ABSTRACT
BACKGROUND AND PURPOSE: Evidence and clinical guidelines support the use of adjuvant RT in high-risk low-grade gliomas. However, patients with oligodendroglioma have a more indolent disease course and delaying or avoiding RT is often considered to reduce treatment-related toxicities. As the optimal adjuvant management for oligodendroglioma is unclear, we aimed to assess the effect of adjuvant RT on overall survival (OS) and progression-free survival (PFS). METHODS: MEDLINE, EMBASE, CENTRAL and CINAHL were searched from January 1990 to February 2023 for studies comparing adjuvant RT versus no adjuvant RT for patients with oligodendroglioma. RESULTS: This review found 17 eligible studies including 14 comparative retrospective studies and 3 randomized controlled trials. Using random-effects model, the results suggested that adjuvant RT improved OS by 28 % (HR 0.72, 95 % CI (0.56-0.93), I2 = 86 %), and PFS by 48 % (HR 0.52, (95 % CI 0.40-0.66), I2 = 48 %) compared to patients without adjuvant RT. Subgroup analysis showed that upfront adjuvant RT improved OS and PFS compared to salvage RT. There were no significant differences in OS and PFS between adjuvant RT versus adjuvant chemotherapy. There was improvement in PFS but not OS for adjuvant chemoradiotherapy versus adjuvant chemotherapy alone. Adjuvant RT improved OS in WHO Grade 3 but not WHO Grade 2 oligodendroglioma. CONCLUSION: Overall, adjuvant RT improved OS and PFS in patients with oligodendroglioma. In patients with low-risk features (e.g. Grade 2, gross total resection), alternative approaches and individualization of management such as adjuvant chemotherapy alone may be reasonable considering the lack of survival benefit. Future efforts should prospectively investigate these treatment regimens on molecularly-classified oligodendroglioma patients (defined by presence of IDH mutation and 1p/19q co-deletion), balancing between maximizing survival outcomes and reducing RT-related toxicities.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Oligodendroglioma/radiotherapy , Oligodendroglioma/mortality , Oligodendroglioma/therapy , Humans , Brain Neoplasms/radiotherapy , Brain Neoplasms/mortality , Radiotherapy, Adjuvant/methods , Neoplasm GradingABSTRACT
INTRODUCTION: High grade astrocytic glioma (HGG) is a lethal solid malignancy with high recurrence rates and limited survival. While several cytotoxic agents have demonstrated efficacy against HGG, drug sensitivity testing platforms to aid in therapy selection are lacking. Patient-derived organoids (PDOs) have been shown to faithfully preserve the biological characteristics of several cancer types including HGG, and coupled with the experimental-analytical hybrid platform Quadratic Phenotypic Optimization Platform (QPOP) which evaluates therapeutic sensitivity at a patient-specific level, may aid as a tool for personalized medical decisions to improve treatment outcomes for HGG patients. METHODS: This is an interventional, non-randomized, open-label study, which aims to enroll 10 patients who will receive QPOP-guided chemotherapy at the time of first HGG recurrence following progression on standard first-line therapy. At the initial presentation of HGG, tumor will be harvested for primary PDO generation during the first biopsy/surgery. At the point of tumor recurrence, patients will be enrolled onto the main study to receive systemic therapy as second-line treatment. Subjects who undergo surgery at the time of recurrence will have a second harvest of tissue for PDO generation. Established PDOs will be subject to QPOP analyses to determine their therapeutic sensitivities to specific panels of drugs. A QPOP-guided treatment selection algorithm will then be used to select the most appropriate drug combination. The primary endpoint of the study is six-month progression-free survival. The secondary endpoints include twelve-month overall survival, RANO criteria and toxicities. In our radiological biomarker sub-study, we plan to evaluate novel radiopharmaceutical-based neuroimaging in determining blood-brain barrier permeability and to assess in vivo drug effects on tumor vasculature over time. TRIAL REGISTRATION: This trial was registered on 8th September 2022 with ClinicalTrials.gov Identifier: NCT05532397.
Subject(s)
Brain Neoplasms , Neoplasm Recurrence, Local , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Astrocytoma/drug therapy , Astrocytoma/pathology , Astrocytoma/diagnostic imaging , Organoids/drug effects , Organoids/pathology , Organoids/diagnostic imaging , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm GradingABSTRACT
Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.
