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Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38–7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09–17.55] months versus negative expression 13.3 [95% CI 7.32–19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08–9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICI) have the potential to induce serious and unpredictable immune-related adverse events (irAEs), the underlying mechanisms of which remain incompletely understood. In this study, we investigated the relationship between irAEs and the expression of IFN-inducible chemokines and cytokines in patients with solid tumours treated with PD-(L)1 inhibitors. We analysed plasma levels of various IFN-related cytokines at different time points in patients categorized by irAE development and severity. We found that patients with serious irAEs showed significant increases in CXCL9, CXCL10, CXCL11, IL-18 and IL-10 at the onset of the irAE compared to patients with mild irAEs and those without irAEs. Additionally, IL-18 emerged as a promising predictive biomarker for serious irAE development. In summary, this study provides valuable insights into the immune responses associated with irAEs and proposes potential predictive markers for their severity. Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity. [ABSTRACT FROM AUTHOR]

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10–12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1+ leukocytes, PD-L1+ platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14+ cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1+ leukocytes after 10–12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy. [ABSTRACT FROM AUTHOR]

This is a summary of the original article ‟Overall survival with osimertinib in resected EGFR-mutated NSCLC.ˮ Osimertinib blocks the activity of the epidermal growth factor receptor (EGFR) on cancer cells, causing cancer cell death and tumor shrinkage, and is an effective treatment for EGFR-mutated non-small cell lung cancer (NSCLC). The ADAURA study assessed the effects of osimertinib versus placebo in patients with EGFR-mutated (exon 19 deletion or L858R) early stage (IB–IIIA) NSCLC removed by surgery (resected). Previous results from ADAURA demonstrated that patients treated with osimertinib stayed alive and cancer-free (disease-free survival) significantly longer than patients who received placebo. Recent data showed the overall length of time patients were alive after starting treatment (overall survival). In both the primary stage II–IIIA and overall stage IB–IIIA populations, patients in the osimertinib group had a significant 51% reduction in the risk of death compared with the placebo group. The data demonstrated that osimertinib after surgery significantly improved overall survival in patients with resected, EGFR-mutated, stage IB–IIIA NSCLC. [ABSTRACT FROM AUTHOR]

The incidence and mortality of lung cancer in women are rising, with both increasing by 124% between 2003 and 2019. The main risk factor for lung cancer is tobacco use, but indoor radon gas exposure is one of the leading causes in nonsmokers. The most recent evidence demonstrates that multiple factors can make women more susceptible to harm from these risk factors or carcinogens. For this consensus statement, the Association for Lung Cancer Research in Women (ICAPEM) invited a group of lung cancer experts to perform a detailed gender-based analysis of lung cancer. Clinically, female patients have different lung cancer profiles, and most actionable driver alterations are more prevalent in women, particularly in never-smokers. Additionally, the impact of certain therapies seems to be different. In the future, it will be necessary to carry out specific studies to improve the understanding of the role of certain biomarkers and gender in the prognosis and evolution of lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica—SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón—GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres—ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of advanced melanoma patients has been improved in recent years due to immunotherapy. However, not all patients respond to this treatment. For this reason, it is necessary to know the mechanisms of the response and resistance to immunotherapy. In this work, clinical samples from advanced melanoma patients treated with immunotherapy were analyzed. The obtained results suggested that the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation, as well as the immune and inflammatory responses, play a role in the response to immunotherapy. Additionally, we built a prognostic signature capable of identifying those patients that will respond to immunotherapy. The study of the mechanisms of the resistance and response to immunotherapy could help in the definition of new therapies for these patients that do not respond to immunotherapy. Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment. [ABSTRACT FROM AUTHOR]

