Risk stratification in hypertrophic cardiomyopathy. Insights from genetic analysis and cardiopulmonary exercise testing

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.publishedVersio

A Reverse Thymic Fat Pad Flap to Cover the Anastomosis of an Extended Tracheal Resection Following Induction Chemotherapy: A Challenging Case Report

Extended tracheal resection after neoadjuvant chemotherapy is rarely described in patients with tracheal cancer. Controversies still exist among surgeons about the length of tracheal resectability and possible harmful anastomotic complications. Different vascularized tissue flaps can be used to protect the anastomotic suture line. We reported a 67-year-old patient with middle tracheal squamous cell carcinoma treated by induction chemotherapy followed by a successful extended tracheal resection. The anastomosis was covered by a reversed thymic fat pad flap to prevent the erosion of adjacent brachiocephalic vessels. Postoperative concurrent chemoradiation did not threaten the integrity of the suture line. Careful tracheal dissection and accurate release manoeuvres are mandatory to achieve a tension-limited anastomosis. Extended tracheal resection may be safely performed after induction chemotherapy, with excellent long-term outcomes. A thymic fat flap seems to be beneficial to suture-line healing

New Insights in Pleural Mesothelioma Classification Update: Diagnostic Traps and Prognostic Implications

The 2021 WHO Classification of Tumors of the Pleura has introduced significant changes in mesothelioma codification beyond the three current histological subtypes—epithelioid, sarcomatoid and biphasic. Major advances since the 2015 WHO classification include nuclear grading and the introduction of architectural patterns, cytological and stromal features for epithelioid diffuse mesothelioma. Mesothelioma in situ has been recognized as a diagnostic category. Demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH, is valuable in establishing the diagnosis of epithelioid mesothelioma. Recent emerging data proved that grading and histological subtypes have prognostic implications and may be helpful to patient risk stratification and clinical management. Nevertheless, the latest mesothelioma classification increases the already non-negligible diagnostic pitfalls, especially concerning differential diagnosis of pre-invasive tumors. In this review, recent changes in histologic classification of mesothelioma and advances in molecular markers are presented and their relation to diagnostic challenges and prognostic implications is discussed

Hyperthermic Intrathoracic Chemotherapy for Malignant Pleural Mesothelioma: The Forefront of Surgery-Based Multimodality Treatment

Introduction: Malignant Pleural Mesothelioma (MPM) is characterized by an aggressive behavior and an inevitably fatal prognosis, whose treatment is still far from being standardized. The role of surgery is questionable since a radical resection is unattainable in most cases. Hyperthermic IntraTHOracic Chemotherapy (HITHOC) combines the advantages of antitumoral effects together with those of high temperature on the exposed tissues with the aim to improve surgical radicality. Material and Methods: this is a narrative review on the role of HITHOC in the management of MPM patients. To provide data on the beginnings and the historical evolution of this technique, we searched the available literature by selecting the more exhaustive papers on this topic. Results: from 1994 to date different authors experimented HITHOC following a cytoreductive surgery in MPM, obtaining in most cases a good local control and a better overall survival associated to very low complication rate. Conclusions: HITHOC may be considered as a safe, feasible and effective procedure although there is a high heterogeneity between different protocols adopted worldwide. More structured studies are needed to reach a unanimous consensus on this technique

