the targeted personality and behavior change symptoms for patients with primary brain tumors. Four studies included a measure of personality and behavior change symptoms and two studies included a measure of outcomes for carers and reported improvements in carer knowledge and a reduction in carer distress. All studies sampled fewer than 100 participants. Studies had limited follow-up data and different tools were used to assess the presence and nature of personality and behavior changes. Conclusions: There is a dearth of psychosocial interventions to support patients and their carers to manage brain tumor related personality and behavior changes.