Introduction: There are currently three first-line immunotherapy options used as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand 1 (PD-L1) expression (≥50%). This manuscript aims to evaluate the available data on atezolizumab (AT), cemiplimab (CEMI), and pembrolizumab (PEMBRO) and to study the results obtained during pivotal trials, especially regarding patient subgroups. Methods: Nominal group and Delphi techniques were used. Eight Spanish experts in lung cancer (the scientific committee of the project) analyzed the use of immunotherapy monotherapy as first-line treatment in patients with NSCLC and high PD-L1 expression. The expert scientific committee formulated several statements based on a scientific review and their own clinical experience. Subsequently, 17 additional Spanish lung cancer experts were selected to appraise the committee's statements through two Delphi rounds. They completed a Delphi round via an online platform and voted according to a scale from 1 (strongly disagree) to 10 (strongly agree). The statements were approved if ≥70% of experts voted 7 or more. Results: A total of 20 statements were proposed covering the following areas: (1) general characteristics of pivotal clinical trials; (2) overall main outcomes of pivotal clinical trials; and (3) subgroup analysis. All statements reached consensus in the first round. Conclusions: AT, CEMI, and PEMBRO as monotherapy can be considered the standard of care in patients with advanced NSCLC and high PD-L1 expression (≥50%). Moreover, some differences noted among the drugs analyzed in this document might facilitate treatment decision-making, especially in clinically relevant patient subgroups, when using PD-1/PD-L1 inhibitors. The high level of agreement reached among experts supports the proposed statements. [ABSTRACT FROM AUTHOR]

Purpose: This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC). Methods: A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements). Results: In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB–IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib. Conclusions: This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario. [ABSTRACT FROM AUTHOR]

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor PD-L1 expression is a predictive biomarker for patients with NSCLC receiving PD-(L)1 blockade agents. However, although increased tumor PD-L1 expression predicts responsiveness, clinical benefit has been observed regardless of tumor PD-L1 expression, suggesting the existence of other PD-L1 sources. The aim of our study was to analyze whether integrating systemic and tumor PD-L1 is more predictive of efficacy in patients with advanced NSCLC receiving PD-(L)1 blockade agents. Material and methods: Twenty-nine healthy donors and 119 consecutive patients with advanced NSCLC treated with PD-(L)1 drug were prospectively included. Pretreatment blood samples were collected to evaluate PD-L1 levels on circulating immune cells, platelets (PLTs), platelet microparticles (PMPs), and the plasma soluble PD-L1 concentration (sPD-L1). Tumor PD-L1 status was assessed by immunohistochemistry. The percentages of circulating PD-L1 + leukocytes, sPD-L1 levels, and tumor PD-L1 were correlated with efficacy. Results: No differences in the percentages of circulating PD-L1 + leukocytes were observed according to tumor PD-L1 expression. Significantly longer progression-free survival was observed in patients with higher percentages of PD-L1 + CD14 + , PD-L1 + neutrophils, PD-L1 + PLTs, and PD-L1 + PMPs and significantly longer overall survival was observed in patients with higher percentages of PD-L1 + CD14 + and high tumor PD-L1 expression. Integrating the PD-L1 data of circulating and tumor PD-L1 results significantly stratified patients according to the efficacy of PD-(L1) blockade agents. Conclusions: Our results suggest that integrating circulating PD-L1 + leukocytes, PLT, PMPs, and sPD-L1 and tumor PD-L1 expression may be helpful to decide on the best treatment strategy in patients with advanced NSCLC who are candidates for PD-(L)1 blockade agents. [ABSTRACT FROM AUTHOR]

To describe the clinical outcomes and risk factors for 90‐day mortality in patients with solid tumours (ST) and coronavirus disease 2019 (COVID‐19) during the first outbreak in Catalonia. This is a multicentre retrospective study including adults with ST and COVID‐19 confirmed by real time reverse transcription polymerase chain reaction between 13 March and 30 April 2020. Clinical and survival data were collected. Follow‐up ended on 30 July 2020. Multivariate and survival analysis were performed. A hundred and fifteen patients were included. In all, 42.6% had advanced disease and were receiving anticancer treatment; 7% were admitted to the ICU and 22.6% died during hospitalisation. Thirty‐day mortality was 27.8%, which increased to 33.9% at 90 days. Ninety‐day mortality was associated with current smoker status (hazard ratio [HR]: 2.91, 95% CI [confidence interval]: 1.03‐8.33, P =.044), baseline ECOG‐PS 2 to 3 (HR: 3.88, 95% CI: 1.77‐8.46, P <.001]), dyspnoea (HR: 3.02, 95% CI: 1.31‐6.96, P =.009), a respiratory rate ≥ 24 (HR: 2.24, 95% CI: 1.02‐4.92, P =.046) and sepsis (HR: 3.97, 95% CI: 1.78‐8.88, P <.001). Of the 76 survivors, 73.6% had a follow‐up visit. Of those, 33.9% had their cancer controlled and 23.2% had progressed. Thirty‐five survivors were receiving anticancer treatment before COVID‐19 diagnosis though 14 had to discontinue the treatment. Eight survivors without previous anticancer therapy started therapy. The median time to start anticancer therapy after COVID‐19 was 45 days (interquartile range: 28‐61). In conclusion, 90‐day mortality in patients with ST and COVID‐19 was 33.9%; current smoker status, poor ECOG‐PS, dyspnoea, respiratory rate ≥24 and sepsis were independent risk factors for mortality; and survivors did not restart their anticancer treatment until 1.5 months after COVID‐19 diagnosis. [ABSTRACT FROM AUTHOR]

