Immunotherapy and Targeted Therapies Efficacy in Thymic Epithelial Tumors: A Systematic Review.

BACKGROUND: Thymic epithelial tumors (TET) are rare neoplasms of the anterior mediastinum. Surgery is the mainstay treatment for resectable TET, whereas systemic treatments are reserved for unresectable and metastatic tumors. The development of new treatments, such as immune checkpoint inhibitors (ICI) and targeted therapies, with promising results in other types of solid tumors, has led to the investigation of their potential efficacy in TET. The study of tumor microenvironments (TME) is another field of investigation that has gained the interest of researchers. Taking into account the complex structure of the thymus and its function in the development of immunity, researchers have focused on TME elements that could predict ICI efficacy. MATERIALS AND METHODS: The primary objective of this systematic review was to investigate the efficacy of ICI in TET. Secondary objectives included the toxicity of ICI, the efficacy of targeted therapies in TET, and the evaluation of the elements of TME that may be predictive factors of ICI efficacy. A literature search was conducted in February 2023 using the Ovid Medline and SciVerse Scopus databases. RESULTS: 2944 abstracts were retrieved, of which 31 were retained for the systematic review. Five phase II and one retrospective study assessed ICI efficacy. The overall response rate (ORR) varied from 0% to 34%. Median progression-free survival (PFS) ranged from 3.8 to 8.6 months, being lower in thymic carcinoma (TC) (3.8-4.2 months). Median overall survival (OS) ranged from 14.1 to 35.4 months. Treatment-related adverse events occurred in 6.6% to 27.3% of patients. Sixteen studies assessed targeted therapies. The most active molecule was lenvatinib, with 38% ORR in patients with TC while no activity was detected for imatinib, erlotinib plus bevacizumab, and saracatinib. Ten studies assessed TME elements that could predict ICI efficacy. Four studies focused on the tumor-infiltrating immune cells suggesting improved outcomes in patients with TC and high tumor-infiltrating lymphocyte densities. Another study showed that CD8+, CD20+, and CD204+ tumor-infiltrating immune cells in cancer stroma might be prognostic biomarkers in TC. Another study identified the immune-related long non-coding RNAs as a predictor of response to ICI. Tumor mutational burden was identified as a predictive factor of ICI efficacy in one study. CONCLUSIONS: Despite study heterogeneity, this review shows that ICI could be a therapeutic option for selected patients with TET that are not amenable to curative radical treatment after first-line chemotherapy.

Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study.

BACKGROUND: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. METHODS: This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. FINDINGS: Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. INTERPRETATION: TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. FUNDING: Novocure.

Systemic treatment for neuroendocrine non-small cell lung carcinoma: A cases series and a systematic review of the literature.

INTRODUCTION: Neuroendocrine lung cancer constitutes a continuum from carcinoid tumours (CT) to large cell neuroendocrine (LCNEC) and small-cell carcinomas (SCLC). Except for SCLC, there is no consensual agreement on systemic therapy. The aim of this study is to review our clinical experience among patients with CT and LCNEC in the light of a systematic review of the literature. METHODS: A retrospective study of all patients with CT and LCNEC receiving a systemic therapy at Institut Jules Bordet and Erasme Hospital between 01/01/2000-31/12/2020. A systematic review of the literature was performed in Ovid Medline. RESULTS: 53 patients (21 CT and 32 LCNEC) were included. Despite limited response rates, patients with CT receiving a "carcinoid-like" 1st-line regimen (somatostatin analogues (SSA), everolimus, peptide receptor radionuclide therapy (PRRT)) had a numerically longer survival compared to those receiving other type of regimens (median 51.4 vs 18.6 months, respectively; p = 0.17). We observed a similar survival between 1st line "SCLC-like" vs "non-small cell lung cancer (NSCLC)-like" schemes in LCNEC (median 11.2 vs 12.6 months, respectively; p = 0.46). The systematic review identified 23 studies (12 prospective, 15 and 8 for CT and LCNEC respectively). For CT, everolimus and SSA led to prolonged disease control with an acceptable toxicity profile, while higher response rates but lower tolerance were associated with PRRT and chemotherapy regimens including oxaliplatine and dacarbazine. For LCNEC, no difference emerged when comparing "SCLC-like" and "NSCLC-like" regimens considering response rate, progression-free or overall survival. CONCLUSIONS: SSA, everolimus and PRRT present a good therapeutic index for CT, while the role of chemotherapy remains limited to aggressive and rapidly evolving CT. The best type of chemotherapy regimen remains an open question in LCNEC.