Subject(s)
Glioblastoma , Hypoxia-Inducible Factor 1, alpha Subunit , Methyltransferases , Neoplastic Stem Cells , Proto-Oncogene Proteins c-akt , RNA Methylation , Animals , Humans , Mice , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/genetics , Carcinogenesis/genetics , Carcinogenesis/pathology , Carcinogenesis/metabolism , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Glioblastoma/metabolism , Glioblastoma/pathology , Glioblastoma/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Methyltransferases/metabolism , Methyltransferases/genetics , Mice, Nude , Mitochondria/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Proto-Oncogene Proteins c-akt/metabolism , RNA, Transfer/metabolism , RNA, Transfer/genetics , Signal Transduction , RNA Methylation/genetics , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.
ABSTRACT
Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.
ABSTRACT
Significance: Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism, and are tightly controlled through homeostatic mechanisms to maintain intracellular redox, regulating growth and proliferation in healthy cells. However, ROS production is perturbed in cancers where abnormal accumulation of ROS leads to oxidative stress and genomic instability, triggering oncogenic signaling pathways on one hand, while increasing oxidative damage and triggering ROS-dependent death signaling on the other. Recent Advances: Our review illuminates how critical interactions between ROS and oncogenic signaling, the tumor microenvironment, and DNA damage response (DDR) pathways have led to interest in ROS modulation as a means of enhancing existing anticancer strategies and developing new therapeutic opportunities. Critical Issues: ROS equilibrium exists via a delicate balance of pro-oxidant and antioxidant species within cells. "Antioxidant" approaches have been explored mainly in the form of chemoprevention, but there is insufficient evidence to advocate its routine application. More progress has been made via the "pro-oxidant" approach of targeting cancer vulnerabilities and inducing oxidative stress. Various therapeutic modalities have employed this approach, including direct ROS-inducing agents, chemotherapy, targeted therapies, DDR therapies, radiotherapy, and immunotherapy. Finally, emerging delivery systems such as "nanosensitizers" as radiotherapy enhancers are currently in development. Future Directions: While approaches designed to induce ROS have shown considerable promise in selectively targeting cancer cells and dealing with resistance to conventional therapies, most are still in early phases of development and challenges remain. Further research should endeavor to refine treatment strategies, optimize drug combinations, and identify predictive biomarkers of ROS-based cancer therapies.
Subject(s)
Antineoplastic Agents , Neoplasms , Oxidative Stress , Reactive Oxygen Species , Humans , Reactive Oxygen Species/metabolism , Neoplasms/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Animals , Antioxidants/therapeutic use , Antioxidants/metabolism , Tumor Microenvironment/drug effects , Signal Transduction/drug effects , DNA DamageABSTRACT
OBJECTIVE: Two-staged gamma knife surgery (GKS) is a method that may extend the upper tumor volume limit for using GKS in the management of brain metastases. However, the safety of treating very large posterior fossa lesions with this technique has not been well demonstrated. Therefore, we analyzed our experience in treating cerebellar metastases larger than 12 cm3 with two-staged GKS. METHODS: Four consecutive patients harboring 12 to 30 cm3 cerebellar metastases scheduled two-staged GKS were included in the study, and all but one patient completed the treatment. The treatment doses were 10-13 Gy. All patients were followed with regular MR imaging and clinical assessments, and the tumor volumes were measured on all treatment and follow-up images. RESULTS: Tumor progression was not demonstrated in any of the patients. Tumor volumes decreased by, on average, more than half between the two stages. The median survival was 22 months, and no patient died due to intracranial tumor progression. Peritumoral edema at the first GKS resolved in all patients, replaced by asymptomatic mild T2 changes in two of them not requiring any treatment. No radiation-induced complication has developed thus far. CONCLUSION: Staged GKS seems to be a feasible management option for very large cerebellar metastases.
