Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Consensus of the Spanish society of laboratory medicine and the Spanish society of medical oncology on the methodology and criteria for evaluation of circulating tumour markers in breast cancer.

The measurement of circulating tumour markers (TMs) for the diagnosis or monitoring of breast cancer has sometimes been considered of limited utility. In addition to the overinterpretation of irrelevant changes in marker levels, the characteristics of the patient, the disease or other pathologies that can modify them are often not considered in their evaluation. On the other hand, there are recent data on the relationship of TMs with molecular subtypes and on their prognostic value, the knowledge of which may improve their clinical utility. This consensus article arises from a collaboration between the Spanish Society of Laboratory Medicine (SEQCML) and the Spanish Society of Medical Oncology (SEOM). It aims to improve the use and interpretation of circulating TMs in breast cancer. The text summarizes the current knowledge and available evidence on the subject and proposes a series of recommendations mainly focussed on the indication, the frequency of testing and the factors that should be considered for correctly interpreting changes in the levels of TMs.

RNA editing blood biomarkers for predicting mood alterations in HCV patients.

Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing-related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test.

[Small cell lung cancer and immuno-oncologic agents: End of the cisplatin - etoposide era?] / Cancer bronchique à petites cellules et agent onco-immunologique : peut-on sortir de l'ère du tout cisplatine étoposide ?

In the setting of small cell lung cancer (SCLC), the development of immuno-oncological agents, particularly those targeting Programmed cell Death protein 1 (PD-1) and Programmed cell Death protein Ligand 1 (PD-L1), is still at an early stage. Two critical elements need to be considered : the current data are extracted from Phase I and Phase II trials and the level of evidence from phase III trials has not been reached as it has been for non-small cell lung cancer (NSCLC) or for malignant melanoma ; The second aspect is the slow development of predictive factors for response to the immuno-oncological agents targeting the PD-1 receptor and its ligand. The clinical data are still too fragmentary to produce recommendations, although the improvement in progression-free survival seen in different phase II studies is promising. The expectation of clinicians dealing withSCLC is an indication of the challenge that this disease currently poses to oncology and justifies a focused clinical research effort.

[What do chemotherapy specialists expect of lung cancer?] / Qu'attendent les médecins spécialistes de la chimiothérapie des cancers du poumon ?

OBJECTIVE: In an attempt to understand physicians' expectations of chemotherapy, a group of lung cancer specialists was involved in an online survey investigating their opinions by a self-questionnaire. The questionnaire described five different chemotherapy prescription situations for lung cancer patients (stages IIIB or IV). METHOD: A total of 30 expert specialists were invited; 22 responded (73%). For each of the clinical situations, the expert was asked for his opinion on 3 items: cure, prolongation of survival and alleviation of symptoms. Each item was judged on a Likert scale with categories between -2 "not at all probable" and +2 "quite likely". RESULTS: For "cure", the percentage of -2 responses differed significantly according to the clinical situation (Fisher test: P<0.00001). The trend test showed a relationship between the percentage of -2 responses and the suspected order of the clinical situations (Cochran-Armitage trend test: P<0.0001). For symptom alleviation, the percentage of responses +2 and +1 differed significantly according to the clinical situation (Fisher test: P=0.00013, trend test: P<0.0001). CONCLUSION: What specialist physicians expect of chemotherapy in terms of curability and symptom relief differs according to the actual statistical prognosis of each situation as presented in the literature. The worst prognostic situation leads to the strongest expectation in terms of symptom relief and, conversely, the lowest for curability.

Imaging of postoperative complications following surgery for lung cancer.

The complications following surgery for lung cancer vary depending upon the comorbidities and the type of surgery. Hemorrhage, infections and pulmonary edemas are not specific to the type of resection but frequently occur following pneumonectomies. Morbidity following pneumonectomies is related to the significant changes in the contents of the intrathoracic space. Pulmonary infarction and torsion are emergency situations that develop following lobectomy. CT shows features of localized congestion and stenosis or occlusion of a vein or bronchus. Rapid identification of severe events, in particular by systematic CT is essential for appropriate management of a postoperative or delayed complication of lung cancer surgery.

Interaction between airborne copper exposure and ATP7B polymorphisms on inattentiveness in scholar children.

