ABSTRACT
Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities.Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM, BRCA2, and TP53, for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (< 1%).The FAHIC-Lung (NCT06196424) is the first cross-sectional/prospective study specifically developed to identify FHC patterns and within-family clusters of other risk factors, including smoking, to guide patients with NSCLC to systematic genetic counseling. Acknowledging the largely heterogeneous results of our systematic review and considering the clinical implications of detecting pathogenic germline variants (PGVs), the FAHIC-lung study aims to identify patients potentially enriched with PGVs/likely PGVs to direct them to germline screening outside of the research setting.
Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/genetics , Cross-Sectional Studies , Prospective Studies , Genetic Predisposition to Disease , Risk Factors , Male , Female , Research DesignABSTRACT
Nearest-neighbour clustering is a simple yet powerful machine learning algorithm that finds natural application in the decoding of signals in classical optical-fibre communication systems. Quantum k-means clustering promises a speed-up over the classical k-means algorithm; however, it has been shown to not currently provide this speed-up for decoding optical-fibre signals due to the embedding of classical data, which introduces inaccuracies and slowdowns. Although still not achieving an exponential speed-up for NISQ implementations, this work proposes the generalised inverse stereographic projection as an improved embedding into the Bloch sphere for quantum distance estimation in k-nearest-neighbour clustering, which allows us to get closer to the classical performance. We also use the generalised inverse stereographic projection to develop an analogous classical clustering algorithm and benchmark its accuracy, runtime and convergence for decoding real-world experimental optical-fibre communication data. This proposed 'quantum-inspired' algorithm provides an improvement in both the accuracy and convergence rate with respect to the k-means algorithm. Hence, this work presents two main contributions. Firstly, we propose the general inverse stereographic projection into the Bloch sphere as a better embedding for quantum machine learning algorithms; here, we use the problem of clustering quadrature amplitude modulated optical-fibre signals as an example. Secondly, as a purely classical contribution inspired by the first contribution, we propose and benchmark the use of the general inverse stereographic projection and spherical centroid for clustering optical-fibre signals, showing that optimizing the radius yields a consistent improvement in accuracy and convergence rate.
ABSTRACT
Background: Clinical and laboratory biomarkers in patients with advanced non-small-cell lung cancer (aNSCLC) receiving chemo-immunotherapy (CIT) are still poorly explored. Materials & methods: All consecutive aNSCLC patients who received at least one cycle of first-line CIT were enrolled. The impact of several clinical and laboratory biomarkers on outcomes was evaluated through Cox proportional hazard models. Results: Higher neutrophil-to-lymphocyte ratio was shown to be an independent prognostic biomarker of both worse progression-free survival and worse overall survival. The EPSILoN score was able to divide patients into three different prognostic groups, with a median overall survival of 73.2, 45.6 and 8.6 months for the favorable, intermediate and poor groups, respectively. Conclusion: The neutrophil-to-lymphocyte ratio and EPSILoN score were shown to have a prognostic value in aNSCLC patients treated with CIT.
Patients affected by inoperable lung cancer, due to great extension or to the presence of metastases, are currently treated with intravenous drugs that act on immune system activation alone or in combination with chemotherapy as first-line treatment. The characteristics of these patients (both their medical history and their blood exams) need to be studied to find out if some of them can help clinicians to predict if they will benefit from the combination of immunotherapy with chemotherapy. The authors collected the data of patients with advanced lung cancer treated in their hospital and found out that a value calculated from their blood exams, collected before the start of treatment and a combination of values named EPSILoN score (which considers patients' clinical condition, their history of tobacco smoking, the presence of metastases in the liver and two blood exam parameters, namely the neutrophil-to-lymphocyte ratio and LDH level) can predict how their disease will evolve during first-line treatment with chemotherapy in combination with immunotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Biomarkers , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Immunotherapy , Lung Neoplasms/drug therapy , Lymphocytes , Neutrophils , Prognosis , Retrospective StudiesABSTRACT
Lung is a specialized tissue where metastases from primary lung tumors takeoff and those originating from extra-pulmonary sites land. One commonality characterizing these processes is the supportive role exerted by myeloid cells, particularly neutrophils, whose recruitment is facilitated in this tissue microenvironment. Indeed, neutrophils have important part in the pathophysiology of this organ and the key mechanisms regulating neutrophil expansion and recruitment during infection can be co-opted by tumor cells to promote growth and metastasis. Although neutrophils dominate the myeloid landscape of lung cancer other populations including macrophages, dendritic cells, mast cells, basophils and eosinophils contribute to the complexity of lung cancer TME. In this review, we discuss the origin and significance of myeloid cells heterogeneity in lung cancer, which translates not only in a different frequency of immune populations but it encompasses state of activation, morphology, localization and mutual interactions. The relevance of such heterogeneity is considered in the context of tumor growth and response to immunotherapy.
