Micronodular thymic epithelial tumors with lymphoid hyperplasia and mimicking lesions.

Micronodular arrangement of epithelial cells and lymphoid B-cell hyperplasia with follicles are both peculiar histological features in thymic tissue. Such features may especially occur in thymic epithelial tumors. The most common form is called micronodular thymoma with lymphoid stroma. We have recently described some characteristics of thymic micronodular carcinoma with lymphoid hyperplasia, highlighting how this carcinomatous counterpart should not be misdiagnosed as a thymoma. In this review, we discuss these two entities but also other mimics, which may occur in the anterior mediastinum. These mimics include various types of cellular micronodules and lymphoid backgrounds encompassing a wide range of mediastinal lesions. Non-neoplastic lesions, such as thymic nodular epithelial hyperplasia, thymic lymphoid hyperplasia, or sarcoidosis, as well as tumors of very varying aggressiveness, such as micronodular thymic epithelial tumors, low-grade lymphoma, seminoma, or lymphoepithelial carcinoma, are discussed. We show how these lesions may be misleading and we describe how a correct diagnostic may be obtained in current practice.

Doppler echocardiography for surveillance of acute cardiac allograft rejection: a 28-year single-center experience.

Background: Endomyocardial biopsies (EMB) are recommended for the detection of acute cardiac rejection (ACR) despite limited sensitivity. We report the long-term post-transplant results of Doppler echocardiography as a noninvasive alternative of routine EMB. Methods: Two cohorts of heart transplantation (HT) recipients were chronologically defined as follows: the Dual Monitoring Cohort (DMC) from January 1990 to December 1997 included patients who underwent routine EMB and Doppler echocardiography within 24 hours for ACR surveillance; and the "Echo-First Cohort" (EFC), including patients transplanted from January 1998 to December 2018 with Doppler echocardiography as first-line approach for ACR surveillance. Echocardiographic measurements of interest were collected: early diastolic (E) wave peak velocity; pressure half time (PHT) and isovolumetric relaxation time (IVRT). Post-transplant outcomes were reviewed and the Kaplan-Meier approach was used for survival estimates. Inter-operator variability for ultrasound measurements was investigated. Data were collected from medical records from January 2019 to December 2020. Results: A total of 228 patients were included, 99 patients in the DMC and 129 in the EFC. Overall, 5-, 10- and 15-year survival rates were 65.4%, 55.5% and 44.1% respectively, without any significant difference between the two cohorts (log rank test, P=0.71). Echocardiography variables and EMB findings were associated with a mean area under the receiver operating characteristic curve (AUC-ROC) of 0.73 [95% confidence interval (CI): 0.54-0.91], 0.74 (95% CI: 0.54-0.94) and 0.75 (95% CI: 0.57-0.94) respectively for E wave, PHT and IVRT. IVRT and PHT were significantly decreased, and E wave significantly increased, in case of histologically proven ACR. Inter-operator variability was not significant for E wave and IVRT measurements (P=0.13 and 0.30 respectively). Conclusions: Doppler echocardiography as a first-line method for surveillance of ACR did not impair long-term results after HT. These findings suggest that this non-invasive approach might be a reasonable alternative to systematic EMB, limiting risk and improving the quality of life.

International reproducibility study of thymic epithelial tumors staging: pT stage is an issue. proposals for improvement. A RYTHMIC/ITMIG study.

