Prognostic value of CD4+ T lymphopenia in non-small cell lung Cancer.

BACKGROUND: There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. MATERIALS: Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of < 500/µL and < 224/µL respectively. The prognostic value of T lymphopenia was analyzed in the whole population, in local/loco-regional (stage I-IIIB) and in advanced (stage IV) NSCLC disease, using the Kaplan-Meier method and Cox regression models for survival curves and multivariate analysis, respectively. RESULTS: Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/µL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1-2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9-3.8], p = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065-3.817] p = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/µL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. CONCLUSION: We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. TRIAL REGISTRATION: EUDRACT: 2009-A00642-55.

Feasibility of health-related quality of life (HRQoL) assessment for cancer patients using electronic patient-reported outcome (ePRO) in daily clinical practice.

INTRODUCTION: Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance patient-centered care. We evaluated the feasibility of REMOQOL in the French context in the QOLIBRY study. The primary objective was to assess the patients' compliance with REMOQOL. METHODS: The QOLIBRY study was a single-center, prospective study conducted in the University Hospital of Besançon (France). Eligible patients were those treated with systemic therapies for breast, lung or colorectal cancer at any stage. Patients were invited to complete the EORTC QLQ-C30 questionnaire and cancer-site-specific modules before each visit on tablets and/or computers in the hospital or at home. During the consultation, physicians had real-time access to visual summaries of HRQoL scores. Compliance was assessed as adequate if at least 66% of HRQoL assessments were completed during the 4 months of follow-up. RESULTS: Between March 2016 and October 2018, 177 patients were included in the QOLIBRY study. Median age was 64 years (IQR 54-71). The proportion of patients with an adequate compliance rate was 95.5% (n = 63) in the breast cancer cohort, 98.2% (n = 55) in the colorectal cancer cohort, and 90.9% (n = 50) in the lung cancer cohort. The physicians checked the HRQoL results in 73.1% of visits and prescribed supportive care and adapted patient management in 8.3% and 5.2% of visits, respectively. CONCLUSION & PERSPECTIVES: The results of QOLIBRY study suggest that REMOQOL is feasible in the French context. However, information about HRQoL monitoring, training of the physicians in the use of the software, and recommendations for using HRQoL results to guide care are essential and must be improved.

Distinct prognostic value of circulating anti-telomerase CD4+ Th1 immunity and exhausted PD-1+/TIM-3+ T cells in lung cancer.

BACKGROUND: Despite the critical roles of Th1-polarised CD4+ T cells in cancer immunosurveillance, the translation of their potential to clinical use remains challenging. Here, we investigate the clinical relevance of circulating antitumor Th1 immunity in non-small cell lung cancer (NSCLC). METHODS: The circulating antitumor Th1 response was assessed by the ELISpot assay in 170 NSCLC patients using a mixture of HLA class II-restricted peptides from telomerase (TERT). Phenotyping of blood immune cells was performed by flow cytometry. RESULTS: TERT-reactive CD4 T-cell response was detected in 35% of NSCLC patients before any treatment. Functional analysis showed that these cells were effector memory and Th1 polarised capable to produce effector cytokines, such as IFN-γ, TNF-α and IL-2. The presence of anti-TERT Th1 response was inversely correlated with the level of exhausted PD-1+/TIM-3+CD4 T cells. The level of these two immune parameters differentially affected the survival, so that increased level of anti-TERT Th1 response and low rate of exhausted PD-1+TIM-3+CD4+ T cells were associated with a better prognosis. CONCLUSIONS: Systemic anti-TERT Th1 response plays a strong antitumor protective role in NSCLC. This study underlines the potential interest of monitoring circulating antitumor Th1 response for patients' stratification and therapy decision.

Safety, Immunogenicity, and 1-Year Efficacy of Universal Cancer Peptide-Based Vaccine in Patients With Refractory Advanced Non-Small-Cell Lung Cancer: A Phase Ib/Phase IIa De-Escalation Study.

PURPOSE: Universal cancer peptide-based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS: A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders (P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders (P = .005), respectively. CONCLUSION: UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Prevalence and Characteristics of Sleep Apnea in Intensive Care Unit Survivors After SARS-CoV-2 Pneumonia.

