Drug Survival, Safety, and Effectiveness of Secukinumab for up to 5 Years in Patients with Psoriasis and Psoriatic Arthritis: A Long-Term Real-Life Experience.

INTRODUCTION: the selective IL-17 inhibitor secukinumab has demonstrated efficacy and safety in the treatment of moderate-severe psoriasis in recent years. OBJECTIVE: evaluate effectiveness and drug survival (DS) of secukinumab in patients with psoriasis for up to 5 years. METHODS: This is a retrospective study on a monocentric cohort of patients with psoriasis on secukinumab evaluating the achievement of PASI100, PASI90, and PASI ≤ 3 and DS analysis up to 260 weeks. DS multivariate analysis was carried out considering sex, age, age of onset of the disease, obesity, cardiovascular comorbidities, diabetes, involvement of difficult-to-treat sites, psoriatic arthritis, treatment-naïve status, and mean baseline PASI. RESULTS: At baseline, we evaluated 255 patients on secukinumab. PASI100 was reached by 41.7% and 70.6% of patients at weeks 16 and 260, respectively. PASI90 showed a similar trend with 46.5% of patients achieving it at week 16 and 88.2% at week 260. Non-obese patients showed a faster response than patients with obesity in achieving PASI100, PASI90, and PASI ≤ 3, with significant differences at 28 weeks [55% vs. 40% (p = 0.033), 64% vs. 49% (p = 0.038), and 76% vs. 62% (p = 0.036), respectively]. The estimated DS for secukinumab was 84.3% at 12 and 48% at 60 months. Obesity and smoking habits were associated with a higher risk of discontinuation in multivariate models (HR 1.6 CI 1.05-2.45, p = 0.028; HR 1.48 CI 1.01-2.17, p = 0.043, respectively). CONCLUSIONS: Secukinumab showed effectiveness for up to 5 years of treatment, with a high DS and achievement of PASI100, PASI90, and PASI < 3 at these time points. Only obesity reduced the response and maintenance of DS.

Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome.

Pathogenic variants in RASA1 are typically associated with a clinical condition called "capillary malformation-arteriovenous malformation" (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far. Here, we report four pediatric cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. Polyhydramnios, non-immune hydrops fetalis and chylothorax are only a few possible aspects of this condition, but a correct interpretation of these prenatal signs is essential due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in family members carrying the same RASA1 variant.

The challenge of setting restoration targets for macroalgal forests under climate changes.

The process of site selection and spatial planning has received scarce attention in the scientific literature dealing with marine restoration, suggesting the need to better address how spatial planning tools could guide restoration interventions. In this study, for the first time, the consequences of adopting different restoration targets and criteria on spatial restoration prioritization have been assessed at a regional scale, including the consideration of climate changes. We applied the decision-support tool Marxan, widely used in systematic conservation planning on Mediterranean macroalgal forests. The loss of this habitat has been largely documented, with limited evidences of natural recovery. Spatial priorities were identified under six planning scenarios, considering three main restoration targets to reflect the objectives of the EU Biodiversity Strategy for 2030. Results show that the number of suitable sites for restoration is very limited at basin scale, and targets are only achieved when the recovery of 10% of regressing and extinct macroalgal forests is planned. Increasing targets translates into including unsuitable areas for restoration in Marxan solutions, amplifying the risk of ineffective interventions. Our analysis supports macroalgal forests restoration and provides guiding principles and criteria to strengthen the effectiveness of restoration actions across habitats. The constraints in finding suitable areas for restoration are discussed, and recommendations to guide planning to support future restoration interventions are also included.

Diagnostic and Therapeutic Challenges of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease.

SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.

BACKGROUND: The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. METHODS: Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. RESULTS: In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival. CONCLUSIONS: We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. METHODS: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. RESULTS: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. CONCLUSION: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.

Report of an interactive three-dimensional anatomical model to be used as an intraoperative aid in lung anatomical resections for non-small lung cancer.

The possibility of using three-dimensional reconstructions as an intraoperative aid to thoracic surgeons has not yet been fully explored. With this in mind, we developed a technology based on a three-dimensional virtual model of lungs obtained from lung computed tomography scans, the Hyper-Accuracy Three-Dimensional reconstruction (HA3D™), which aids the surgeon during surgery. We tested this technology while performing a uniportal video-assisted thoracic surgery right upper lobectomy for lung cancer.

Effect of opioid-free anaesthesia on postoperative epidural ropivacaine requirement after thoracic surgery: A retrospective unmatched case-control study.