INTRODUCTION: Pathologists are staging thymic epithelial tumors (TET) according to the 8th UICC/AJCC TNM system. Within the French RYTHMIC network, dedicated to TET, agreement on pathologic tumor stage (pT) among the pathology panelists was difficult. The aim of our study was to determine the interobserver reproducibility of pT at an international level, to explore the source of discrepancies and potential interventions to address these. METHODS: An international panel of pathologists was recruited through the International Thymic Malignancy Interest Group (ITMIG). The study focused on invasion of mediastinal pleura, pericardium, and lung. From a cohort of cases identified as challenging within the RYTHMIC network, we chose a series of test and validation cases (n = 5 and 10, respectively). RESULTS: Reproducibility of the pT stage was also challenging at an international level as none of the 15 cases was classified as the same pT stage by all ITMIG pathologists. The agreement rose from slight (κ = 0.13) to moderate (κ = 0.48) between test and validation series. Discussion among the expert pathologists pinpointed two major reasons underlying discrepancies: 1) Thymomas growing with their "capsule" and adhering to the pleurae, pericardium, or lung were often misinterpreted as invading these structures. 2) Recognition of the mediastinal pleura was identified as challenging. CONCLUSION: Our study underlines that the evaluation of the pT stage of TET is problematic and needs to be addressed in more detail in an upcoming TNM classification. The publication of histopathologic images of landmarks, including ancillary tests could improve reproducibility for future TNM classifications.

Immune checkpoints are predominantly co-expressed by clonally expanded CD4+FoxP3+ intratumoral T-cells in primary human cancers.

BACKGROUND: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. METHODS: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. RESULTS: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. CONCLUSIONS: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Intimal granulomatous angiitis in sarcoid pulmonary vasculitis: worth remembering.

Intimal granulomatous angiitis is a facet of pulmonary sarcoidosis vasculitis that has almost been forgotten. Its observation may offer new understanding of the various patterns of pulmonary hypertension associated with sarcoidosis. https://bit.ly/3g6Ms76.

A Patient-Centered Model of Fast-Track Lung Cancer Diagnosis.

INTRODUCTION: Despite the increasing importance of digital resources in modern life over the past decades, little is known about the impact of internet-based solutions on patient's health. We aimed to study the potential benefit of a digital platform helping patients to deal with abnormal chest CT scan revealing possible lung cancer. METHODS: We set up a fast-track lung cancer diagnosis pathway through a secure online platform. Patient-generated information combined with online review of their imaging enables preplanning of further investigations ahead of clinical assessment. We compared outcomes of "self-referred" patients (patient group), who directly fill out the online questionnaire, to general practitioner-driven patients (GP group), who were referred by their GP. RESULTS: From June 2021 to June 2022, we included 125 patients (61% males, median age 67 years, IQR 56.9-72.5): 41% in the patient group and 59% in the GP group. No difference was found between groups in terms of time from contact to first appointment (median 5 days in both groups, P = .6), percentage of pathways including prebooked tests (94% vs. 92%, P = .6), number of scheduled invasive procedures (median 1, IQR 1-2 vs. 2, IQR 1-2, P = .4) and in final cancer diagnosis (76% vs. 78%, P = .4). CONCLUSION: A lung cancer diagnosis pathway directly accessible by patients through a secure online platform was feasible and as efficient as the usual general practitioner pathway. It demonstrated the benefit of leaning on new digital tools in order to answer to the new challenges of a patient-centered health care system.

Outcomes of extended resection for locally advanced thymic malignancies.

BACKGROUND: Thymic malignancies are rare tumors about which data are limited. Our objective here was to evaluate the outcomes and risk factors for complications and death in patients who underwent extended surgery to remove thymic malignancies. METHODS: We retrospectively included patients who underwent extended resection of locally advanced, nonmetastatic thymic malignancies at our institution. Patients were deemed eligible for resection by a multidisciplinary team. During surgery, priority was given to achieving complete resection rather than to sparing organs. RESULTS: The 108 patients had a mean age of 53 ± 15 years (range, 9-83); among them, 91 had thymoma, 12 thymic carcinoma, and 5 neuroendocrine tumor. The Masaoka stage was III or higher in 86 patients; examination of operative specimens resulted in downstaging of 22 patients. Tumor-free resection margins were achieved in 98 patients. Overall 5- and 10-year survival rates were 80% and 68%, respectively. Myasthenia gravis, present in 36 patients, was the only independent significant risk factor for major postoperative complications. Age older than 70 years, thymic carcinoma or neuroendocrine tumor, pT3 or pT4 stage, and R1 or R2 resection margins independently predicted death. The number of resected structures was not associated with survival. Thymic carcinoma or neuroendocrine tumor was independently associated with shorter disease-free survival. CONCLUSION: In an expert center, extended resection targeting complete resection rather than organ preservation provided good outcomes in patients with locally advanced thymic malignancies. The risk/benefit ratio of surgery should be assessed with special care in patients who are elderly or have myasthenia gravis.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Retrospective study of outcomes after extended resection for tracheobronchial adenoid cystic carcinoma.

