Outcomes of patients with non-small cell lung cancer and poor performance status treated with immune checkpoint inhibitors in the real-world setting.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are standard treatments for metastatic non-small cell lung cancer (NSCLC). Patients with poor performance status (PS) are underrepresented in clinical trials. We evaluate the efficacy and safety of ICIs in a real-world setting. METHODS: We conducted a multi-institutional retrospective study to assess clinical outcomes of NSCLC treated with ICIs. We categorized pts within two groups (PS 0-1 vs 2) and assessed clinical outcomes and safety. RESULTS: Two hundred and sixty nine patients were included, 44 patients (16.4%) had baseline PS 2 and 223 patients (82.9%) PS 0-1. The overall response rate (ORR) was 30.4%, median PFS was 7.26 months (95% CI 5.1-9.4), and median OS was 15.18 months (95% CI 9.5-20.9). Patients with a PS 2 were most likely to received ICIs in the second or later line (84.1% vs 64.6%; p = 0.01), had baseline steroids (21.4% vs 8.2%; p 0.010), lower response rate (16.7% vs 34.5%; p 0.02) and clinical benefit (35.7% vs 71%; p 0.000) compared to PS 0-1 pts. Moreover, PS ≥ 2 patients had shorter PFS, median 2.2 months (95% CI 1.3-3.1) compared to 9.9 months (95% CI 6.7-13.1] and shorter OS, 3.3 months (95% CI 2.6-4.2) versus 24.1 months (95% CI 16.1-32.1), respectively. PS was significantly associated with PFS and OS in multivariate analysis. As it was expected, immunotherapy was well tolerated with a safety profile comparable to the previous published data. CONCLUSION: Based on these retrospective results, patients with poor baseline performance status seem to have poor clinical outcomes with ICIs in the real-world setting.

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.

Immunotherapy combinations for the treatment of patients with solid tumors.

Immune checkpoint inhibitors directed against CTLA-4, PD-1 and PD-L1 have transformed the treatment of patients with cancer. Immunotherapy regimens have evolved from a single agent approach to the combination of immune checkpoint inhibitors like anti CTLA-4 and PD-1, immune checkpoint blockade combined with chemotherapy, anti-angiogenic agents and kinase inhibitors. These synergistic combinations were developed to heighten the potency and duration of immune responses against cancer cells. Hence, immunotherapy combinations have shaped the landscape of therapeutic options against a wide range of cancer types, and are current standard treatment regimens worldwide. In this review, we describe the clinical evidence supporting the use of immunotherapy combination regimens for the treatment of patients with solid tumors.

The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease.

PURPOSE: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. METHODS: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. RESULTS: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. CONCLUSIONS: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Systemic lupus erythematosus associated with thymoma: A fifteen-year observational study in France.

OBJECTIVE: To describe the clinical, biological and pathological characteristics of patients with the association of SLE and thymic epithelial tumors (TET) in a retrospective multicenter series. METHODS: Cases diagnosed in France between 2000 and 2015 were collected after a call for observations from the French network for thymic epithelial tumors (RYTHMIC database) and the French National Society of Internal Medicine (SNFMI). RESULTS: Fourteen patients were identified, the majority were women (93%). The median age at diagnosis of lupus was 43.5 [range: 30-66] years and 43.5 [range: 26-73] years at diagnosis of thymoma. TET required chemotherapy and/or radiotherapy complementary to surgery in >90% cases. Lupus was diagnosed before, simultaneously, or after diagnosis of thymoma in 6, 3 and 5 cases, respectively. Among the lupus manifestations, joint involvement was predominant (78.6%), followed by autoimmune cytopenia (35.7%), cutaneous affections (28.6%), serositis (28.6%) and renal involvement (21.4%). SLE was associated with one or more AID in 5/14 patients. These characteristics were compared with those from 17 patients identified in the literature. Among them, joint and skin involvement as well as pleural/pericardial effusions occurred in >50%. SLE was controlled by prednisone and hydroxychloroquine in the majority of cases, but 7 out of 31 patients had an immunosuppressant. CONCLUSION: The association of SLE and TET is rare, and its clinical profile seems to be distinguished by the frequency of cytopenias. The management of these patients is complicated by the need to treat cancer, lupus and/or associated autoimmune diseases.

Immune biomarkers in thymic epithelial tumors: expression patterns, prognostic value and comparison of diagnostic tests for PD-L1.

BACKGROUND: Immunotherapy is currently under investigation in B3 Thymoma (TB3) and Thymic Carcinoma (TC). PD-L1 expression has been evaluated on a limited number of patients with selected antibodies. We aimed to analyze cohort of TB3 and TC with a panel of antibodies to assess the prevalence of PD-L1 expression, its prognostic value and to set up a reproducible test. METHODS: We retrospectively studied 103 patients samples of FFPE histologically confirmed TB3 (n = 53) and TC (n = 50) by expert pathologists within the RYTHMIC national network. We compared PD-L1, PD1, CD8 and PD-L2 expression and performed correlation with tumor types and patients outcomes. Four PD-L1 antibodies were tested, three of them validated as companion tests in lung cancer, one tested on two automates on whole section of tumors. We evaluated the percentage and intensity of both epithelial and immune stained cells. RESULTS: TB3 epithelial cells had a higher and more diffuse expression of PD-L1 than TC regardless the antibodies tested (p < 0.0001). Three out of four antibodies targeting PD-L1 tested on the DAKO autostainer gave similar staining. Concordance between antibodies was lower for PD-L1 staining on immune cells with no significant difference between TB3 and TC except on E1L3N antibody. PD-L2 antibody stained no tumor epithelial cells. High PD-L1 expression was correlated with a better overall survival for TB3 and was not correlated with tumor staging. CONCLUSION: Frequent PD-L1 expression, particularly in TB3, paves the way for immunotherapy in TET (Thymic Epithelial Tumor). Otherwise, we have set up three reproducible LDT (laboratory-developed test) for four PD-L1 antibodies.