PITAC: Pressurized Intrathoracic Aerosol Chemotherapy

Pressurized intrathoracic aerosol chemotherapy (PITAC) is a novel and promising treatment for malignant pleural effusion, allowing surgeons to achieve an effective pleurodesis together with a potential anti-neoplastic effect. The treatment delivers chemotherapeutic agents via a nebulizer into the thoracic cavity, where a therapeutic aerosol is formed. PITAC rationale is based on physical properties such as the homogeneous distribution of a gas within a closed space and creating a pressure gradient to overcome the tumor interstitial fluid pressure, which enhances in-tissue drug penetration. This procedure is performed using VATS, incorporating all the advantages of a minimally invasive approach. In addition, a low dose of chemotherapeutic drugs is administered with no systemic toxicity.Given these advantages, PITAC may soon represent a pioneering treatment in the field of loco-regional therapy for pleural carcinomatosis. This video presents a demonstration of the procedure.First, the patient was laid in the lateral decubitus position under general anesthesia. Two 12 mm balloon trocars were positioned in the chest wall, one in the seventh intercostal space (ICS) in the mid-axillary line and one in the fifth ICS in the anterior axillary line. The camera was inserted through the trocar at the seventh ICS. A standard thoracoscopy was then performed with a careful exploration of the entire thoracic cavity. Balloon trocars were required to create a closed system and avoid pressurized aerosol dispersal outside the thoracic cavity. After MPE removal and lysis of eventual pleural adhesions, multiple parietal pleural biopsies were sampled as common practice. In patients without a preoperative diagnosis of pleural carcinomatosis, pathologic confirmation should be obtained by intraoperative frozen section.A dedicated checklist containing all safety aspects of the PITAC procedure was double checked before administration of chemotherapy drugs. CO2 was used to pressurize the pleural space and the gas was inflated into thoracic cavity by the trocar at the fifth ICS. The dedicated CE-certified nebulizer in surgical stainless steel was then inserted through the trocar at the fifth ICS and connected to a high pressure injector. Cytostatic solutions were prepared according to the patient’s body surface area (BSA), calculated with the Boyd formula, and were then drawn into the injector syringe. Before starting the nebulization, the patient was covered with a sterile drape to minimize operating room air contamination with aerosol chemotherapeutic agents.Next, all the staff left the operating room (OR) to prevent eventual exposure to chemotherapy. Using a remote control, cisplatin (10.5 mg/m2 in 150 mL NaCl 0.9 percent) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9 percent) were aerosolized into the pleural cavity at 0.7 mL/s flow with a maximal upstream pressure of 220 PSI. This closed system was left in a steady state for 30 minutes at 37 °C under a constant intrathoracic pressure of 12 mmHg CO2 to increase drug penetration into the neoplastic tissue. Cisplatin and doxorubicin were selected for both direct cytotoxic and sclerosing effects on pleural layers.Vital signs and the nebulization procedure were remote controlled by both surgeons and anesthesiologists from outside the OR, even though there is no significant inhalation risk. At the end of 30 minutes of nebulization, the staff entered the OR to remove the remaining toxic aerosol using a closed surgical smoke evacuation system with two microparticle filters to capture residual molecules. Next, the pleural space was carefully explored to check hemostasis. The trocar ballons were then deflated and retracted under vision control. Finally, two chest drains were placed and the lung was ventilated.To conclude, PITAC is a safe, feasible, and effective technique to control malignant pleural effusion recurrence. Further investigations should also assess its oncological role. PITAC might represent a pioneering treatment in the field of locoregional therapy for pleural carcinomatosis.Reference(s)1) Clive AOJ, Bhatnagar R, Preston NJ, et al. Interventions for the management of malignant pleural effusions: a network meta-analysis. Cochrane Database Syst Rev 2016;5:CD010529.2) Bibby AC, Dorn P, Psallidas I, Porcel JM, Janssen J, Froudarakis M et al. ERS/EACTS statement on the management of malignant pleural effusions. Eur J Cardiothorac Surg 2018; doi:10.1093/ejcts/ezy258.3) Solass W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc 2012;26(7):1849–55.4) Solass W, Giger-Pabst U, Zieren J, Reymond MA. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC): occupational health and safety aspects. Ann Surg Oncol 2013;20(11):3504–11.5) Solass W, Kerb R, Murdter T, et al. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol 2014; 21(2):553–9.6) B. Tempfer, G. Winnekendonk, W. Solass et al. Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: a phase2 study. Gynecologic Oncology, vol. 137, no. 2, pp. 223–228, 2015.7) Kuchen N, Cereser T, Hailemariam S and Schoeb O. Safety and efficacy of pressurized intraperitoneal/intrathoracic aerosol chemotherapy (PIPAC/PITAC) in patients with peritoneal and/or pleural carcinomatosis: A preliminary experience. J Med Therap. 2018; 2(1): 1-6.8) Drevet G, Maury JM, Bakrin N, Tronc F. Technique of pressurized intrathoracic aerosol chemotherapy (PITAC) for malignant pleural effusion. Pleura Peritoneum. 2020 Nov 9;5(4):20200129.9) Tempfer CB, Giger-Pabst U, Seebacher V, Petersen M, Dogan A, Rezniczek GA. A phase I, single-arm, open-label, dose escalation study of intraperitoneal cisplatin and doxorubicin in patients with recurrent ovarian cancer and peritoneal carcinomatosis. Gynecol Oncol 2018; 150: 23–30.10) Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol. 2004 Apr;57(4):358-65.</p