Subject(s)
Brain Neoplasms , Radiosurgery , Humans , Retrospective Studies , Radiosurgery/methods , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/radiotherapy , Brain Neoplasms/surgery , Treatment Outcome , Follow-Up StudiesABSTRACT
Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Subject(s)
Post-Acute COVID-19 Syndrome , Serotonin , Humans , COVID-19/complications , Disease Progression , Inflammation , Post-Acute COVID-19 Syndrome/blood , Post-Acute COVID-19 Syndrome/pathology , Serotonin/blood , Virus DiseasesABSTRACT
INTRODUCTION: Conventional interventional modalities for preserving or improving cognitive function in patients with brain tumour undergoing radiotherapy usually involve pharmacological and/or cognitive rehabilitation therapy administered at fixed doses or intensities, often resulting in suboptimal or no response, due to the dynamically evolving patient state over the course of disease. The personalisation of interventions may result in more effective results for this population. We have developed the CURATE.AI COR-Tx platform, which combines a previously validated, artificial intelligence-derived personalised dosing technology with digital cognitive training. METHODS AND ANALYSIS: This is a prospective, single-centre, single-arm, mixed-methods feasibility clinical trial with the primary objective of testing the feasibility of the CURATE.AI COR-Tx platform intervention as both a digital intervention and digital diagnostic for cognitive function. Fifteen patient participants diagnosed with a brain tumour requiring radiotherapy will be recruited. Participants will undergo a remote, home-based 10-week personalised digital intervention using the CURATE.AI COR-Tx platform three times a week. Cognitive function will be assessed via a combined non-digital cognitive evaluation and a digital diagnostic session at five time points: preradiotherapy, preintervention and postintervention and 16-weeks and 32-weeks postintervention. Feasibility outcomes relating to acceptability, demand, implementation, practicality and limited efficacy testing as well as usability and user experience will be assessed at the end of the intervention through semistructured patient interviews and a study team focus group discussion at study completion. All outcomes will be analysed quantitatively and qualitatively. ETHICS AND DISSEMINATION: This study has been approved by the National Healthcare Group (NHG) DSRB (DSRB2020/00249). We will report our findings at scientific conferences and/or in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04848935.
Subject(s)
Artificial Intelligence , Brain Neoplasms , Humans , Brain Neoplasms/radiotherapy , Cognition , Feasibility Studies , Prospective StudiesABSTRACT
Introduction: The most recent local study on the incidence of histological subtypes of all brain and spinal tumours treated surgically was published in 2000. In view of the outdated data, we investigated the presenting characteristics, histological subtypes and outcomes of adult patients who underwent surgery for brain or spinal tumours at our institution. Methods: A single-centre retrospective review of 501 patients who underwent surgery for brain or spinal tumours from 2016 to 2020 was conducted. The inclusion criteria were (a) patients who had a brain or spinal tumour that was histologically verified and (b) patients who were aged 18 years and above at the time of surgery. Results: Four hundred and thirty-five patients (86.8%) had brain tumours and 66 patients (13.2%) had spinal tumours. Patients with brain tumours frequently presented with cranial nerve palsy, headache and weakness, while patients with spinal tumours frequently presented with weakness, numbness and back pain. Overall, the most common histological types of brain and spinal tumours were metastases, meningiomas and tumours of the sellar region. The most common complications after surgery were cerebrospinal fluid leak, diabetes insipidus and urinary tract infection. In addition, 15.2% of the brain tumours and 13.6% of the spinal tumours recurred, while 25.7% of patients with brain tumours and 18.2% of patients with spinal tumours died. High-grade gliomas and metastases had the poorest survival and highest recurrence rates. Conclusion: This study serves as a comprehensive update of the epidemiology of brain and spinal tumours and could help guide further studies on brain and spinal tumours.
ABSTRACT
BACKGROUND: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.
ABSTRACT
2'-O-Methoxyethyl antisense oligonucleotide (2'-MOE ASO)-induced severe thrombocytopenia (TCP) [platelet (PLT) count <50 K/µL] was observed in the Asian-sourced cynomolgus monkeys with low incidence (2%-4% at doses >5 mg/kg/week). The potential mechanisms for TCP were studied using the Mauritian-sourced cynomolgus monkeys, which were shown to be more susceptible to ASO-induced TCP, along with the Asian-sourced animals. ISIS 405879, a 2'-MOE ASO, induced severe TCP (PLT <50 K/µL) in seven of nine Mauritian-sourced monkeys but not in the Asian-sourced monkeys after 16 weeks of treatment at 40 mg/kg/week. Marked increases in PLT-bound C3d/C4d were detected in all thrombocytopenic Mauritian-sourced monkeys but not in the unaffected Mauritian- or Asian-sourced monkeys, suggesting increased PLT clearance due to complement deposition on the PLTs. However, this effect was independent of the ASO-mediated fluid-phase alternative complement activation. A correlation was also observed between serum antiglycoprotein (GP) IIb/IIIa immunoglobulin G (IgG) and PLT reduction. In addition, increases in total serum IgM, anti-PLT IgM, and anti-PLT factor 4 IgM levels were observed in monkeys from both sources but were more evident in the Mauritian-sourced monkeys. These data suggest an enhanced innate immune cell activation to ISIS 405879, leading to increased PLT destruction through complement fixation on the PLTs or PLT crossreacting polyclonal antibody production.