OBJECTIVE: Tracheobronchial adenoid cystic carcinoma is a rare, slow-growing malignancy with a considerable propensity for local extension that may require complex airway resection to achieve tumor-free margins. The objective of this study was to assess whether our experience supports complex airway resection for tracheobronchial adenoid cystic carcinoma. METHODS: Consecutive patients who underwent curative resection for tracheobronchial adenoid cystic carcinoma at our institution between 1970 and 2019 were included retrospectively and classified as having had complex or standard resection. Complex surgery included total tracheal replacement, associated esophageal resection, pneumonectomy, total laryngectomy with tracheal resection, and carinal resection. Standard surgery included tracheal resection, bronchoplastic resection, lobectomy, and bilobectomy. We obtained data from medical records, referring physicians, patients, relatives, and public death records. RESULTS: Of 59 included patients, 38 had complex and 21 had standard surgery. All 4 (6.8%) patients who died postoperatively had undergone complex surgery. Postoperative morbidity was 32.2% overall and was significantly higher after complex surgery (P = .043). Overall 5- and 10-year survival rates were 81.5% and 60.2%, with no significant differences between groups (P = .31). By univariate analysis, T4 tumor and microscopically detectable tumor in the operative specimen margins and gross tumor in the operative specimen margins were associated with poorer survival (P < .05). In the subgroup with microscopically detectable tumor resection, survival was significantly better with adjuvant radiotherapy (P < .05). CONCLUSIONS: Complex resection for extended tracheobronchial adenoid cystic carcinoma may achieve local control and satisfying long-term survival. However, this demanding procedure is associated with high postoperative morbidity and mortality rates. Because adjuvant radiotherapy improved outcomes after resection resulting in microscopically detectable tumor in the operative specimen margins, expected outcomes after resection with no detectable tumor in the margins must be compared to those after resection resulting in microscopically detectable tumor in the margins plus radiotherapy, according to the operative risk.

Unexpected Cardiotoxicity in Patients With HER2-Mutant NSCLC Treated With Trastuzumab Deruxtecan: A Case Report.

Antibody-drug conjugates targeting receptor tyrosine-protein kinase erbB-2 (ERBB2, HER2) have emerged as promising targeted options for HER2-mutant NSCLC. Among antibody-drug conjugates targeting HER2, trastuzumab deruxtecan was found to have the most impressive efficacy and is a potential new standard of care. Drug-related interstitial lung disease remains a serious unpredictable identified risk for patients treated with trastuzumab deruxtecan, requiring careful monitoring and multidisciplinary management. We report the first two cases of drug-related cardiotoxicity with acute myocarditis that developed after the first trastuzumab deruxtecan cycle. Routine cardiovascular risk screening is advisable, with close collaboration between cardiology specialists and oncologists.

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca2+) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca2+ entry is involved in Ca2+ homeostasis in PASMCs, but its properties in PAH are unclear. METHODS: Using a combination of Ca2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH). RESULTS: Store-operated Ca2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated protein kinase kinase 1/2), NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using small interfering RNA (siRNA) and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca2+ entry, mitochondrial Ca2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], or 5J4) protected against PH. CONCLUSIONS: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

Feasibility and long-term outcomes of surgery for primary thoracic synovial sarcoma.