European Respiratory Society guideline on various aspects of quality in lung cancer care.

This European Respiratory Society guideline is dedicated to the provision of good quality recommendations in lung cancer care. All the clinical recommendations contained were based on a comprehensive systematic review and evidence syntheses based on eight PICO (Patients, Intervention, Comparison, Outcomes) questions. The evidence was appraised in compliance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence profiles and the GRADE Evidence to Decision frameworks were used to summarise results and to make the decision-making process transparent. A multidisciplinary Task Force panel of lung cancer experts formulated and consented the clinical recommendations following thorough discussions of the systematic review results. In particular, we have made recommendations relating to the following quality improvement measures deemed applicable to routine lung cancer care: 1) avoidance of delay in the diagnostic and therapeutic period, 2) integration of multidisciplinary teams and multidisciplinary consultations, 3) implementation of and adherence to lung cancer guidelines, 4) benefit of higher institutional/individual volume and advanced specialisation in lung cancer surgery and other procedures, 5) need for pathological confirmation of lesions in patients with pulmonary lesions and suspected lung cancer, and histological subtyping and molecular characterisation for actionable targets or response to treatment of confirmed lung cancers, 6) added value of early integration of palliative care teams or specialists, 7) advantage of integrating specific quality improvement measures, and 8) benefit of using patient decision tools. These recommendations should be reconsidered and updated, as appropriate, as new evidence becomes available.

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short-survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

Alectinib for the treatment of pretreated RET-rearranged advanced NSCLC: Results of the ETOP ALERT-lung trial.

BACKGROUND: Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage. METHODS: ALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication. RESULTS: All 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1. No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 - 7.3 months). Overall, three deaths (23 %) were reported. Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported. CONCLUSIONS: Accrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Exercise in lung Cancer, the healthcare providers opinion (E.C.H.O.): Results of the EORTC lung cancer Group (LCG) survey.

OBJECTIVES: Exercise has been reported to alleviate disease as well as treatment impact in patients with lung cancer. Nevertheless, there is limited information available regarding the perception of lung cancer dedicated healthcare professionals' and their advice on exercise. MATERIALS AND METHODS: An online survey exploring healthcare professionals' practice patterns, perceptions, barriers, and facilitators of exercise in patients with lung cancer was conducted within members of the EORTC Lung Cancer Group (LCG). RESULTS: One hundred forty-one healthcare providers completed the survey, mainly medical and radiation oncologists. Overall, 63% of the study participants declared that they frequently assessed exercise level in their patients, and 43% of them reinforced the importance of exercise. However, only 10% referred patients to an exercise program or specialist. Although the majority of the respondents had a positive perception regarding the benefits and safety of exercise (even in patients with advanced disease and/or bone metastasis), two-thirds of clinicians reported not having adequate training about exercise counselling. Moreover, 53% reported to lack of knowledge of guidelines referring to exercise in patients with cancer. Several obstacles and facilitators to improve exercise promotion in lung cancer care were identified. CONCLUSION: Healthcare providers recognize the relevance and feasibility of exercise as part of cancer treatment intervention, but specific pathways to do the referral are frequently missing. Future structured and well-designed strategies and initiatives are needed to support an effective referral in order to implement exercise interventions routinely in clinical practice.

Cryobiopsy and dye marking guided by electromagnetic navigation bronchoscopy before resection of pulmonary nodule.

BACKGROUND: Our aims were to explore the feasibility, safety, and efficacy of peroperative transbronchial lung cryobiopsy (TBLC) guided by electromagnetic navigation bronchoscopy (ENB) and ENB-guided methylene blue marking of presumably non-palpable pulmonary nodules, and to assess its impact on video-assisted thoracoscopic surgery (VATS) and postoperative lung function. METHODS: This approach was applied to 16 consecutive patients (Group A, mean age 64 years) who were compared retrospectively to a historical group of 49 patients (Group B, mean age 62 years) with similar nodules resected without guidance. The usefulness of dye marking was graded. The success rates of both ENB-guided TBLC and nodule localization through dye marking were computed. The type of resection, volume of resected parenchyma, duration of procedures, and postoperative lung function were compared between groups. Unpaired t-test, chi-square test, unpaired Wilcoxon test, and exact Fisher test were used when appropriate. RESULTS: Malignancy was pathologically proven in all patients. TBLC revealed malignancy in 9 patients in Group A. The success rate of ENB-guided dye marking was 94%. Lobectomy was less frequently performed in Group A than in Group B (p = 0.022). Forced expiratory volume in 1 s and total lung capacity were significantly less reduced in Group A than in Group B (p = 0.006 and p = 0.019, respectively). Combined procedure was longer than surgery alone (p<0.001), but its surgical part was shorter than VATS without guidance (p < 0.001). CONCLUSION: Peroperative ENB-guided TBLC with methylene blue marking of non-palpable lung nodules is feasible. A sparing lung parenchyma procedure could be achieved thanks to the ENB-guided dye marking before VATS.