Background: Sleep apnea (SA) was reported as possibly exacerbating symptoms of COVID-19, a disease induced by SARS-CoV-2 virus. The same comorbidities are common with both pathologies. This study aimed to estimate the prevalence, characteristics of SA and variation in AHI three months after severe COVID-19 requiring intensive care unit (ICU) admission. Methods: A prospective cohort of patients admitted to ICU for severe COVID-19 underwent an overnight home polygraphy 3 months after onset of symptoms, as part of a comprehensive follow-up program (pulmonary function tests, 6-minute walk tests and chest CT-scan). Patients with an apnea hypopnea index (AHI) ≥5 were considered as having SA. We performed a comparative descriptive analysis of 2 subgroups according to the existence, severity of SA and indication for effective SA treatment: patients with absent or mild SA (AHI <15) vs patients with moderate to severe SA (AHI ≥15). Results: Among 68 patients included, 62 (91%) had known comorbidities (34 hypertension, 21 obesity, 20 dyslipidemia, 16 type 2 diabetes). It has been observed a preexisting SA for 13 patients (19.1%). At 3 months, 62 patients (91%) had SA with 85.5% of obstructive events. Twenty-four patients had no or a mild SA (AHI <15) and 44 had moderate to severe SA (AHI ≥15). Ischemic heart disease exclusively affected the moderate to severe SA group. Except for thoracic CT-scan which revealed less honeycomb lesions, COVID-19 symptoms were more severe in the group with moderate to severe SA, requiring a longer curarization, more prone position sessions and more frequent tracheotomy. Conclusion: SA involved 91% of patients in our population at 3 months of severe COVID-19 and was mainly obstructive type. Although SA might be a risk factor as well as consequences of ICU care in severe COVID-19 infection, our results underline the importance of sleep explorations after an ICU stay for this disease.

Let us not underestimate the long-term risk of SPLC after surgical resection of NSCLC.

OBJECTIVES: Several studies have reported that patients operated on for non-small cell lung cancer (NSCLC) are at high risk of second primary lung cancer (SPLC). However, widely varying estimates of this risk have been reported, with very few studies taking into account that these patients are at particularly high competing risk of death, due to recurrence of the initial disease and to comorbidities. Risk factor evaluation over time has significant repercussions on the post-surgery surveillance strategy offered for NSCLC. This study primarily sought to measure the risk of SPLC in a long-term follow-up series, using statistical methods considering competing risks of death. MATERIALS AND METHODS: The cumulative SPLC risk was estimated using the cumulative incidence of patients with completely resected Stage I-III NSCLC diagnosed between 2002 and 2015 based on the Doubs and Belfort cancer registry (France). A proportional sub-distribution hazard model (sdRH) was used to investigate factors associated with SPLC risk in the presence of competing risks. RESULTS: Among the 522 patients, adenocarcinoma and Stage I or II disease accounted for 52.3% and 75.7% of patients, respectively. Overall, 84 patients developed SPLC (16.1%). The cumulative risk of SPLC was 20.2% at 10 years post-surgery (95% confidence interval [CI]: 15.3-23.2), and 25.2% (CI: 19.4-31.3) at 14 years post-surgery. On multivariate analysis, the SPLC risk was significantly higher in patients with postoperative thoracic radiotherapy (sdRH 2.79; 95% CI: 1.41-5.52; p = 0.003). CONCLUSION: This study using appropriate statistical methods to consider competing risks showed that after complete NSCLC resection, the cumulative incidence function of SPLC was high, with patients receiving postoperative thoracic radiotherapy at higher risk. These data support the need for life-long follow-up of patients who undergo NSCLC surgery, with the objective of screening for SPLC.

Pulmonary and cutaneous sarcoidosis associated with interferon therapy for melanoma.

Interferon alfa is widely used as adjuvant therapy for melanoma. Numerous side effects have been attributed to interferon alfa. Interferon alfa-induced sarcoidosis is an uncommon event. We report the third case of pulmonary and cutaneous sarcoidosis in the course of interferon alfa treatment for melanoma. Most cases of sarcoidosis have been reported during treatment of chronic hepatitis C. The prognosis is good with discontinuation of treatment. Other than interferon therapy, sarcoidosis or granulomatosis reactions rarely have been reported in malignant melanoma. We discuss and review the literature on the physiopathology of sarcoidosis brought on by interferon therapy.

Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4(+) Th1 responses against telomerase in cancer patients.

Cumulative evidence supports that CD4(+) Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4(+) Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541-555, TERT573-587, TERT613-627 and TERT911-925 and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4(+) T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II. Direct comparative study of spontaneous anti-TERT CD4(+) T cell responses in a cohort of 87 lung cancer patients showed that HLA-DP4 and HLA-DR sustained specific Th1 responses in 10.1% and 25.2% of cancer patients respectively (p = 0.01). The magnitude of the HLA-DR-restricted responses was two to three times significantly higher than HLA-DP one (p = 0.005). Similar results were found in other cancers such as melanoma, breast cancer, renal cell carcinoma and colon cancer. Thus, our results describe for the first time in a large cohort of cancer patients a high immunoprevalence of HLA-DR-restricted spontaneous anti-TERT Th1 immunity compared to HLA-DP restriction. These results provide a new tool for comprehensive monitoring of antitumor CD4(+) Th1 response in various cancers.