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO. [ABSTRACT FROM AUTHOR]

Among the side effects of anticancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most feared given its high prevalence, affecting up to 40% of patients. It can impair patient's quality of life and provoke low adherence to cancer treatment or chemotherapy dose reductions that can comprise treatment efficacy. Suffering CINV depends on factors related to the intrinsic emetogenicity of antineoplastic drugs and on patient characteristics. CINV can appear at different times regarding the administration of antitumor treatment and the variability of risk according to the different antitumor regimens has, as a consequence, the need for a different and adapted antiemetic treatment prophylaxis to achieve the desired objective of complete protection of the patient in the acute phase, in the late phase and in the global phase of emesis. As a basis for the recommendations, the level of emetogenicity of anticancer treatment is considered and they are classified as high, moderate, low and minimal emetogenicity and these recommendations are based on the use of antiemetic drugs with a high therapeutic index: anti 5-HT, anti-NK and steroids. Despite having highly effective treatments, clinical reality shows that they are not applied enough, so evidence-based recommendations are needed to show the best options and help in decision-making. To cover all the antiemetic prophylaxis options, we have also included recommendations for oral treatments, multiday regimens and radiation-induced emesis prevention. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, target therapies to specific molecular alterations in advanced non--small cell lung cancer (NSCLC) have been identified and have shown superior efficacy compared to non-targeted treatments. Anaplastic lymphoma kinase (ALK) is one of the therapeutic targets; nevertheless, ALK diagnosis is not performed in all NSCLC patients in Spain. The objective of this study is to estimate in monetary terms the benefit for the Spanish society of ALK diagnosis in advanced NSCLC patients. Methods: A cost-benefit analysis of ALK diagnosis vs. non-diagnosis in advanced NSCLC patients was carried out from the Spanish social perspective, with a time horizon of 5 years. Costs, benefits and the cost-benefit ratio were measured. The analysis has considered the overall survival in advanced NSCLC patients treated with the ALKtyrosine kinase inhibitor (TKI) alectinib. The natural history of NSCLC was simulated using a Markov model. A 3% discount rate was applied to both costs and benefits. The result was tested using a deterministic sensitivity analysis. Results: The cost of ALK diagnosis vs. non-diagnosis in the base case would be €10.19 million, generating benefits of €11.71 million. The cost-benefit ratio would be €1.15. In the sensitivity analysis, the cost-benefit ratio could range from €0.89 to €2.10. Conclusions: The results justify the universal application of ALK diagnosis in advanced NSCLC, which generates a benefit for Spanish society that outweighs its costs and allows optimal treatment with targeted therapies for these patients. [ABSTRACT FROM AUTHOR]

Background: Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. Methods: We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan–Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). Results: Median age was 58.9 years (range 42.8–81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2–3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1–38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9–7.3] and the median OS 10.1 months (95% CI 5.9–14.3). The objective response rate (ORR) was 44.4% (23.7–66.8%) and the disease control rate (DCR) 72.2% (49.4–88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1–10.5) versus (vs.) 4.8 (95% CI 3.5–6.1) and a median OS of 12.3 months (95% CI 8.6–16.0) vs. 6.7 months (95% CI 3.9–9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0–6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported. Conclusions: Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected. [ABSTRACT FROM AUTHOR]

Here, we summarize the initial results from the ADAURA clinical study looking at treatment with osimertinib in patients with a specific type of non-small cell lung cancer (also called NSCLC). Osimertinib (TAGRISSO®) is a medication used to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for 'epidermal growth factor receptor'. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. ClinicalTrials.gov NCT number: NCT02511106. [ABSTRACT FROM AUTHOR]