Subject(s)
Blood Platelets , Thrombocytopenia , Animals , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/pharmacology , Complement C3d , Macaca fascicularis , Oligonucleotides , Thrombocytopenia/chemically induced , Thrombocytopenia/genetics , Immunoglobulin MABSTRACT
Background: Stress amidst the COVID-19 pandemic is becoming more prevalent. This paper aimed to describe the validation process of the Malay Perceived Stress Scale modified for COVID-19 (PSS-10-C) amongst Malaysian youths. Methods: The cross-sectional validation study design was employed in this study. In Phase I, the scale was translated into Malay by using the forward-backward method. In Phase 2, principal axis factoring and confirmatory factor analysis were conducted in Study 1 (n = 267) and Study 2 (n = 324), respectively. Results: A two-factor solution, comprising 'distress' and 'coping' domains was derived (cumulative variance = 65.2%) in Phase 2. Concurrent validity evaluated via the Beck Hopelessness Scale revealed a moderate positive correlation (0.528). In Study 2 (n = 324), the confirmatory factor analysis showed that the two-factor model achieved acceptable model fit indices, including χ2/df ratio = 2.57; root mean square error of approximation (RMSEA) = 0.07; 95% CI = 0.05, 0.09; Tucker-Lewis Index (TLI) = 0.95 and Normed Fit Index (NFI) = 0.94. The Cronbach's alpha scale score was 0.855 for the study samples. Conclusion: The Malay PSS-10-C is a valid and reliable scale to be used amongst Malaysian youths.
ABSTRACT
BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is involved in cellular processes driving metastasis, cell proliferation, invasion, motility and survival. It has been shown to be upregulated and overexpressed in cancer tissue, in contrast to low or no expression in most normal tissue. PRL3-zumab is a first-in-class humanized antibody that specifically binds to PRL-3 oncotarget with high affinity and has been shown to reduce tumor growth and increase survival. OBJECTIVE: In the study, we aimed to determine the safety and efficacy of PRL3-zumab in patients with advanced solid tumors and hematological malignancies. METHODS: We conducted a phase I, first-in-human study in advanced solid tumors and hematological malignancies to investigate the safety, tolerability and efficacy of PRL3-zumab. Response rates were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) for solid tumors. For acute myeloid leukemia (AML) patients, bone marrow response criteria based on the European Leukaemia Network (ELN) 2017 guidelines for AML were used. We also explored the pharmacokinetics and pharmacodynamic relationships of PRL3-zumab in patients. This study was registered with ClinicalTrials.gov: NCT03191682. RESULTS: In the dose-escalation cohort, 11 patients with advanced solid tumors were enrolled into the study. An additional 12 patients with solid tumors and four patients with AML were enrolled in the dose-expansion cohort. Maximum tolerability was not achieved in this study, as there were no dose-limiting toxicities. Potential treatment-emergent adverse events were grade 1 increased stoma output and fatigue and grade 2 vomiting. Best response observed was stable disease in three solid-tumor patients (11.1%). The pharmacokinetics of PRL3-zumab were dose proportional, consistent with an IgG type monoclonal antibody. CONCLUSIONS: PRL3-zumab, a first-in-class humanized antibody, was safe and tolerable in solid tumors and hematological malignancies.
Subject(s)
Antineoplastic Agents , Hematologic Neoplasms , Leukemia, Myeloid, Acute , Neoplasms , Humans , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Hematologic Neoplasms/drug therapy , Maximum Tolerated DoseABSTRACT
BACKGROUND: Patient selection is key in Phase I studies, and prognosis can be difficult to estimate in heavily pre-treated patients. Previous prognostic models like the Royal Marsden Hospital (RMH) score or using the neutrophil-lymphocyte ratio (NLR) have not been validated in current novel therapies nor in the Asian Phase I population. METHODS: We conducted a retrospective review of 414 patients with solid tumours participating in Phase I studies at our centre between October 2013 and December 2020. RESULTS: The RMH model showed poorer prognosis with increasing scores [RMH score 1, HR 1.28 (95% CI: 0.96-1.70); RMH score 2, HR 2.27 (95% CI: 1.62-3.17); RMH score 3, HR 4.14 (95% CI: 2.62-6.53)]. NLR did not improve the AUC of the model. Poorer ECOG status (ECOG 1 vs. 0: HR = 1.59 (95% CI = 1.24-2.04), P < 0.001) and primary tumour site (GI vs. breast cancer: HR = 3.06, 95% CI = 2.16-4.35, P < 0.001) were prognostic. CONCLUSIONS: We developed a NCIS prognostic score with excellent prognostic ability for both short-term and longer-term survival (iAUC: 0.71 [95% CI 0.65-0.76]), and validated the RMH model in the largest Asian study to date.