INTRODUCTION: Patients undergoing thoracic surgery are at risk of severe postoperative pain. Post-thoracotomy pain relief is usually provided with thoracic epidural analgesia (TEA). Intraoperative use of opioids may result in hyperalgesia and increase analgesics consumption. We investigated the effect of opioid-free anaesthesia (OFA) on epidural ropivacaine requirement after thoracotomy. METHODS: This retrospective study compared postoperative epidural ropivacaine requirement of patients undergoing open thoracotomy and receiving either opioid-based anaesthesia (OBA group) or a non-opioid regimen including clonidine, ketamine and lidocaine (OFA group). All patients received postoperative multimodal analgesia including both epidural analgesia and intravenous analgesics. The primary outcome was the cumulative first 48 postoperative hours epidural ropivacaine consumption. Secondary outcomes included postoperative pain scores, requirement for postoperative morphine titration, total opioid analgesics consumption within the first 48 postoperative hours, incidence of nausea and vomiting, intraoperative haemodynamic. RESULTS: From January 2015 to February 2018, 50 patients received an OBA and 25 received an OFA. The cumulative first 48 postoperative hours epidural ropivacaine consumption was significantly higher in the OBA-group (919 ± 311 mg versus 693 ± 270 mg, P = 0.002). Numerical Rating Scale at 6 and 24 h were significantly lower in the OFA-group (1[0-2] versus 3 [1-5], P = 0.0005 and 1[0-2] versus 3.5 [1-5], P = 0.001). In post-anaesthesia care unit, the proportion of patients requiring morphine was significantly higher in the OBA-group (42% versus 4%, P < 0.001). During anaesthesia, the OBA-group required more vasopressor support, while there were more hypertensive events in the OFA-group. CONCLUSION: OFA might reduce ropivacaine consumption, early postoperative pain scores and requirement for morphine titration after thoracotomy.

Thymoma and thymic carcinomas.

Thymomas (Ts) and thymic carcinomas (TCs) are rare tumours of the mediastinum with an incidence rate of 1.7/million per year in Europe. Histological classification is based on rate of non-malignant-appearing thymic epithelial cells and proportions of lymphocytes (A, AB, B1, B2, B3, and C), while staging system concerns localisation of the involved areas. Surgery is the mainstay of treatment with a 10-year survival of 80%, 78%, 75%, and 42% for stages I, II, III and IV, respectively, with an R0 resection. Radiotherapy has a role in selected cases (stage III patients or R1-2 residual) and platinum-based chemotherapy remains the standard of care for patients with advanced disease. A multimodality approach would be advisable when surgery is not recommended. Since molecular aberrations are poorly understood and few responses are reported, targeted therapies are yet being studied. In this review, we describe key aspects of clinical management for Ts and TCs.

Thulium laser versus staplers for anatomic pulmonary resections with incomplete fissures: negative results of a randomized trial.

AIMS: This randomized trial evaluated the feasibility and safety of thulium 2010-nm laser to perform anatomic lung resections in patients with incomplete fissures, as compared to mechanical staplers with or without sealants. STUDY DESIGN: Seventy-two patients scheduled for segmentectomy or lobectomy were enrolled. After intraoperative confirmation of the extent of resection and incomplete fissures (Craig type 2, 3 or 4), they were randomized and allocated to one of the following arms: laser resection by thulium (group A) or standard resection with mechanical staplers with or without sealants (group B). The primary endpoints of the study included analysis of intraoperative and postoperative course, and costs. RESULTS: Thirty-eight patients were assigned to group A (32 lobectomies, 6 segmentectomies) and 34 to group B (31 lobectomies, 3 segmentectomies). No 30-day mortality was observed. Median operative times were 145.0 minutes (group A) and 142.5 minutes (group B, P = 0.83). The median time to drainage removal was 5 days (group A) and 4 days (group B), while the median length of hospital stay was the same (7 days). Prolonged air leaks >7 days were observed in 12 patients of group A (32%) and 10 patients of group B (29%, P = 0.46). Unpredictable late pneumothorax occurred in 3 patients of group A (2 readmissions, need for 1 repeat thoracotomy). Cost analysis demonstrated an intraoperative advantage for group A (mean 807 ± 212 euro) versus group B (mean 1,047+/-276 euro, P <0.0001), but the differences in total costs could be due to chance (P = 0.83). CONCLUSIONS: The use of laser to complete fissures can lead to late pneumothorax, even in the absence of postoperative air leaks. Moreover, the use of laser to complete fissures did not prove to reduce overall costs. Trial Registration Identification Number: 41/10 (IRB00001457 - FWA00001798 - IORG0001063).

Thoracopleuropneumonectomy with riblike reconstruction for recurrent thoracic sarcomas.

