A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this ...study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients.
A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers.
Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received.
HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions.
•At direct-acting antiviral (DAA) failure, patients carry subtype-dependent resistance-associated substitutions (RAS).•Next-generation sequencing (NGS)-based RAS testing can provide useful data for managing HCV patients failing DAAs.•RAS can appear in DAA-targeted and non-targeted regions. RAS screening should include all 3 target regions (NS3, 5A and 5B).
This paper introduces a new trading strategy in investment: including the asset (Asset A) with the highest mean, the asset (Asset B) that stochastically dominates many other assets, and the asset ...(Asset C) with the smallest standard deviation in their portfolio to form portfolios in the efficient frontier for emerging and developed markets that could get higher expected utility and/or expected arbitrage opportunities. To test whether our proposed new trading strategy performs better, we set a few conjectures including the conjectures that investors should include any one, two, or three of Assets A, B, and C from emerging and developed markets. We test whether the conjectures hold by employing both mean-variance and stochastic dominance (SD) approaches to examine the performance of the portfolio formed by using hedge funds from emerging and developed markets with and without Assets A, B, and C, the naïve 1/N portfolio, and all other assets studied in our paper. We find that most of the portfolios with assets A, B, and C++ stochastically dominate the corresponding portfolio without any one, two, or all three of the A, B, and C strategies and dominate most, if not all, of the individual assets and the naïve 1/N portfolio in the emerging and developed markets, implying the existence of expected arbitrage opportunities in either emerging or developed markets and the market is inefficient. In addition, in this paper, we set a conjecture that combinations of portfolios with no arbitrage opportunity could generate portfolios that could have expected arbitrage opportunity. Our findings conclude that the conjecture holds and we claim that this phenomenon is a new anomaly in the financial market and our paper discovers a new anomaly in the financial market that expected arbitrage opportunity could be generated.
We also conduct an out-of-sample analysis to check whether our proposed approach will work well in the out-of-sample period. Our findings also confirm our proposed new trading strategy to include Assets A, B, and C in the portfolio is the best strategy among all the other strategies used in our paper and gets the highest expected wealth and the highest expected utility for the emerging and developed markets. Our findings contribute to the literature on the emerging and developed markets of hedge funds and the reliability of alternative risk frameworks in the evaluation. Our findings also provide practical experience to academics, fund managers, and investors on how to choose assets in their portfolio to get significantly higher expected utility in emerging and developed markets.
•Patients with R/M HNSCC treated with immunotherapy (IO) were reviewed.•PNI was the only parameter associated with both PFS and OS.•The incidence of irAEs was not associated with IO PFS or OS.•The ...nutritional status should be considered in HNSCC patients treated with IO.
Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients.
R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable.
A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07–2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46–0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001).
In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.
There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal ...(MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers.
Abstract
EO2401 expands existing memory T cells recognizing protein sequences from gut bacteria, which cross-react with tumor associated antigens (TAAs). EO2401 contains three CD8 HLA-A2 epitopes ...with mimicry to glioblastoma-TAAs (IL13Rα2, BIRC5, and FOXM1) and the CD4 epitope UCP2. Patients received EO2401 (300μg/peptide, q2weeks x4, then every 4weeks) with nivolumab (3mg/kg, q2weeks) in cohorts: C1a (n = 21, Ex2→EN; option for symptom directed low-dose bevacizumab sLDB; 5mg/kg, q2weeks as anti-edema treatment); C2a/1 (n = 23, EN); C2a/2 (n = 15, EN+sLDB); C2b (n = 6, adjuvant EN+sLDB); C2c (n = 9, neoadjuvant ENx2→surgery→adjuvant EN+sLDB); C3 (n = 26, EN+bevacizumab, q2weeks, 10mg/kg). EO2401/nivolumab+/-bevacizumab safety profile consistent with profile of nivolumab, and when applicable bevacizumab, except the addition of local administration site reactions which occurred in 39% of patients; 96% of events Grade 1/2 and 4% Grade 3. Immune monitoring (peripheral blood, ELISPOT, tetramer assessments) demonstrated expanded mimic specific CD8 T cells with cross-reactivity against the targeted human TAAs. In C2a/1 (83% tested) and in C3 (81% tested), 89% and 95% of tested patients showed expansion. Expansions were early (week 2 after starting EO2401), durable (up to 23 months), and robust (approximately 30% of all peripheral CD8 T cells were mimic specific in 3 clinical responders). In C2c, surgery specimens after two EO2401/nivolumab doses showed increased tumor T cell infiltration versus pre-treatment tumor in 5 of 6 patients. Addition of sLDB to EO2401/nivolumab prolonged treatment duration vs EO2401/nivolumab alone by reducing edema likely worsened by study therapy induced immune cell infiltration. Integration of bevacizumab with EO2401/nivolumab in C3 further increased efficacy in C3. C2a/1vsC2a/2vsC3: median treatment duration 1.4vs3.2vs4.8 months, disease control rate 22%vs40%vs88%, median PFS 1.6vs3.6vs5.5 months; median survival 9.0vs12.6vstoo early (C3 median FU 8.3 mo, survival ongoing up to 2 years). Further follow-up will be presented.