Objectives: The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non‐small cell lung cancer (NSCLC) patients treated with first‐ or second‐generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods: Stage IV NSCLC patients with locally confirmed EGFR‐TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first‐ or second‐generation EGFR‐TKI as first‐line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression‐free survival (PFS) event or until study completion (72‐week follow‐up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. Results: A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty‐six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow‐up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48–2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01–7.36; p < 0.001). Conclusion: Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy is being tested in early‐stage non‐small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment‐related changes to find biomarkers associated to CPR. Methods: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. Results: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p‐value <.05. CPR patients had significantly higher levels of CD4+PD‐1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+CD56–CTLA‐4+ cells, CD14++CD16+CTLA‐4+ cells, CTLA‐4 expression on T CD56 cells and lower levels of b‐NGF, NT‐3, and VEGF‐D in plasma compared to non‐CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4‐1BB, MCSF, and PARC and lower levels of MPIF‐1 and Flt‐3L in plasma compared to non‐CPR. Conclusions: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non‐CPR responses. [ABSTRACT FROM AUTHOR]

Background: Anti-PD-(L)1 blocking agents can induce immune-related adverse events (irAEs), which can compromise treatment continuation. Since circulating leukocyte–platelet (PLT) complexes contribute to inflammatory and autoimmune diseases, we aimed to analyze the role of these complexes as predictors of irAEs in non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1. Materials and methods: Twenty-six healthy donors (HD) and 87 consecutive advanced NSCLC patients treated with anti-PD-(L)1 were prospectively included. Percentages of circulating leukocyte–PLT complexes were analyzed by flow cytometry and compared between HD and NSCLC patients. The association of leukocyte–PLT complexes with the presence and severity of irAEs was analyzed. Results: NSCLC patients had higher percentages of circulating leukocyte–PLT complexes. Higher percentages of monocytes with bound PLT (CD14 + PLT +) were observed in patients who received prior therapies while CD4 + T lymphocytes with bound PLT (CD4 + PLT +) correlated with platelets counts. The CD4 + PLT + high percentage group presented a higher rate of dermatological irAEs while the CD4 + PLT + low percentage group showed a higher rate of non-dermatological irAEs (p < 0.001). A lower frequency of grade ≥ 2 irAEs was observed in the CD4 + PLT + high percentage group (p < 0.05). Patients with CD4 + PLT + low and CD14 + PLT + high percentages presented a higher rate of grade ≥ 3 irAEs and predominantly developed non-dermatological irAEs (p < 0.01). Conclusions: Our results suggest that circulating leukocyte–PLT complexes and the combination of CD4 + PLT + and CD14 + PLT + percentages can be used as a predictive biomarker of the development and severity of irAEs in advanced NSCLC patients receiving anti-PD-(L)1 agents. [ABSTRACT FROM AUTHOR]

Purpose: Treatment guidelines for advanced non–small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS: Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers (EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS: The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue (P <.05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. Conclusion: This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed. [ABSTRACT FROM AUTHOR]

Purpose: Treatment guidelines for advanced non–small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS: Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers (EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS: The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue (P <.05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. Conclusion: This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed. [ABSTRACT FROM AUTHOR]

Background: Immune-related adverse events (irAEs) have been associated with improved efficacy in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1 blockade agents, while the concurrent use of corticosteroids seems to worsen it. We evaluated outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents in relation to the presence of irAEs and the reasons for using corticosteroids: whether for palliative cancer-related reasons or for the management of irAEs. Methods: Clinical outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents were calculated with regard to the presence of irAEs and the use of corticosteroids. A landmark analysis was performed to avoid immortal time bias due to the time-dependent nature of irAEs. Results: Out of a total of 267 patients, the 56.9% of patients who experienced irAEs had significantly improved outcomes. In the landmark analysis, median progression-free survival (PFS) was 12.4 months for patients with irAEs vs. 4.1 months for patients without irAEs (p < 0.001), while median overall survival (OS) was 28.2 vs. 12.5 months, respectively (p < 0.001). Likewise, objective response and disease control rates were significantly higher in patients experiencing irAEs: 48.6 vs. 22.8% and 77.1 vs. 39.6% (p < 0.001), respectively. Median OS was significantly shorter for patients receiving ≥10 mg of prednisone equivalent daily for cancer-related symptoms than for the rest of patients (<10 mg prednisone equivalent daily or for management of irAEs): 6 vs. 15.9 months (p < 0.001). Conclusions: IrAEs were associated with improved efficacy in advanced NSCLC patients when a landmark analysis was applied. Patients receiving corticosteroids had significantly poorer outcomes when they were used for cancer-related symptoms. [ABSTRACT FROM AUTHOR]