BACKGROUND: Large intrathoracic tumors may occasionally present with massive infiltration of the lung and chest wall that would require pneumonectomy and total removal of the rib cage to obtain radical surgical excision, but this operation carries a prohibitive risk of death for cardiopulmonary failure in the absence of adequate chest wall reconstruction. METHODS: We report here four consecutive cases of thoracopleuropneumonectomy (TPP) with en-bloc resection of the entire lung, chest wall, and diaphragm and immediate riblike reconstruction for recurrent thoracic sarcomas. Patients had undergone the initial thoracic surgical resection with curative intent 2-14 years before TPP. There was no postoperative mortality, and all patients were alive and free of disease 8-21 months after TPP. RESULTS: To our knowledge, this is the first report in the medical literature of such an extensive operation, demonstrating technical feasibility, tolerability, and efficacy of one-stage resection and reconstruction by a semirigid three-dimensional riblike prosthesis modeled on a human-derived aluminum cast. CONCLUSIONS: Selected patients with advanced low-intermediate thoracic sarcomas are the ideal candidates for this extreme procedure, to maximize the chance of long-term tumor control and possibly cure.

A false positive fluorodeoxyglucose lymphadenopathy in a patient with pulmonary carcinoid tumor and previous breast reconstruction after bilateral mastectomy.

We present a case of a 60-year-old woman with a positive fluorodeoxyglucose integrated positron emission tomography and computed tomography (PET/TC) mammary chain lymphadenopathy and carcinoid tumor of the left lower lobe who had a previous bilateral mastectomy and breast reconstruction for breast cancer. She underwent a right muscle sparing mini-thoracotomy and mammary chain lymphadenectomy; the final histopathology showed granulomatous reaction to silicone.

Does external pleural suction reduce prolonged air leak after lung resection? Results from the AirINTrial after 500 randomized cases.

BACKGROUND: External pleural suction is used after lung resection to promote lung expansion and minimize air leak duration. Published randomized trials failed to prove this advantage but they are limited in number and underpowered in many cases. The aim of the AirINTrial study was to test the hypothesis that external pleural suction may reduce the rate of prolonged air leak in a large, randomized cohort. METHODS: All candidates for lung resection (with the exception of pneumonectomy) were considered eligible for this single-center study. At the end of operation, patients were stratified by the type of resection (anatomic versus nonanatomic) and randomly allocated into the external suction arm (-15 cmH2O, group A) or into the no external suction arm (control arm, group B) in a 1:1 ratio. Chest drains were maintained for 3 days and then they were either removed or connected to an Heimlich valve, when an air leak was present. The main endpoint was to compare groups in terms of prolonged air leak (defined as the rate of patients having a chest drain still in place by postoperative day 7). RESULTS: Starting on February 2011, 500 patients were randomized over a 21-month period, 250 in group A and 250 in group B. Twenty-one patients in group B (8.4%) required pleural suction owing to large pneumothorax or diffuse subcutaneous emphysema. On postoperative day 7, the chest drain was still in place in 25 patients in group A and in 34 patients in group B (10% and 14%, respectively; p = 0.2). Subgroup analysis showed that external pleural suction reduced the prolonged air leak rate in the subgroup of patients who underwent anatomic resection (n = 296, 9.6% in group A and 16.8% in group B; p = 0.05). CONCLUSIONS: Results from the AirINTrial showed that the routine use of external suction reduces the rate of prolonged air leak after anatomic lung resection. More accurate strategies of pleural suction based on the amount of air flow and the degree of lung expansion should be probably established to improve its effectiveness.

Giant liposarcoma elongating mediastinal vessels with intrathoracic inferior vena cava replacement.

Intrathoracic infiltration of the inferior vena cava (IVC) is rare; mobilization and prosthetic replacement may increase the risk of cardiac arrest and postoperative complications. We report a case of a giant liposarcoma which elongated and grew around the IVC, invading both hemithoraces. The removal of this mass required a bypass between the left femoral and ipsilateral axillary vein to guarantee an adequate venous return. The IVC was replaced by a polytetrafluoroethylene prosthesis. A postoperative paralysis of patient's lower limbs occurred. Hypotension or involvement of aberrant medullary artery origin could be responsible for this complication.

PET scan contribution in chest tumor management: a systematic review for thoracic surgeons.