Subject(s)
Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Animals , Biomarkers , Biomarkers, Tumor , Disease Management , Disease Susceptibility , Gene Expression , Humans , Immunohistochemistry , Immunotherapy , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Molecular Targeted Therapy/methodsABSTRACT
Immuno checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis is the main breakthrough for the treatment of several cancers. Nevertheless, not all patients benefit from this treatment and clinical response not always correlates with PD-L1 expression by tumor cells. The tumor microenvironment, including myeloid derived suppressor cells (MDSCs), can influence therapeutic resistance to ICB. MDSCs also express PD-L1, which contributes to their suppressive activity. Moreover, anticancer therapies including chemotherapy, radiotherapy, hormone- and targeted- therapies can modulate MDSCs recruitment, activity and PD-L1 expression. Such effects can be induced also by innovative anticancer treatments targeting metabolism and lifestyle. The outcome on cancer progression can be either positive or negative, depending on tumor type, treatment schedule and possible combination with ICB. Further studies are needed to better understand the effects of cancer therapies on the PD-1/PD-L1 axis, to identify patients that could benefit from combinatorial regimens including ICB or that rather should avoid it.
Subject(s)
B7-H1 Antigen/metabolism , Myeloid-Derived Suppressor Cells/immunology , Programmed Cell Death 1 Receptor/metabolism , B7-H1 Antigen/immunology , B7-H1 Antigen/physiology , Cell Line, Tumor , Humans , Immunotherapy , Myeloid-Derived Suppressor Cells/metabolism , Myeloid-Derived Suppressor Cells/physiology , Neoplasms/immunology , Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , Tumor MicroenvironmentABSTRACT
Quantum key distribution (QKD) is a method that distributes a secret key to a sender and a receiver by the transmission of quantum particles (e.g., photons). Device-independent quantum key distribution (DIQKD) is a version of QKD with a stronger notion of security, in that the sender and receiver base their protocol only on the statistics of input and outputs of their devices as inspired by Bell's theorem. We study the rate at which DIQKD can be carried out for a given bipartite quantum state distributed between the sender and receiver or a quantum channel connecting them. We provide upper bounds on the achievable rate going beyond upper bounds possible for QKD. In particular, we construct states and channels where the QKD rate is significant while the DIQKD rate is negligible. This gap is illustrated for a practical case arising when using standard postprocessing techniques for entangled two-qubit states.
ABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. OBJECTIVES: To determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. SEARCH METHODS: We performed an electronic search of the main databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 31 December 2020 and conferences meetings from 2015 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. MAIN RESULTS: Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. AUTHORS' CONCLUSIONS: Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups. This review used to be a living review. It is transitioned out of living mode because current research is exploring ICI in association with chemotherapy or other immunotherapeutic drugs versus ICI as single agent rather than platinum based chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/metabolism , Bevacizumab/adverse effects , Bias , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Nivolumab/adverse effects , Nivolumab/therapeutic use , Platinum Compounds/adverse effects , Platinum Compounds/therapeutic use , Progression-Free Survival , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR). METHODS: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events. RESULTS: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort. CONCLUSION: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/physiopathology , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/physiopathology , Female , Humans , Leukocyte Count , Lung Neoplasms/blood , Lung Neoplasms/physiopathology , Lymphocyte Count , Male , Middle Aged , Neutrophils , Nivolumab/therapeutic use , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Retrospective Studies , Severity of Illness Index , Sex FactorsABSTRACT
There are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors-hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers. There are not yet consensus standardized criteria for defining hyperprogressive disease, but most commonly time to treatment failure less than 2 months and an increase in pace of progression of at least twofold between pre-immunotherapy and on-treatment imaging has been used. In some patients, the change in rate of progression can be especially dramatic-up to 35- to 40-fold. MDM2 amplification and EGFR mutations have been suggested as genomic correlates of increased risk of hyperprogression, but these correlates require validation. The underlying mechanism for hyperprogression is not known but warrants urgent investigation.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Disease Progression , Genomics , Humans , Immunotherapy/adverse effects , Neoplasms/drug therapyABSTRACT