Meningioma, the second most common primary tumour of the central nervous system, is classified into three different grades based on their characteristics. Each tumour grade includes different ...molecular subtype, growth potential, and thus, different prognosis. Grade I meningioma is the most common subtype with a benign course, in which systemic dissemination rarely occurs. We present the case of a 48-year-old male patient with a history of grade I meningioma who was referred 3 years after the initial diagnosis to our centre due to pelvic pain. Computed tomography (CT) images showed new pelvic bone lesions whose histopathological report was compatible with a grade I meningioma. Neither hormonal therapy concomitant with octreotide nor hydroxiurea treatments were effective. Very little is known about this entity’s prevalence and treatment when disseminated disease occurs. Thus, we think it is important to increase the positive and negative clinical experiences in this setting.
BackgroundEO2401 is a novel generation of cancer immunotherapies designed to activate memory T cells that recognize commensal-derived peptides and cross-react with tumor-associated antigens (TAAs). ...EO2401 includes synthetically-produced HLA-A2 peptides with molecular mimicry to IL13RA2, BIRC5 and FOXM1, which are commonly upregulated in glioblastoma (GB), and the CD4 helper peptide UCP2. The study (NCT04116658) was approved by all participating institution’s Ethics Boards.MethodsPatients with GB at first progression following standard treatment received EO2401 with nivolumab ± bevacizumab. Blood was collected at baseline, every two weeks during the first 5 months, then every month until progression. Immune response in cryopreserved PBMCs was investigated using tetramer staining, IFNγ ELISpot and intracellular cytokine staining (ICS) ex vivo and after in vitro stimulation (IVS).ResultsThe efficacy of commensal-derived peptides in generating immune responses against their homologous TAAs was studied ex vivo. Tetramer staining showed that commensal-specific T cells were observed in 93% of tested patients (n=55), with early responses (after 1 vaccine) seen in 42% of patients evaluated at this visit (n=24). The most immunogenic peptides were EO2317 and EO2318, with 90% (maximal response: 15.4% of CD8+ T cells) and 85% (maximal response: 3.7%) of responding patients, respectively. Cross-reactivity against targeted-TAA (BIRC5 for EO2317, FOXM1 for EO2318) could be detected in most tested patients (100% and 48%, respectively). These results were supported by ex-vivo IFNg ELISpot, where 90% of patients (n=21) showed functional T cells against the pool of commensal-derived peptides, and 56% and 22% reacted against two or three of these peptides, respectively. 76% of the patients also showed ex vivo responses against UCP2. Importantly, generated antigen-specific CD8+ T cells (>90%) were effector memory (TEM and TEMRA). Additionally, expression of the late activation marker CD57 increased throughout time. However, no increase in PD-1 or LAG-3 was observed, hinting that these cells do not become exhausted. Indeed, vaccine-specific T cells were strongly expanded and produced high levels of cytokines (ICS) after IVS and long-term analyses revealed a durable response of almost one year after first vaccination.ConclusionsEO2401 in combination with nivolumab can generate fast, strong and durable immune responses in patients. Expansion of commensal-specific CD8+ T cells that cross-react with TAAs is a promising approach to create broad immune responses against tumors with low neoantigen expression and poor T cell priming, such as GB.Further phenotypic analyses of antigen-specific T cells and other immune subsets are ongoing and will be correlated with clinical outcome.Ethics ApprovalAll subjects gave their informed consent for inclusion before participating in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the faculty of medicine of Heidelberg - Germany (Ref: AFmu-511/2019); the Ethics Committee of Saint-Antoine Hospital - France (Ile-de-France V – ref: 54319); and the Ethics Committee of the Hospital Universitario 12 de Octubre – Spain (ref: 19/396) as well as by the Institutional Review Board from the Office of human research studies of the Dana-Farber Cancer Institute – USA (iRIS ref: 326446).