Background: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC).Methods: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS.Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004).Conclusion: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001.Clinical Trial Registration: NCT01935154. [ABSTRACT FROM AUTHOR]

Swimmer plot indicating duration of treatment with osimertinib (months) by resistance mechanisms (n = 109 total, n = 38 with detected resistance mutation)." Correction to: I Nature Communications i https://doi.org/10.1038/s41467-023-35961-y, published online 27 February 2023 The original Article contained errors in the legend of Figure 3 that incorrectly read " I Comparator EGFR-TKI duration of treatment by candidate resistance mechanisms. Swimmer plot indicating duration of treatment with comparator EGFR-TKI (months) by resistance mechanisms (n = 145) i .". [Extracted from the article]

Background: Coping with cancer and the oncologist–patient relationship can vary depending on the patient's age. Our aim is to examine and compare young and elderly adults with non‐metastatic, resected cancer. Methods: Two groups of patients were selected, young (< 40 years) and elderly (> 70) with a diagnosis of non‐metastatic, resected cancer requiring adjuvant chemotherapy from a pre‐exiting, national database (NEOCOPING Study). Epidemiological variables were collected and subjects' emotional responses, perceptions of the physician–patient relationship, support network, fears, and regret about the decision to receive chemotherapy were assessed with questionnaires validated in previous studies: Mini‐Mental Adjustment to Cancer, Brief Summary Inventory (18 items), European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire‐C30, Shared Decision‐Making Questionnaire‐Physician's version, Shared Decision‐Making Questionnaire‐Patient's version, and Informed Risk (physician and patient versions). Results: Data from 46 young and 46 elderly participants were collected. The most common neoplasms in both groups were breast (50%) and colorectal (22%). The younger adults had a higher level of education and were actively employed (72% vs. 7%). The leading coping strategy in the younger cohort was hope, and resignation among the elderly. Young adults sought more social support and the impact of diagnosis was more negative for them than for older individuals. No significant differences were detected in quality of life; both age groups demanded more time at their first visit with the doctor, while the older group exhibited greater satisfaction with shared decision‐making. At the end of adjuvant chemotherapy, neither age group regretted their decision to receive said treatment. Conclusion: Higher levels of education, greater demands of the labour market, and the advent of the age of information have entailed drastic changes in the physician–patient relationship paradigm. This is especially true in the younger cancer patient population, who require more information and active participation in decision‐making, can display more anxiety about their diagnosis, but also greater capacity to fight. [ABSTRACT FROM AUTHOR]

Introduction: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. Materials and methods: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). Results: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5–0.9); p = 0.026 and HR 1.5 (1.1–2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4–4.3; p = 0.002 and HR 0.6 (0.5–0.9); p = 0.013, respectively]. Conclusion: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

(c) The IC50 values for gefitinib increase in the three sensitive EGFR-mutant lung adenocarcinoma cell lines, H3255, PC-9 and 11-18, as mTOR expression increases (protein or mRNA). Graph: Figure 3 The IC50 values for gefitinib in EGFR-mutant lung adenocarcinoma cell lines are associated with basal BIM and mTOR expression (protein or mRNA). [Extracted from the article]

Background: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain.Methods: All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated.Results: Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations.Conclusion: EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC. [ABSTRACT FROM AUTHOR]

The WORLD07 study characterizes lung cancer in Spanish women. This analysis investigated lung cancer features in never-smoking women. Of 2072 women recruited, 2035 were analyzed. Patient characteristics and demographics were similar for current/former smokers and never smokers. Among never smokers, 38.3% were exposed to passive smoking. Non-small-cell lung cancer was the most common type (78.8% of current/former smokers and 96.1% of never smokers) and adenocarcinoma the most common histology (69.1% and 83.4% respectively). There was a high incidence of lung cancer in Spanish never-smoking women and a high proportion (about 50%) had mutant epidermal growth factor receptor. [ABSTRACT FROM PUBLISHER]

Background: BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.Methods: We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point.Results: The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004).Conclusions: These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model. [ABSTRACT FROM AUTHOR]