PURPOSE OF REVIEW: Describe the controversial aspects of hyperprogressive disease (HPD) definition, mechanisms, and biomarkers. RECENT FINDINGS: Although immune checkpoint inhibitors (ICIs) demonstrated a survival benefit in non-small cell lung cancer (NSCLC), an acceleration of tumor growth during ICI, defined as HPD, was reported in ~ 13-26% of NSCLC patients and correlated with worse survival compared with conventional progression. Different criteria have been used for HPD definition. The main limitation for the use of tumor growth rate and tumor growth kinetics variations is its inapplicability for patients without a pre-baseline imaging or progressing on non-measurable lesions. On the contrary, time to treatment failure and clinical criteria (i.e., worsening of performance status, presence of new lesions, or metastatic spread to different sites) can be useful in the above-mentioned settings but do not consent an assessment of tumor growth before ICI initiation. Several mechanisms of HPD have been proposed so far, involving both adaptive and innate immunity or based on cell-autonomous signals of cancer growth triggered by ICI. The characterization of HPD biomarkers and the identification and validation on large series of one or more mechanistic explanations for the HPD phenomenon are of paramount significance to avoid detrimental immunotherapy in a subgroup of patients and exploit novel therapeutic targets for future immunotherapy combinations. HPD occur in a subgroup of NSCLC patients treated with ICI. Several definitions and mechanisms have been proposed and a consensus on HPD criteria and biological bases is currently lacking.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/mortality , Disease Progression , Humans , Lung Neoplasms/immunology , Lung Neoplasms/mortalityABSTRACT
In the immunoncology era, an acceleration of tumor growth upon immune checkpoint inhibitors (ICI), defined as hyperprogressive disease (HPD) has been observed across different cancers. Although in non-small-cell lung cancer, most of the available evidence regarding HPD has been reported for patients treated with single agent PD-1 and PD-L1 inhibitors, in retrospective series a variable proportion of patients receiving ICI combinations also experienced HPD. Similarly, the shape of survival curves and the progression rates in clinical trials testing combinations of PD-1/PD-L1 inhibitors and anti-CTLA-4 agents suggest the occurrence of HPD. Few data are available regarding pseudoprogression upon ICI combinations. However, considering that pseudoprogression has been reported for anti-PD-1/PD-L1 agents and for CTLA-4 inhibitors separately, it is likely that it may occur also upon combinations of these two classes of drugs.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Neoplasms/drug therapy , Neoplasms/pathology , Response Evaluation Criteria in Solid Tumors , Clinical Trials as Topic , Disease Progression , Humans , Neoplasms/immunology , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have changed the first-line treatment of people with advanced non-small cell lung cancer (NSCLC). Single-agent pembrolizumab (a PD-1 inhibitor) is currently the standard of care as monotherapy in patients with PD-L1 expression ≥ 50%, either alone or in combination with chemotherapy when PD-L1 expression is less than 50%. Atezolizumab (PD-L1 inhibitor) has also been approved in combination with chemotherapy and bevacizumab (an anti-angiogenic antibody) in first-line NSCLC regardless of PD-L1 expression. The combination of first-line PD-1/PD-L1 inhibitors with anti-CTLA-4 antibodies has also been shown to improve survival compared to platinum-based chemotherapy in advanced NSCLC, particularly in people with high tumour mutational burden (TMB). The association of ipilimumab (an anti CTLA4) and nivolumab (PD-1 inhibitor) has been approved by the US Food and Drug Administration (FDA) in all patients with PD-L1 expression ≥1%. Although these antibodies are currently used in clinical practice, some questions remain unanswered, such as the best-treatment strategy, the role of different biomarkers for treatment selection and the effectiveness of immunotherapy according to specific clinical characteristics. OBJECTIVES: Primary objective: to determine the effectiveness and safety of first-line immune checkpoint inhibitors (ICIs), as monotherapy or in combination, compared to platinum-based chemotherapy, with or without bevacizumab for people with advanced NSCLC, according to the level of PD-L1 expression. SECONDARY OBJECTIVE: to maintain the currency of evidence using a living systematic review approach. SEARCH METHODS: We performed an electronic search of the main databases (Cochrane Lung Cancer Group Trial Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase) from inception until 21 October 2020 and conferences meetings from 2015 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) reporting on the efficacy or safety of first-line ICI treatment for adults with advanced NSCLC who had not previously received any anticancer treatment. We included trials comparing single- or double-ICI treatment to standard first-line therapy (platinum-based chemotherapy +/- bevacizumab). All data come from 'international multicentre studies involving adults, age 18 or over, with histologically-confirmed stage IV NSCLC who had not received any previous systemic anti-cancer treatment for advanced disease. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the search results and a fourth review author resolved any disagreements. Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were overall objective response rate (ORR) by RECIST v 1.1, grade 3 to 5 treatment-related adverse events (AEs) (CTCAE v 5.0) and health-related quality of life (HRQoL). We performed meta-analyses where appropriate using the random-effects model for hazard ratios (HRs) or risk ratios (RRs), with 95% confidence intervals (95% CIs), and used the I² statistic to investigate heterogeneity. MAIN RESULTS: Main results We identified 15 trials for inclusion, seven completed and eight ongoing trials. We obtained data for 5893 participants from seven trials comparing first-line single- (six trials) or double- (two trials) agent ICI with platinum-based chemotherapy, one trial comparing both first-line single- and double-agent ICsI with platinum-based chemotherapy. All trials were at low risk of selection and detection bias, some were classified at high risk of performance, attrition or other source of bias. The overall certainty of evidence according to GRADE ranged from moderate-to-low because of risk of bias, inconsistency, or imprecision. The majority of the included trials reported their outcomes by PD-L1 expressions, with PD-L1 ≥ 50 being considered the most clinically useful cut-off level for decision makers. Also, iIn order to avoid overlaps between various PDL-1 expressions we prioritised the review outcomes according to PD-L1 ≥ 50. Single-agent ICI In the PD-L1 expression ≥ 50% group single-agent ICI probably improved OS compared to platinum-based chemotherapy (hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60 to 0.76, 6 RCTs, 2111 participants, moderate-certainty evidence). In this group, single-agent ICI also may improve PFS (HR: 0.68, 95% CI 0.52 to 0.88, 5 RCTs, 1886 participants, low-certainty evidence) and ORR (risk ratio (RR):1.40, 95% CI 1.12 to 1.75, 4 RCTs, 1672 participants, low-certainty evidence). HRQoL data were available for only one study including only people with PD-L1 expression ≥ 50%, which suggested that single-agent ICI may improve HRQoL at 15 weeks compared to platinum-based chemotherapy (RR: 1.51, 95% CI 1.08 to 2.10, 1 RCT, 297 participants, low-certainty evidence). In the included studies, treatment-related AEs were not reported according to PD-L1 expression levels. Grade 3-4 AEs may be less frequent with single-agent ICI compared to platinum-based chemotherapy (RR: 0.41, 95% CI 0.33 to 0.50, I² = 62%, 5 RCTs, 3346 participants, low-certainty evidence). More information about efficacy of single-agent ICI compared to platinum-based chemotherapy according to the level of PD-L1 expression and to TMB status or specific clinical characteristics is available in the full text. Double-agent ICI Double-ICI treatment probably prolonged OS compared to platinum-based chemotherapy in people with PD-L1 expression ≥50% (HR: 0.72, 95% CI 0.59 to 0.89 2 RCTs, 612 participants, moderate-certainty evidence). Trials did not report data on HRQoL, PFS and ORR according to PD-L1 groups. Treatment related AEs were not reported according to PD-L1 expression levels. The frequency of grade 3-4 AEs may not differ between double-ICI treatment and platinum-based chemotherapy (RR: 0.78, 95% CI 0.55 to 1.09, I² = 81%, 2 RCTs, 1869 participants, low-certainty evidence). More information about efficacy of double-agent ICI according to the level of PD-L1 expression and to TMB status is available in the full text. AUTHORS' CONCLUSIONS: Authors' conclusions The evidence in this review suggests that single-agent ICI in people with NSCLC and PD-L1 ≥50% probably leads to a higher overall survival rate and may lead to a higher progression-free survival and overall response rate when compared to platinum-based chemotherapy and may also lead to a lower rate of adverse events and higher HRQoL. Combined ICI in people with NSCLC and PD-L1 ≥50% also probably leads to a higher overall survival rate when compared to platinum-based chemotherapy, but its effect on progression-free survival, overall response rate and HRQoL is unknown due to a lack of data. The rate of adverse events may not differ between groups.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/metabolism , Bevacizumab/adverse effects , Bias , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Nivolumab/adverse effects , Nivolumab/therapeutic use , Platinum Compounds/adverse effects , Platinum Compounds/therapeutic use , Progression-Free Survival , Randomized Controlled Trials as TopicABSTRACT
In this paper, we analyze the construction of identification codes. Identification codes are based on the question: "Is the message I have just received the one I am interested in?", as opposed to Shannon's transmission, where the receiver is interested in not only one, but any, message. The advantage of identification is that it allows rates growing double exponentially in the blocklength at the cost of not being able to decode every message, which might be beneficial in certain applications. We focus on a special identification code construction based on two concatenated Reed-Solomon codes and have a closer look at its implementation, analyzing the trade-offs of identification with respect to transmission and the trade-offs introduced by the computational cost of identification codes.