Belgian expert consensus for tumor-agnostic treatment of NTRK gene fusion-driven solid tumors with larotrectinib.

Fusions of NTRK (neurotrophic tyrosine receptor kinase) genes with 5' partner genes can result in the expression of chimeric proteins that drive oncogenesis through ligand-independent kinase activation. Despite variable frequencies of NTRK fusions in different tumor types, the fact that they are common to a wide range of cancers raises the possibility of developing tumor-agnostic treatments specifically targeting NTRK fusion products, irrespective of tumor type. The first-generation Trk (tropomyosin receptor kinase) inhibitor, larotrectinib, was the first tumor-agnostic treatment of NTRK fusion-positive cancers in adults and children, to be approved in the European Union. This consensus, developed by a Belgian multidisciplinary expert panel, aims to highlight the unmet medical need associated to NTRK fusion-driven cancer treatment and, based on current knowledge of NTRK fusions and larotrectinib treatment outcome and safety, provide comprehensive guidance to oncologists regarding NTRK fusion-driven cancer diagnostics and the best use of larotrectinib in real-world clinical settings.

Critically ill cancer patient's resuscitation: a Belgian/French societies' consensus conference.

To respond to the legitimate questions raised by the application of invasive methods of monitoring and life-support techniques in cancer patients admitted in the ICU, the European Lung Cancer Working Party and the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique, set up a consensus conference. The methodology involved a systematic literature review, experts' opinion and a final consensus conference about nine predefined questions1. Which triage criteria, in terms of complications and considering the underlying neoplastic disease and possible therapeutic limitations, should be used to guide admission of cancer patient to intensive care units?2. Which ventilatory support [High Flow Oxygenation, Non-invasive Ventilation (NIV), Invasive Mechanical Ventilation (IMV), Extra-Corporeal Membrane Oxygenation (ECMO)] should be used, for which complications and in which environment?3. Which support should be used for extra-renal purification, in which conditions and environment?4. Which haemodynamic support should be used, for which complications, and in which environment?5. Which benefit of cardiopulmonary resuscitation in cancer patients and for which complications?6. Which intensive monitoring in the context of oncologic treatment (surgery, anti-cancer treatment …)?7. What specific considerations should be taken into account in the intensive care unit?8. Based on which criteria, in terms of benefit and complications and taking into account the neoplastic disease, patients hospitalized in an intensive care unit (or equivalent) should receive cellular elements derived from the blood (red blood cells, white blood cells and platelets)?9. Which training is required for critical care doctors in charge of cancer patients?

Current and future research efforts in oligometastatic non-small cell lung cancer-a systematic review.

BACKGROUND: Major progresses in the systemic treatment of non-small cell lung cancer (NSCLC) were obtained during the last decade, including the use of immunotherapy and tyrosine kinase inhibitors (TKIs), with impressive results in terms of response and survival rates. Moreover, novel imaging and radiotherapy techniques have allowed the development of stereotactic body radiotherapy (SBRT), with high rates of local disease control and minimal toxicity. These factors propelled the use of combined systemic and local treatment strategies in patients with a low burden of metastases-the oligometastatic disease (OMD). METHODS: We systematically review the evidence from prospective randomized and non-randomized trials on local ablative therapy for OMD NSCLC published until June 2020. In addition, we present a review of the ongoing and/or recruiting trials in the field. RESULTS: We included 16 articles, reporting on 14 prospective clinical trials, starting from the pilot trial conducted in the early 2000's to the recent randomized trials that have showed benefits in survival. We found 24 ongoing trials, which combine multiple local ablative regimens with new systemic therapies, such as new generation TKIs and immunotherapy. DISCUSSION: Despite these vast current and ongoing prospective research efforts, there are several issues that impair the generalizability of their findings. These include the heterogeneous definition of OMD, trial design, staging, patient selection, tumor mutational status and treatments used, which may limit their applicability in the clinical practice.