Gemcitabine induction chemotherapy in non-small cell lung cancer.

Surgery has long been considered standard treatment in early stage non-small cell lung cancer. Preoperative chemotherapy is a real challenge in the treatment of these stages. Some conclusions can be drawn from the first phase II studies in stage IIIA tumors. Response rates were higher than those observed in stage IV tumors, reaching approximately 70%. Although toxicity seemed acceptable, increased morbidity and mortality have to be taken into account for the choice of preoperative regimens. Two randomized studies that included only a few patients were conducted in stage IIIA disease and showed highly positive survival results. The French randomized study argued in favor of preoperative chemotherapy with an absolute difference in survival rates that remains constant beyond the third year. New studies are ongoing to evaluate the role of the gemcitabine/cisplatin combination. Several phase II studies of this regimen in the preoperative setting or in combination with radiotherapy have been presented at the most recent meetings of the American Society of Clinical Oncology. These studies confirmed both its efficacy and good tolerability. In several ongoing randomized studies, this combination has been chosen to test the concept of preoperative chemotherapy. One such study, which compares two different strategies of preoperative chemotherapy, is by the Intergroupe Francophone de Cancérologie Thoracique.

[New neoadjuvant approaches using gemcitabine in non-small-cell lung cancer]. / Nouvelles approches néoadjuvantes avec la gemcitabine dans le cancer bronchique non à petites cellules.

Preoperative chemotherapy is a real challenge in the treatment of non-small cell lung cancer. From the first phase II studies, we have learned that response rates to preoperative chemotherapy were high, around 70% with approximately 10% of complete responses. Although toxicity seemed acceptable, increased morbidity and mortality were observed and have to be taken into account for the choice of the preoperative chemotherapy regimen. Two randomized trials were initially conducted in stage IIIA disease and showed highly positive survival results. However, only few patients had been included in both studies, and their statistical value has been considered as questionable. The French MIP91 study, whose results have been published in 2002, argues in favour of preoperative chemotherapy but could not demonstrate a clear-cut advantage. New studies are ongoing. In the search of effective and less toxic combinations, cisplatin-gemcitabine has a role to play. Several phase II studies of this regimen have been presented at the last meeting of the American Society of Clinical Oncology (ASCO) in the preoperative setting or in combination with radiotherapy, and confirmed its efficacy and good tolerability. Chemoradiation is important as part of the trimodality strategy including chemotherapy, radiotherapy, and surgery, which might become standard of care in the treatment of stage IIIa disease.

[To be cured of lung cancer]. / Guéri d'un cancer bronchique.

Pronostic of lung carcinoma is very poor but, every year in Europe and North America, thousands of patients are offered a chance of cure. However only a long period of time without relapse allows to state the reality of cure. Sequelae generated by cancer treatments are potentially increased by the use of treatments combinations. In operated patients, chronic respiratory insufficiency is the most common late complication often interfering with professionnal activity especially for manual workers. Late toxicity after radiotherapy for lung cancer has been little studied. Thoracic irradiation especially affects lung and cardiac functions. Late toxicity of chemotherapy may be more frequent with the increasing use of neoadjuvant chemotherapy before surgery or radiotherapy in patients potentially cure.

[Standards, Options and Recommendations for the management of non-small cell lung carcinoma patients]. / Standards, Options et Recommandations 2000 pour la prise en charge des patients atteints d'un cancer bronchopulmonaire non á petites cellules (rapport abrégé).

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French cancer centers and specialists from French public university and general hospitals and private clinics. Its main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop, according to the definitions of the Standards, Options and Recommendations, clinical practice guidelines for the management of non small cell lung carcinoma patients. METHODS: Data were identified by searching Medline and the personal reference lists of members of the expert groups, then submitted for review to independent reviewers. This is a short version of the SOR guideline covering diagnosis, treatment and follow-up and includes the algorithms for the management of patients with non-small cell lung cancer.

[2000 Standards, Options and Recommendations for prognostic value of oncogenes and tumor suppressor genes in non small cell lung cancer]. / Standards, Options et Recommandations 2000 pour l'intérêt pronostique des oncogènes et gènes suppresseurs de tumeurs dans les cancers bronchopulmonaires non à petites cellules.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French cancer centers (FNCLCC), the 20 French cancer centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines for non small cell lung cancer patients according to the definitions of the Standards, Options and Recommendations project. METHODS: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers. RESULTS: This article presents the chapter "Prognosis significance of oncogenes and tumor suppressor genes" from the full report "Standards, Options and Recommendation for non small cell lung cancer" validated in August 2000. The main recommendations are: 1) No clear clinical prognostic value of oncogenes and tumor suppressor genes (p53, bcl-2, Ki-ras, c-erbB-2, Rb, p16) in non small cell lung cancer, can be established from the available evidences (standard, level of evidence C). 2) Prospective multicenter studies should be performed to assess prognostic significance of oncogenes and tumor suppressor genes in non small cell lung cancer.