Subject(s)
Breast Neoplasms , Humans , Female , Prognosis , Treatment Outcome , Breast Neoplasms/therapy , Lymphocytes , Patient Selection , Retrospective Studies , NeutrophilsABSTRACT
Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.
Subject(s)
Carcinogenesis , Carcinoma, Non-Small-Cell Lung , Extracellular Vesicles , Lung Neoplasms , Animals , Humans , Mice , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/secondary , Cell Line, Tumor , Extracellular Vesicles/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , ProteomicsABSTRACT
Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials. Methods: This multi-centre study analysed retrospective and prospective data from 456 patients treated with CDK4/6i between January 2015 and December 2020. We examined patient characteristics, variation in prescribing practices, efficacy and toxicity outcomes. Results: In all, 456 patients were included in this study. The median age was 59 (range: 24-92). In total, 85 (19%) were ⩾70 years old. In all, 122 (27%) and 119 (26%) of patients were treated in the first-line and second-line settings, respectively. In total, 25 (5%), 31 (7%) and 145 (32%) of patients had brain, peritoneum and liver metastasis, respectively, at the time of CDK4/6i initiation. On univariate analysis, heavily pre-treated patients and those with distant metastases, involving the liver, brain or peritoneum, had significantly shorter progression-free survival (PFS) and 24-month overall survival (OS). Elderly patients (⩾70) had a shorter PFS; OS results were not mature. Majority of patients (n = 362, 80%) initiated treatment with the United States FDA-approved starting dose of CDK4/6i. In all, 330 (72%) had at least one DD and 217 (48%) patients required at least one DR, but these dose modifications were not associated with poorer survival outcomes. Patients age ⩾70 were more likely to require dose modifications leading to a lower treatment dose. The most common reason for DD/DR was neutropenia (60%) and the incidence of febrile neutropenia was only 2%. Conclusions: Our study indicates CDK4/6i is effective and safe. Age ⩾ 70, distant metastases to liver, peritoneal or brain were negative prognostic factors. Age ⩾ 70 was associated with significantly increased requirement for dose modification; however, this did not impact survival outcomes. These findings provide reassurance that survival outcomes are not adversely affected in elderly patients when DD/DR is indicated.
ABSTRACT
Objective: To identify the independent risk factors for 30-day perioperative seizures, as well as to evaluate the effect of perioperative seizures on overall mortality and tumor recurrence among patients who underwent surgical resection of brain metastases. Methods: Patients who underwent surgical resection of brain metastases at our institution between 2011 and 2019 were included. 30-day perioperative seizures were defined as the presence of any preoperative or postoperative seizures diagnosed by a neurosurgeon or neurologist within 30 days of metastases resection. Independent risk factors for 30-day perioperative seizures were evaluated using multivariate logistic regression models. Kaplan-Meier plots and Cox regression models were constructed to evaluate the effects of 30-day perioperative seizures on overall mortality and tumor recurrence. Subgroup analyses were conducted for 30-day preoperative and 30-day postoperative seizures. Results: A total of 158 patients were included in the analysis. The mean (SD) age was 59.3 (12.0) years, and 20 (12.7%) patients had 30-day perioperative seizures. The presence of 30-day preoperative seizures (OR=41.4; 95% CI=4.76, 924; p=0.002) was an independent risk factor for 30-day postoperative seizures. Multivariate Cox regression revealed that any 30-day perioperative seizure (HR=3.25; 95% CI=1.60, 6.62; p=0.001) was independently and significantly associated with overall mortality but not tumor recurrence (HR=1.95; 95% CI=0.78, 4.91; p=0.154). Conclusions: Among patients with resected brain metastases, the presence of any 30-day perioperative seizure was independently associated with overall mortality. This suggests that 30-day perioperative seizures may be a prognostic marker of poor outcome. Further research evaluating this association as well as the effect of perioperative antiepileptic drugs in patients with resected brain metastases may be warranted.