Management of thymoma associated autoimmune pure red cell aplasia: Case report and systematic review of the literature.

Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome observed in 2-5 % of thymomas. Literature reports great variability in its management. Based on an illustrative clinical case, we present a systematic literature review whose main objective is to evaluate the therapeutic management of PRCA. The literature search was performed based on the PICO method in the Medline and Scopus databases. The reference clinical case concerns a 51-year-old woman with stage IVa thymoma. After initial response to chemotherapy, a locoregional progression occurred with PRCA development that responded favorably under second line chemotherapy. The patient finally died in a context of bicytopenia with febrile neutropenia. The systematic review covers 135 articles published between 1950 and 2019. Thymectomy alone or in combination with other therapies showed a 31 % complete remission (CR) rate for PRCA of, whereas none was reported with anti-tumor treatments without thymectomy. Among immunomodulatory therapies, cyclosporin gave the highest percentage of CR (74 %). Finally, the combination of thymectomy and immunomodulatory treatments showed a CR rate of 45 %. Thymectomy appeared to be the most effective anti-tumor treatment for PRCA. Immunomodulatory therapies, particularly cyclosporine, are shown effective, but the risk of infectious complications must be considered. The optimal place of anti-tumor and immunomodulatory therapies against PRCA has yet to be determined.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC): Lung cancer.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Lung cancer is the leading cause of cancer mortality and has a wide variation in treatment and outcomes in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must only be carried out in lung cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

Adverse events reporting in stage III NSCLC trials investigating surgery and radiotherapy.

BACKGROUND: Current treatment options for stage III non-small cell lung cancer (NSCLC) consist of different combinations of chemotherapy, surgery, radiotherapy and immunotherapy. Treatment choices are highly individual decisions, in which adverse events (AEs) are relevant for decision-making. This study aims to analyse reporting of AEs in prospective stage III NSCLC trials, focussing on trials including radiotherapy and/or surgery. METHODS: PubMed was searched for prospective studies dealing with stage III NSCLC from January 1987 to April 2019. Meta-analyses were screened as a positive control. Pearson's Chi-squared test and smooth kernel distribution were used to estimate distributions. Data was resampled using bootstrapping. RESULTS: Out of 1193 initially identified studies, 119 met the inclusion criteria. Of these, 31 had a surgical procedure in any study arm. Grade 3 and 4 AEs were reported in 94.12% and 92.44% of the included studies, respectively. Reporting of grade 5 AEs was provided in 87.39% of cases. Grade 1 and 2 AEs were less commonly reported at 53.78% and 63.03%, respectively. One study did not mention any AEs. Of the 31 treatment arms including any form of surgery, AEs were not reported in 10. Overall, 231 different AE items were reported, only 18 of them were included in at least 20% of the analysed studies. CONCLUSION: Overall, AE reporting in stage III NSCLC was inconsistent and inhomogeneous. Studies including surgical study arms often reported only treatment-related deaths in regards of surgical AEs. Underreporting of AEs prohibits the extraction of patient-relevant information for decision-making and represents a suboptimal use of invested resources.

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A (p16) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A (p16) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pretherapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasize that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.

Efficacy and Toxicity of Immune -Checkpoint Inhibitors in Patients With Preexisting Autoimmune Disorders.

Immunotherapy is an important armamentarium for cancer treatment nowadays. Apart from their significant effectiveness in controlling disease they also generate potential severe immune related adverse effects. Preexistence of immune related conditions may eventually predispose to the development of more severe complication and extreme caution have been taken in treating these patients. We performed a literature review searching for case reports and case series in order to offer evidence-based data for clinical management of these patients. Preexisting serological-only immune abnormalities or presence of a predisposing genetic background does not seem to confer significant risk but existing data is scarce. Most patients with preexistent autoimmune diseases can probably treated with checkpoint inhibitors as they seem to have at least the same response rate as the general cancer population. Under treatment, a significant part of them (at least 30%) can experience a flare of their baseline disease which can sometime be severe. Life-threatening cases seems rare and disease flare can be generally managed with steroids. The volume of available data is more important for rheumatologic diseases than for inflammatory bowel diseases were more caution should be observed. However, it has to be kept in mind that new immune related adverse effects (IrAE) are seen with a similar frequency as the flare of the baseline disease. Both flare-up's and newly developed IrAE are generally manageable with a careful clinical follow-up and prompt therapy.