Abstract
EO2401 includes microbial-derived, synthetically produced HLA-A2 restricted peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 ...helper peptide UCP2. Patients with glioblastoma at first progression received EO2401 (300µg/peptide, q2weeks x4 then q4weeks), EO2401+nivolumab (3mg/kg q2weeks), or E02401+nivolumab+bevacizumab (10mg/kg q2weeks). Cohort-1 included EO2401x2 then EO2401+nivolumab. EO2401+nivolumab was evaluated in Cohort-2a, as adjuvant treatment in Cohort-2b, and as neoadjuvant/adjuvant treatment in Cohort-2c. Cohort-3 assessed EO2401+nivolumab+bevacizumab. Part 1 included 40 patients (Cohort-1/3, Cohort-2a/23, Cohort-2b/3, Cohort-3/11). Part 2 allowed low-dose-bevacizumab (5mg/kg q2weeks) for symptomatic edema and enrolled 38 patients (Cohort-1/18, Cohort-2a/15, Cohort-2b/3; and recruiting Cohort-2c/2 target 6, Cohort-3/0 target 15).Safety assessment of part 1 showed EO2401+nivolumab+/-bevacizumab to be well tolerated with EO2401 associated toxicity limited to local administration site reactions (48%; all grade 1-2). The nivolumab-/bevacizumab-toxicity was consistent with historical single-agent data. Strong CD8 T cell ELISPOT responses against the 3 vaccine peptides and cross-reactivity against targeted antigens was demonstrated in the majority of evaluable patients. Immune response was confirmed with tetramer staining of specific CD8 either ex vivo or after in vitro stimulation. For part 1, median progression-free survival (mPFS), and median survival (mOS) for EO2401+nivolumab (Cohorts-1/2/2b, n=29 median follow-up mFU 14.0 months) were 1.8 and 10.6 months. Patients on EO2401+nivolumab+bevacizumab (n = 11 mFU 9.6 m) had mPFS 5.5 months and 9 patients alive 7-12.4 months. Objective Response Rate/Disease Control Rate for EO2401+nivolumab and EO2401+nivolumab+bevacizumab was 10%/34% and 55%/82%.Median treatment duration for Cohort-2a part 1 was 6.1 weeks (1/23 on treatment), while it was 10.0 weeks (8/15 on treatment) for Cohort-2a part 2. Overall, in part 2, 36% received low-dose-bevacizumab.EO2401 generated strong immune responses and was well tolerated. Addition of standard bevacizumab to EO2401+nivolumab improved PFS and tumor response. Symptom driven low-dose-bevacizumab supported longer treatment durations. Outcome of study part 2 will be presented.
Faecal immunochemical test (FIT) has been recommended to assess symptomatic patients for colorectal cancer (CRC) detection. Nevertheless, some conditions could theoretically favour blood originating ...in proximal areas of the gastrointestinal tract passing through the colon unmetabolized. A positive FIT result could be related to other gastrointestinal cancers (GIC).
To assess the risk of GIC detection and related death in FIT-positive symptomatic patients (threshold 10 μg Hb/g faeces) without CRC.
Post hoc cohort analysis performed within two prospective diagnostic test studies evaluating the diagnostic accuracy of different FIT analytical systems for CRC and significant colonic lesion detection. Ambulatory patients with gastrointestinal symptoms referred consecutively for colonoscopy from primary and secondary healthcare, underwent a quantitative FIT before undergoing a complete colonoscopy. Patients without CRC were divided into two groups (positive and negative FIT) using the threshold of 10 μg Hb/g of faeces and data from follow-up were retrieved from electronic medical records of the public hospitals involved in the research. We determined the cumulative risk of GIC, CRC and upper GIC. Hazard rate (HR) was calculated adjusted by age, sex and presence of significant colonic lesion.
We included 2709 patients without CRC and a complete baseline colonoscopy, 730 (26.9%) with FIT ≥ 10 µgr Hb/gr. During a mean time of 45.5 ± 20.0 mo, a GIC was detected in 57 (2.1%) patients: An upper GIC in 35 (1.3%) and a CRC in 14 (0.5%). Thirty-six patients (1.3%) died due to GIC: 22 (0.8%) due to an upper GIC and 9 (0.3%) due to CRC. FIT-positive subjects showed a higher CRC risk (HR 3.8, 95%CI: 1.2-11.9) with no differences in GIC (HR 1.5, 95%CI: 0.8-2.7) or upper GIC risk (HR 1.0, 95%CI: 0.5-2.2). Patients with a positive FIT had only an increased risk of CRC-related death (HR 10.8, 95%CI: 2.1-57.1) and GIC-related death (HR 2.2, 95%CI: 1.1-4.3), with no differences in upper GIC-related death (HR 1.4, 95%CI: 0.6-3.3). An upper GIC was detected in 22 (0.8%) patients during the first year. Two variables were independently associated: anaemia (OR 5.6, 95%CI: 2.2-13.9) and age ≥ 70 years (OR 2.7, 95%CI: 1.1-7.0).
Symptomatic patients without CRC have a moderate risk increase in upper GIC, regardless of the FIT result. Patients with a positive FIT have an increased risk of post-colonoscopy CRC.
We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, ...as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3-3.1), CRC (HR 4.4, 95% CI 1.1-17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0-2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3-5.8), rectal bleeding (OR 0.3, 95% CI 0.1-0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7-7.1). However, CEA was increased only in 31.8% (95% CI, 16.4-52.7%) and 50% (95% CI, 25.4-74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRC.
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