ABSTRACT
Aim: A minority of patients gains advantage from immunotherapy (IO). Predictive variables of long-term benefit (LTB) are incompletely understood. Materials & methods: We retrospectively collected data about metastatic non-small-cell lung cancer patients treated with IO from April 2013 to July 2017. We defined LTB to IO as complete response (CR), partial response (PR) or disease stability as best response and maintaining it for ≥12 months. Results: Thirty-five of the 147 patients had LTB. More LTB patients than controls showed CR/PR as first and best response to IO. Only CR/PR as best response to IO retained association to LTB at multivariate analyses. Conclusion: Objective response appears as a central factor for LTB from IO.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Immunotherapy/methods , Lung Neoplasms/therapy , Adult , Aged , Aged, 80 and over , CTLA-4 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Immunologic Factors/therapeutic use , Lung Neoplasms/pathology , Male , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Retrospective StudiesABSTRACT
Next-generation sequencing (NGS) was applied to 148 lung neuroendocrine tumours (LNETs) comprising the four World Health Organization classification categories: 53 typical carcinoid (TCs), 35 atypical carcinoid (ACs), 27 large-cell neuroendocrine carcinomas, and 33 small-cell lung carcinomas. A discovery screen was conducted on 46 samples by the use of whole-exome sequencing and high-coverage targeted sequencing of 418 genes. Eighty-eight recurrently mutated genes from both the discovery screen and current literature were verified in the 46 cases of the discovery screen, and validated on additional 102 LNETs by targeted NGS; their prevalence was then evaluated on the whole series. Thirteen of these 88 genes were also evaluated for copy number alterations (CNAs). Carcinoids and carcinomas shared most of the altered genes but with different prevalence rates. When mutations and copy number changes were combined, MEN1 alterations were almost exclusive to carcinoids, whereas alterations of TP53 and RB1 cell cycle regulation genes and PI3K/AKT/mTOR pathway genes were significantly enriched in carcinomas. Conversely, mutations in chromatin-remodelling genes, including those encoding histone modifiers and members of SWI-SNF complexes, were found at similar rates in carcinoids (45.5%) and carcinomas (55.0%), suggesting a major role in LNET pathogenesis. One AC and one TC showed a hypermutated profile associated with a POLQ damaging mutation. There were fewer CNAs in carcinoids than in carcinomas; however ACs showed a hybrid pattern, whereby gains of TERT, SDHA, RICTOR, PIK3CA, MYCL and SRC were found at rates similar to those in carcinomas, whereas the MEN1 loss rate mirrored that of TCs. Multivariate survival analysis revealed RB1 mutation (p = 0.0005) and TERT copy gain (p = 0.016) as independent predictors of poorer prognosis. MEN1 mutation was associated with poor prognosis in AC (p = 0.0045), whereas KMT2D mutation correlated with longer survival in SCLC (p = 0.0022). In conclusion, molecular profiling may complement histology for better diagnostic definition and prognostic stratification of LNETs. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Subject(s)
Carcinoid Tumor/genetics , Carcinoma, Neuroendocrine/genetics , Chromatin Assembly and Disassembly/genetics , Lung Neoplasms/genetics , Neuroendocrine Tumors/genetics , Small Cell Lung Carcinoma/genetics , Adult , Aged , Carcinoid Tumor/pathology , Carcinoma, Neuroendocrine/pathology , Cohort Studies , DNA Copy Number Variations , DNA-Binding Proteins/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Italy , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Neoplasm Proteins/genetics , Neuroendocrine Tumors/pathology , Prognosis , Proto-Oncogene Proteins/genetics , Retinoblastoma Binding Proteins/genetics , Sequence Analysis, DNA , Small Cell Lung Carcinoma/pathology , Telomerase/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
An important contribution to the understanding of quantum key distribution has been the discovery of entangled states from which secret bits, but no maximally entangled states, can be extracted [Horodecki et al., Phys. Rev. Lett. 94, 200501 (2005)PRLTAO0031-900710.1103/PhysRevLett.94.200501]. The construction of those states was based on an intuition that the quantum mechanical phenomena of data hiding and privacy might be related. In this Letter we firmly connect these two phenomena and highlight three aspects of this result. First, we simplify the definition of the secret key rate. Second, we give a formula for the one-way distillable entanglement of certain private states. Third, we consider the problem of extending the distance of quantum key distribution with help of intermediate stations, a setting called the quantum key repeater. We show that for protocols that first distill private states, it is essentially optimal to use the standard quantum repeater protocol based on entanglement distillation and entanglement swapping.