LKB1/STK11 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value.

BACKGROUND: LKB1/STK11 (STK11) is among the most inactivated tumor-suppressor genes in non-small cell lung cancer (NSCLC). While evidence concerning the biologic role of STK11 is accumulating, its prognostic significance in advanced NSCLC has not been envisaged yet. MATERIALS AND METHODS: This retrospective analysis included consecutive NSCLC patients with available STK11 information who underwent a platinum-based chemotherapy. STK11 mutational status was correlated to clinico-pathological and mutational features. Kaplan-Meier and Cox models were used for survival curves and multivariate analyses, respectively. RESULTS: Among the 302 patients included, 267 (89%) were diagnosed with stage IIIB/IV NSCLC and 25 (8%) harbored a STK11 mutation (STK11mut). No statistical differences were observed between STK11 status and clinico-pathological variables. We detected a significant correlation between STK11 and KRAS status (p=0.008); among the 25 STK11mut patients, 13 (52%) harbored a concomitant KRAS mutation. Overall survival (OS) was shorter for STK11mut (median OS=10.4months) compared to wild-type patients (STK11wt; median OS=17.3months) in univariate analysis (p=0.085). STK11 status did not impact upon OS in multivariate analysis (p=0.45) and non-significant results were observed for progression-free survival. The co-occurrence of KRAS and STK11 mutations suggest a trend toward detrimental effect in OS (p=0.12). CONCLUSIONS: In our cohort enriched for advanced NSCLC patients who received platinum-based chemotherapy, STK11 mutations were not specifically associated with clinico-pathological features and they did not impact upon survival. We confirm the positive correlation between STK11 and KRAS mutations. The co-occurrence of KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

Prognostic value of HLA-A2 status in advanced non-small cell lung cancer patients.

INTRODUCTION: The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. METHODS: Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. RESULTS: Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0-1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21-84). Incidence of patients with EGFRmut, ALK-positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0-14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4-15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86-1.29], p=0.61). Median progression-free survival was similar in the two cohorts. CONCLUSION: HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy.

Second-line combination therapies in nonsmall cell lung cancer without known driver mutations.

In advanced nonsmall cell lung cancer (NSCLC) patients, platinum-based combination chemotherapy is standard treatment in the first-line setting; however, the large majority of patients ultimately progress. For more than a decade, single-agent therapy with docetaxel, pemetrexed or erlotinib has been the standard of care after failure with platinum salts, showing some benefit over best supportive care. Nonetheless, prognosis remains poor and new second-line strategies are urgently needed. Combinations of cytotoxic agents, including rechallenge with platinum salts, do not offer clear benefit over single-agent therapy for the majority of patients. In patients without a known tumoural oncogenic driver mutation, regimens based on combinations of targeted agents have shown promising results; however, a clear role in therapeutic management is yet to be established. Some success has been reported in recent research combining a cytotoxic agent with targeted therapies.In this review, we summarise published data for the various strategies evaluated over the past decade in second-line treatment of NSCLC patients without a known driver mutation. We focus on combination treatments and consider future perspectives, including the need to identify predictive markers to support personalised therapeutic strategies.

Tomografía helicoidal de tórax y enfermedad tromboembólica pulmonar / Helical computed tomography in suspected pulmonary

El objetivo del trabajo es evaluar en forma retrospectiva la utilización de la TC para diagnóstico de TEP en un hospital privado e identificar su verdadera utilidad y correcta indicación ante tal sospecha diagnóstica.

Tomografía helicoidal de tórax y enfermedad tromboembólica pulmonar / Helical computed tomography of the thorax and pulmonary thromboembolic disease

La utilización de la tomografía helicoidal en el diagnóstico de tromboembolismo pulmonar, data de más de una década. Desde entonces múltiples estudios han intentado definir su utilidad y a pesar de la falta de protocolos correctamente diseñados, esta metodología está ganando rápidamente aceptación como primer estudio a solicitar ante la sospecha de TEP. El objetivo del trabajo es evaluar en forma retrospectiva la utilización de la TC para diagnóstico de TEP en un hospital privado e identificar suverdadera utilidad y correcta indicación ante tal sospecha diagnóstica

Tomografía helicoidal de tórax y enfermedad tromboembólica pulmonar / Helical computed tomography of the thorax and pulmonary thromboembolic disease

La utilización de la tomografía helicoidal en el diagnóstico de tromboembolismo pulmonar, data de más de una década. Desde entonces múltiples estudios han intentado definir su utilidad y a pesar de la falta de protocolos correctamente diseñados, esta metodología está ganando rápidamente aceptación como primer estudio a solicitar ante la sospecha de TEP. El objetivo del trabajo es evaluar en forma retrospectiva la utilización de la TC para diagnóstico de TEP en un hospital privado e identificar suverdadera utilidad y correcta indicación ante tal sospecha diagnóstica