AIMS AND BACKGROUND: In the 90s, the introduction of positron emission tomography (PET) represented a milestone in the staging of thoracic tumors. In the last 10 years, PET scan has been widely adopted in thoracic oncology, showing high accuracy in diagnosis and staging and with promising issues in defining prognosis. The aim of this systematic review was to focus on the results and pitfalls of PET scan use in the modern management of chest tumors. METHODS AND STUDY DESIGN: The literature search was performed on May 2010 in PubMed, Embase, and Cochrane according to PRISMA protocol. The search was restricted to publications in English, using in the same string the word "PET" with 9 different chest tumors; results were then filtered by eliminating technical articles, focusing only on papers in which surgery was considered as a potential diagnostic or therapeutic tool. From 6600 papers initially selected, 99 manuscripts were fully analyzed. RESULTS: Glucose uptake is a metabolic marker useful in the diagnosis and staging of chest tumors. In lung cancer screening, standard uptake value is helpful in defining the risk of malignancy of isolated pulmonary nodules. The addition of PET scan to conventional staging increases detection of nodal and distant metastases in lung cancer, esophageal cancer and malignant mesothelioma. In thymoma, a close relationship between standard uptake value, histology, and Masaoka stage has been advocated. This link between glucose uptake and prognosis suggests that PET translates biological tumor behavior into clinically detectable findings. CONCLUSIONS: PET scan has a crucial role in thoracic oncology due to its impact on diagnosis, staging and prognosis. PET scan expresses the biological behavior of tumors, opening interesting perspectives in chest tumor management and improving detection and stage grouping in lung cancer. It anticipates the diagnosis in long-incubating diseases such as mesothelioma and increases biological knowledge of rare diseases, such as thymoma and other mediastinal tumors.

Pulmonary resections: cytostructural effects of different-wavelength lasers versus electrocautery.

AIMS AND BACKGROUND: There are few papers on the cytostructural effects of surgical instruments used during pulmonary resections. The aim of the present study was to evaluate the parenchymal damage caused by different surgical instruments: a new generation electrosurgical scalpel and two different-wavelength lasers. METHODS: Six surgical procedures of pulmonary resection for nodules were performed using a new generation electrosurgical scalpel, a 1318 nm neodymium (Nd:YAG) laser or a 2010 nm thulium laser (two procedures for each instrument). Specimens were analyzed using optical microscopy and scansion electronic microscopy. RESULTS: Severe cytostructural damage was found to be present in an average of 1.25 mm in depth from the cutting surface in the patients treated using electrosurgical cautery. The depth of this zone dropped to less than 1 mm in patients treated by laser, being as small as 0.2 mm using the laser with a 2010 nm-wavelength and 0.6 mm with the 1318 nm-wavelength laser. DISCUSSION: These preliminary findings support the use of laser to perform conservative pulmonary resections (i.e., metastasectomies), since it is more likely to avoid damage to surrounding structures. Controlled randomized trials are needed to support the clinical usefulness and feasibility of new types of lasers for pulmonary resections.

Unusual giant cell tumor of a floating rib: a case report.

Giant cell tumor is an unusual neoplasm of the ribs. Herein is presented the case of a patient with an abdominal wall mass, which turned out to be a giant cell tumor of the 11th rib. This is a very uncommon site for a giant cell tumor, which also had a peculiar shape. No other similar case has been reported in the medical literature.

The "rib-like" technique for surgical treatment of sternal tumors: lessons learned from 101 consecutive cases.

BACKGROUND: Sternal tumors represent a rare subgroup of chest wall neoplasms in which indication, surgical issues, and long-term results are rarely reported. Thus, in this study we reevaluated our experience in sternal replacement from a series of 101 consecutive cases during the last 30 years. METHODS: Clinical records of patients who underwent sternal resection between January 1980 and December 2008 were reviewed. The technique of reconstruction after sternectomy varied over time, including mesh replacement in 52 patients (group A), rigid prosthesis in 27 patients (group B), and the "rib-like" technique, a semi-rigid tridimensional prosthesis reproducing the shape of native ribs, in 22 patients (group C). Postoperative outcomes and long-term survival were analyzed. RESULTS: Of 101 patients, 42 underwent resection for primary chest wall tumors, 30 for breast cancer, 15 for locally advanced tumors, 11 for metastatic disease, and 3 for benign disease. One patient died postoperatively. The overall major complications rate was similar between groups. Local infection required prosthetic removal in 7 patients of groups A and B (9%). No infection occurred in group C (p = 0.02). Median survival exceeded 60 months for primary sternal tumors and 22 months for other cancer (p = 0.01). The worst survival was recorded in radioinduced sarcoma (17 months) and in patients who underwent previous resection before salvage sternectomy (18 months). CONCLUSIONS: Results from this study showed that an adequate sternal resection should be done at the first operation and that improving prosthetic integration with surrounding tissues may reduce the local complication rate.