OBJECTIVES: Primary thoracic synovial sarcoma (SS) is a rare, high-grade, malignancy. Involvement of vital organs is frequent and may decrease the benefits of surgical resection. We reviewed our practice at a highly experienced thoracic-surgery centre to assess early- and long-term outcomes after surgery. METHODS: We conducted a retrospective, observational, single-centre study of patients undergoing curative-intent surgery for primary thoracic SS between 1 January 2000 and 31 January 2021 as part of a multidisciplinary management. We assessed demographics, medical history, histopathology and follow-up information. RESULTS: We enrolled 20 patients (13 males) with a median age of 40 years old and a median tumour size of 11 cm. Neoadjuvant chemotherapy was administered to 13 patients. Surgery consisted in extrapleural pneumonectomy (n = 7), extrapleural lobectomy (n = 5), chest wall resection (n = 4) or tumour resection (n = 4). R0 resection was achieved in 16 (80%) patients. Adjuvant therapy was given to 13 patients. 6 patients developed postoperative complications. The median hospital stay was 11.5 days. Overall survival at 2 and 5 years was 51% and 22%, respectively; median overall survival was 25 months and median disease-free survival was 8.5 months. Relapses occurred in 15 patients. By univariate analysis, incomplete resection was the only significant predictor of survival (P = 0.01). CONCLUSIONS: Primary thoracic SS is an aggressive disease. Surgery included in a multimodal treatment may contribute to achieving a good outcome, providing that an R0 resection is obtained. Given the considerable technical challenges of surgery, patient selection and referral to an experienced centre are crucial to minimize morbidity and mortality.

Metastatic pulmonary carcinoids with EML4-ALK fusion response to ALK inhibitors: two case reports and review of literature.

Background: Pulmonary carcinoids (PC), including typical (TC) and atypical carcinoids (AC), are low-grade neuroendocrine tumors (NETs) which account for 1-5% of all lung tumors. Due to the low prevalence of PC and extreme rarity of anaplastic lymphoma kinase (ALK) rearrangements in patients with PC, the advances in targeted therapy development in PC are still limited and there is no standard treatment. Even though in patients with PC harboring ALK rearrangements there is a room for a success in targeted therapy. To our knowledge, case 1 was the first report to detect ALK gene p.I1171N mutation after taking alectinib and sensitive to ceritinib in patients with atypical carcinoid. Case Description: Herein, we report the cases of 2 non-smoking patients, 51 year-old female with tumor in left lower lobe and 49 year-old female with tumor in right upper lobe, both with metastatic PC who harbored EML4-ALK fusion and were sensitive to small-molecule ALK inhibitors. The first patient initially received alectinib, then therapy was switched to ceritinib after developing drug resistance due to the missense mutation of ALK gene p.I1171N mutation in exon 22 detected by next-generation sequencing (NGS), and finally died of intracranial disease progression. The second patient also received alectinib, and her treatment is currently ongoing with good effect and tolerance. After conducting comprehensive review of literature, we found that 14 lung NETs with ALK rearrangements have been reported to date. The clinical outcome was partial response for 6 NETs patients and 5 patients exhibited stable disease after treatment with ALK inhibitors. Conclusions: According to the effectiveness of ALK inhibitors in our cases and previous articles, we recommend alectinib for the first-line treatment of metastatic PC with EML4-ALK fusion and highlight the need for molecular profiling of metastatic lung NETs patients and that ALK inhibitors are feasible in the treatment for metastatic lung NETs patients with ALK rearrangements. Finally, further studies to assess the real prevalence of ALK gene fusions and their spectrum of sensitivity to different ALK inhibitors are needed in larger cohorts.

Multicenter Evaluation of the Idylla GeneFusion in Non-Small-Cell Lung Cancer.