ABSTRACT
This study aimed to compare neuromuscular fatigability of the elbow flexors and extensors between athletes with amputation (AMP) and athletes with spinal cord injury (SCI) for maximum voluntary force (MVF) and rate of force development (RFD). We recruited 20 para-athletes among those participating at two training camps (2022) for Italian Paralympic veterans. Ten athletes with SCI (two with tetraplegia and eight with paraplegia) were compared to 10 athletes with amputation (above the knee, N = 3; below the knee, N = 6; forearm, N = 1). We quantified MVF, RFD at 50, 100, and 150 ms, and maximal RFD (RFDpeak) of elbow flexors and extensors before and after an incremental arm cranking to voluntary fatigue. We also measured the RFD scaling factor (RFD-SF), which is the linear relationship between peak force and peak RFD quantified in a series of ballistic contractions of submaximal amplitude. SCI showed lower levels of MVF and RFD in both muscle groups (all p values ≤ 0.045). Despite this, the decrease in MVF (Cohen's d = 0.425, p < 0.001) and RFDpeak (d = 0.424, p = 0.003) after the incremental test did not show any difference between pathological conditions. Overall, RFD at 50 ms showed the greatest decrease (d = 0.741, p < 0.001), RFD at 100 ms showed a small decrease (d = 0.382, p = 0.020), and RFD at 150 ms did not decrease (p = 0.272). The RFD-SF decreased more in SCI than AMP (p < 0.0001). Muscle fatigability impacted not only maximal force expressions but also the quickness of ballistic contractions of submaximal amplitude, particularly in SCI. This may affect various sports and daily living activities of wheelchair users. Early RFD (i.e., ≤50 ms) was notably affected by muscle fatigability.
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INTRODUCTION: The discovery of oncogenic mutations that drive the growth and progression of Non-small-cell lung cancer (NSCLC) led to the development of a range of molecular targeted therapies. Tyrosine kinase inhibitors (TKIs) improve the overall outcome of patients with oncogene addicted NSCLC, ensure a better compliance to treatment and few side effects compared to traditional chemotherapy. However, the treatment is still completely "drug-centric", in a population of patients who usually survive for a long time and desire to regain their quality of life. Despite an extensive literature on the importance of complementary treatments and lifestyle promotion, the guidelines on physical exercise are general and usually refer to the entire lung cancer pathology. METHODS AND OBJECTIVES: EXcellenT is an Italian monocentric randomized prospective study enrolling 40 patients diagnosed with oncogene-addicted advanced NSCLC in active treatment with TKIs. Patients will be randomized (1:1 ratio) to an 'interventional' or a 'control' group. In the interventional arm (arm A), participants will receive a 3-month multicomponent personalized physical activity prescription combining a supervised coaching program at the training center and an app-based physical activity schedule at patients home. In the control group (arm B) patients will receive a fitness professional-guided montly session that will result in an unsupervised home-based physical activity counselling. Prospective collection of blood metabolome and immune phenotypes will be performed to investigate the integration with genetic alterations that drive the patient's disease. The overall aim of the project is to evaluate if a tailored physical program may have a significant impact on quality of life and performances of this specific homogeneous subgroup of patients. The exploratory goal is to elucidate a potential link between metabolites, immune parameters and genetic deregulations and how this interplay may be influenced by physical exercise. CONCLUSION: EXcellent trial aims to propose a new approach to personalized medicine in the specific subgroup of oncogene-addicted NSCLC patients, where targeted therapy is integrated with an equally tailored physical activity program. The homogeneity of this cancer population will provide insights on the influence of exercise on metabolism and immunity during treatment with TKIs.
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This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM.
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INTRODUCTION: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. METHODS: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. RESULTS: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively. CONCLUSIONS: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.