Recent research indicates that airborne copper exposure in scholar children negatively affects brain functioning. These effects are likely to be influenced by the efficiency of copper metabolism, which is partly regulated by the ATPase copper transporting beta (ATP7B) gene. We investigated whether indoor and outdoor airborne copper exposure is differentially associated with child inattentiveness depending on genetic variation within the ATP7B gene in 1645 scholar children from the BREATHE project. Outdoor (courtyard) and indoor (classroom) air pollution levels were measured during class hours in each school. Inattentiveness was assessed through a follow-up with four measurements via the Attentional Network Test (4475 observations). Linear mixed models considering repeated measures were conducted to assess genetic and exposure main and interaction effects. Two interactions were detected indicating that ATP7B-rs1061472 (P for interaction 0.016) and ATP7B-rs1801243 (P for interaction 0.003) polymorphisms modified the association between indoor copper exposure and inattentiveness. Stratified analysis by genotypes revealed that both outdoor and indoor copper exposure increased inattentiveness in rs1061472-CC and rs1801243-CC carriers. These findings suggest that the genetic background promotes the association between airborne copper exposure at school with inattentiveness in children.

Normal postoperative appearances of lung cancer.

The major lung resections are the pneumonectomies and lobectomies. The sublobar resections are segmentectomies and wedge resections. These are performed either through open surgery through a thoracotomy or by video-assisted mini-invasive surgery for lobectomies and sublobar resections. Understanding the procedures involved allows the normal postoperative appearances to be interpreted and these normal anatomical changes to be distinguished from potential postoperative complications. Surgery results in a more or less extensive physiological adaptation of the chest cavity depending on the lung volume, which has been resected. This adaptation evolves during the initial months postoperatively. Chest radiography and computed tomography can show narrowing of the intercostal spaces, a rise of the diaphragm and shift of the mediastinum on the side concerned following major resections.

Social class based on occupation is associated with hospitalization for A(H1N1)pdm09 infection. Comparison between hospitalized and ambulatory cases.

This study aimed to analyse the existence of an association between social class (categorized by type of occupation) and the occurrence of A(H1N1)pmd09 infection and hospitalization for two seasons (2009-2010 and 2010-2011). This multicentre study compared ambulatory A(H1N1)pmd09 confirmed cases with ambulatory controls to measure risk of infection, and with hospitalized A(H1N1)pmd09 confirmed cases to asses hospitalization risk. Study variables were: age, marital status, tobacco and alcohol use, pregnancy, chronic obstructive pulmonary disease, chronic respiratory failure, cardiovascular disease, diabetes, chronic liver disease, body mass index >40, systemic corticosteroid treatment and influenza vaccination status. Occupation was registered literally and coded into manual and non-manual worker occupational social class groups. A conditional logistic regression analysis was performed. There were 720 hospitalized cases, 996 ambulatory cases and 1062 ambulatory controls included in the study. No relationship between occupational social class and A(H1N1)pmd09 infection was found [adjusted odds ratio (aOR) 0·97, 95% confidence interval (CI) 0·74-1·27], but an association (aOR 1·53, 95% CI 1·01-2·31) between occupational class and hospitalization for A(H1N1)pmd09 was observed. Influenza vaccination was a protective factor for A(H1N1)pmd09 infection (aOR 0·41, 95% CI 0·23-0·73) but not for hospitalization. We conclude that manual workers have the highest risk of hospitalization when infected by influenza than other occupations but they do not have a different probability of being infected by influenza.

Randomized phase II-III study of bevacizumab in combination with chemotherapy in previously untreated extensive small-cell lung cancer: results from the IFCT-0802 trial†.

BACKGROUND: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle. RESULTS: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers. CONCLUSION: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients.

Diazepam and Jacobson's progressive relaxation show similar attenuating short-term effects on stress-related brain glucose consumption.

A non-pharmacological method to reduce anxiety is "progressive relaxation" (PR). The aim of the method is to reduce mental stress and associated mental processes by means of progressive suppression of muscle tension. The study was addressed to evaluate changes in brain glucose metabolism induced by PR in patients under a stressing state generated by a diagnostic medical intervention. The effect of PR was compared to a dose of sublingual diazepam, with the prediction that both interventions would be associated with a reduction in brain metabolism. Eighty-four oncological patients were assessed with 18F-fluorodeoxyglucose-positron emission tomography. Maps of brain glucose distribution from 28 patients receiving PR were compared with maps from 28 patients receiving sublingual diazepam and with 28 patients with no treatment intervention. Compared to reference control subjects, the PR and diazepam groups showed a statistically significant, bilateral and generalized cortical hypometabolism. Regions showing the most prominent changes were the prefrontal cortex and anterior cingulate cortex. No significant differences were identified in the direct comparison between relaxation technique and sublingual diazepam. Our findings suggest that relaxation induced by a physical/psychological procedure can be as effective as a reference anxiolytic in reducing brain activity during a stressful state.