Targeted therapy in lung cancer requires the assessment of multiple oncogenic driver alterations, including fusion genes. This retrospective study evaluated the Idylla GeneFusion prototype, an automated and ease-of-use (<2 minutes) test, with a short turnaround time (3 hours) to detect fusions involving ALK, ROS1, RET, and NTRK1/2/3 genes and MET exon 14 skipping. This multicenter study (18 centers) included 313 tissue samples from lung cancer patients with 97 ALK, 44 ROS1, 20 RET, and 5 NTRKs fusions, 32 MET exon 14 skipping, and 115 wild-type samples, previously identified with reference methods (RNA-based next-generation sequencing/fluorescence in situ hybridization/quantitative PCR). Valid results were obtained for 306 cases (98%), overall concordance between Idylla and the reference methods was 89% (273/306); overall sensitivity and specificity were 85% (165/193) and 96% (108/113), respectively. Discordances were observed in 28 samples, where Idylla did not detect the alteration identified by the reference methods; and 5 samples where Idylla identified an alteration not detected by the reference methods. All of the ALK-, ROS1-, and RET-specific fusions and MET exon 14 skipping identified by Idylla GeneFusion were confirmed by reference method. To conclude, Idylla GeneFusion is a clinically valuable test that does not require a specific infrastructure, allowing a rapid result. The absence of alteration or the detection of expression imbalance only requires additional testing by orthogonal methods.

SUR1 As a New Therapeutic Target for Pulmonary Arterial Hypertension.

Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of in vivo activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. In vivo, long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, in vivo diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, in vivo, activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. In vivo pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly.

Treatment strategies for thymic carcinoma in a real-life setting. Insights from the RYTHMIC network.

BACKGROUND: Thymic carcinomas are aggressive and difficult to treat a subset of thymic epithelial tumours that represent a heterogeneous group of rare intrathoracic malignancies. The treatment strategy of thymic carcinomas is based on whether surgical resection may be achieved, which represents the most significant favourable prognostic factor on survival. For this study, we took advantage of the unique prospective Réseau tumeurs THYMiques et Cancer (RYTHMIC) database to describe baseline characteristics, analyse treatment strategies in light of existing guidelines and provide landmark patient outcomes data with regards to response and survival of patients in a real-life clinical practice setting. METHODS: Inclusion criteria for this analysis were the following: (1) histologically-confirmed thymic carcinomas - excluding neuroendocrine tumours-after pathological review by the RYTHMIC pathology panel, (2) discussion of the case at the RYTHMIC multidisciplinary tumour board, (3) at least one active treatment modality. RESULTS: A total of 213 patients were analysed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) patients received primary chemotherapy, and 62 (29%) patients received exclusive chemotherapy. Median overall survival (OS) was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p < 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p < 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p < 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.051, respectively). CONCLUSIONS: Our cohort is the first to analyse in-depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimised multidisciplinary management and innovative therapies as the survival of patients remains limited.

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension.

Aims: We hypothesized that the ATP-sensitive K+ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH. Methods and results: Using in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH. Conclusion: We showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH.

Mediastinal tumours and pseudo-tumours: a comprehensive review with emphasis on multidisciplinary approach.

The diagnosis of a mediastinal mass may be challenging for clinicians, since lesions arising within the mediastinum include a variety of disease entities, frequently requiring a multidisciplinary approach. Age and sex represent important information, which need to be integrated with imaging and laboratory findings. In addition, the location of the mediastinal lesion is fundamental; indeed, we propose to illustrate mediastinal diseases based on the compartment of origin. We consider that this structured approach may serve as hint to the diagnostic modalities and management of mediastinal diseases. In this review, we present primary mediastinal tumours in the evolving context of new diagnostic and therapeutic tools, with recently described entities, based on our own experience with >900 cases encountered in the past 10 years.

Integrin-αV-mediated activation of TGF-ß regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade.

TGF-ß is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit. The activation of latent TGF-ß by cancer-cell-expressed αV re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell αV is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8+CD103+ tumour-infiltrating lymphocytes. Mechanistically, tumour αV regulates CD8 T cell recruitment, induces CD103 expression on activated CD8+ T cells and promotes their differentiation to granzyme B-producing CD103+CD69+ resident memory T cells via autocrine TGF-ß signalling. Thus, our work provides the underlying principle of targeting cancer cell αV for more efficient PD-1 checkpoint blockade therapy.