[Secondary tumoral pleurisy]. / Les pleurésies tumorales secondaires.

WHEN THE PRIMARY CANCER IS KNOWN: Secondary tumoral pleurisy can develop at any stage in the evolution of a neoplastic disease and its diagnosis is easy when the primitive cancer is known. Cytological analysis of the pleural liquid and/or biopsy often provides material and the slides can then be compared with those of the primitive cancer and a relationship established. However, a probabilistic diagnosis should not be in haste, without anatomopathological confirmation, since the causes of pleurisy in a cancer patient are varied. WHEN THE PRIMARY CANCER IS NOT KNOWN: The most difficult situation is that when the pleurisy is revelatory of a neoplastic disease. In this case, explorations should be limited to a few essential examinations guided by the clinical profile, without being tempted to carrying out exhaustive explorations of the primitive cancer, which would not change the prognosis. Before such explorations, it is essential to obtain a precise pleural diagnosis, and for this, the indication for a pleuroscopy must be easily and rapidly accessible. FROM A THERAPEUTIC POINT OF VIEW: Once the diagnosis of pleurisy has be established, treatment is in two parts, associated or not: local treatment consisting in pleural sympysis and general treatment (chemotherapy or even hormone therapy, adapted to the primitive neoplasia). Pleural sympysis is often performed using talc, either during the pleuroscopy (talc insufflated under visual control), or during thoracic draining (talc slurry).

[Non-small cell lung cancer: Perioperative treatments]. / Carcinomes bronchiques non à petites cellules: traitements périopératoires.

The objectives of perioperative treatments in non-small cell lung cancer (NSCLC) are to reduce the risk of recurrence, by the early destruction of micrometastases. Data from the literature have been used to precise their indications and modalities. However, for each patient, the decision of a perioperative treatment must result from a multidisciplinary discussion. Perioperative chemotherapy is indicated in stage II or III NSCLC. Adjuvant chemotherapy, which has a highest best level of evidence, is standard, with a 5% survival benefit at 5 years. Preoperative chemotherapy is an option. Postoperative mediastinal radiotherapy has to be discussed in pN2 disease. Ongoing studies in the perioperative setting evaluate the role of targeted agents, and the interest of personalized strategies based on biological markers.

Third-line chemotherapy in advanced non-small cell lung cancer: identifying the candidates for routine practice.

BACKGROUND: The interest of first- and second-line treatments in non-small cell lung cancer (NSCLC) has been demonstrated by successive randomized trials. Improvements in lung cancer care have routinely allowed a significant proportion of patients to be considered for third-line treatment. METHODS: A retrospective analysis was performed, including all consecutive patients with advanced NSCLC, who received at least three lines of systemic antineoplastic treatment at our institution. RESULTS: From a population of 613 patients treated with first-line treatment, a total of 173 patients received third-line treatment (cytotoxic chemotherapy in 131 patients; epidermal growth factor (EGFR) tyrosine kinase inhibitors in 42 patients). Only 13 patients (8%) received less than 75% of the theoretical dose intensity; 22 patients (13%) presented with severe toxicities. Symptom relief and performance status (PS) improvement were observed in 121 (92% of the 131 patients with symptoms) and 90 patients (52%), respectively. Using multivariate analysis, survival after third-line treatment was significantly increased in patients younger than 70 years-old (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.53-0.99, p = 0.047), who smoked less than 10 pack-years (HR = 0.82, 95% CI: 0.57-0.93, p = 0.036), with no cancer-related symptoms (HR = 0.75, 95% CI: 0.61-0.92, p = 0.007), a weight loss inferior to 5 kg since the beginning of second-line (HR = 0.63, 95% CI: 0.52-0.75, p = 0.013), a PS 0 to 1 (HR = 0.81, 95% CI: 0.76-0.86, p = 0.008), and no extrathoracic tumor spread at initiation of third-line treatment (HR = 0.67, 95% CI: 0.47-0.94, p = 0.042). Disease control after both first- and second-line treatments was the strongest predictor of prolonged survival after third-line treatment (HR = 0.47, 95% CI: 0.33-0.67, p = 0.001). CONCLUSIONS: Patients with advanced NSCLC may benefit from third-line treatment. The best candidates can be identified using standard prognostic factors, such as PS, and disease control after first- and second-line treatments.