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials.

OBJECTIVES: Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500mg/m(2) plus cisplatin 75mg/m(2) every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression. METHODS: Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. RESULTS: Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p=0.117, HR=1.16; median OS: 14.0 versus 14.2 months, p=0.979, HR=1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p<0.00001, HR=0.66; median OS: 16.9 versus 14.2 months, p=0.003, HR=0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. CONCLUSIONS: The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

[Surgical procedures involved in claims for alleged defects in praxis]. / Procedimientos quirúrgicos objeto de reclamación por presunto defecto de praxis.

Medical professional liability and adverse events in health care are major concerns worldwide and the analysis of claims for alleged defects in praxis is a potential source of knowledge. High rates of adverse events and complaints have been reported in surgical procedures. This article analyzes the claims registered by the Council of Medical Colleges in Catalonia between 1986 and 2012, and explores surgical procedures claimed (ICD- 9-CM coding), as well as the final outcome of the claim. Among the 5,419 records identified on surgical procedures, the interventions of the musculoskeletal system and skin and integument showed the highest frequencies. Interventions related to "non-curative" medicine should be emphasized because of their higher rates of economical agreement or condemnation outcomes, which were significantly higher for mastopexia. The results underscore the importance of the surgical area in medical professional liability and the high risk of payouts among those procedures belonging to the so-called "non-curative" medicine.

[One more word about the diagnostic. A metapsychological approach]. / Encore un mot sur l'annonce Une approche métapsychologique.

Nearly a decade since the first experiment in France of the so-called "announcement policy" a concerted effort, the pooling of skills of health professionals from different backgrounds, have had noticeable positive effects on the daily practice. This article attempts at analyzing the question that was causing the application of former patients and their main complaint: the lack of communication and its direct consequences, anguish and loneliness. Subsequently, the announcement policy, this multifaceted approach, had consisted of creating for the patient what can be called "a good enough environment able to hold". It is therefore not a plan but a disposal (if we are willing to agree on the fact that these are the qualities of the therapeutic setting that count and not the format by itself). Considering the ipseity of each patient, the uniqueness of each particular situation, of each social background, the need for harmonization of the announcement policy is questionable. Harmonization does not mean uniformity. The quality of this policy must be adapted closer to each case. However, it must be based on the basic principles and might also take into account the dimension of anguish. These fundamental principles are directly derived from the principles of medical humanism, those that have brought meaning to scientific progress.

[Specificity of the psychological undertaking of a patient in thoracic oncology]. / Spécificité de la prise en charge psychologique en oncologie thoracique.

The question raised by the title calls for a balanced answer. As a matter of fact, like in many clinical situations in which an illness threatens the patient's survival, the singularity of each case makes any attempt of generalization simplistic. Writing about the speficity of the psychological undertaking in thoracic oncology has to avoid two pitfalls: denying any psychosociological specificity of thoracic cancerology, and thus not providing the reader's understanding with anything which could help them read the most frequent problematics. And secondly turn clinical qualitative data into generalities stuck on each case, and rejecting the singularity of the sick person as a subject. As we attempt to avoid both traps, the three next points will be tackled: the announcement of cancer is prototypical of a trauma, and calls up an intense affect of anguish. This affect can be read through social representations, which intervene within the exchange doctor - sick person. The subjectivation of this relation cannot be understood without taking the environment into account, and especially what the affected person knows about cancer owing to their belonging to a socius. In the traumatic atmosphere thus created, the rereading of the phenomenons - cropping up between a somatic symptom experienced by the patient and a traumatic language revolving around the compulsory term "cancer" - is achieved according recurrent thematic lines. As we do not wish to reach the exhaustiveness of the significant unities, neither their reassembly, we will limit ourselves to the development of one main line: that of the relation to time, to temporality, and to presentism.

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.