New Immunohistochemical Markers for Pleural Mesothelioma Subtyping

Pleural mesothelioma (PM) comprises three main subtypes: epithelioid, biphasic and sarcomatoid, which have different impacts on prognosis and treatment definition. However, PM subtyping can be complex given the inter- and intra-tumour morphological heterogeneity. We aim to use immunohistochemistry (IHC) to evaluate five markers (Mesothelin, Claudin-15, Complement Factor B, Plasminogen Activator Inhibitor 1 and p21-activated Kinase 4), whose encoding genes have been previously reported as deregulated among PM subtypes. Immunohistochemical expressions were determined in a case series of 73 PMs, and cut-offs for the epithelioid and non-epithelioid subtypes were selected. Further validation was performed on an independent cohort (30 PMs). For biphasic PM, the percentage of the epithelioid component was assessed, and IHC evaluation was also performed on the individual components separately. Mesothelin and Claudin-15 showed good sensitivity (79% and 84%) and specificity (84% and 73%) for the epithelioid subtype. CFB and PAK4 had inferior performance, with higher sensitivity (89% and 84%) but lower specificity (64% and 36%). In the biphasic group, all markers showed different expression when comparing epithelioid with sarcomatoid areas. Mesothelin, Claudin-15 and CFB can be useful in subtype discrimination. PAI1 and PAK4 can improve component distinction in biphasic PM

Successful Three-Stage Ethanol Ablation of Esophageal Mucocele

successfull three stage ethanol ablation of esophageal mucocel

Risk stratification in hypertrophic cardiomyopathy. Insights from genetic analysis and cardiopulmonary exercise testing

The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification

Initial experience with uniportal video-assisted thoracic surgery esophagectomy

Background: Multiportal thoracoscopic approach is already a well standardized procedure for minimally invasive esophagectomy (MIE); conversely very few reports have been published about uniportal video-assisted thoracic surgery (VATS) technique till now. We present our preliminary experience with uniportal VATS esophagectomy, evaluating short-term outcomes as perioperative mortality, complications, oncological radicality, postoperative pain and cosmetic results. Methods: From December 2016 to November 2017, the prospectively collected clinical data of 12 patients, who underwent uniportal VATS esophagectomy and reconstruction with a stomach conduit, according to McKeown technique, were reviewed and outcomes evaluated. Results: The mean age of population was 60.67\ub18.61 years. Ten (83.3%) patients were males. The main histological type was a squamous cell carcinoma in six patients (50%). No patient had a local recurrence. After 4.33\ub13.31 months 10 patients (83.3%) were alive with no evidence of disease; 2 (16.7%) patients died of other causes. Two (16.7%) patients developed an anastomotic leak (treated conservatively) and one (8.3%) patient a chylothorax (which required a surgical treatment). The mean operative time of uniportal VATS esophagectomy was 104.67\ub120.66 min. Mean number of thoracic nodes removed was 10.44\ub13.94. Postoperative hospitalization was 15.73\ub114.29 days (median of 9 days). The mean level of pain was 1.92\ub10.90 in first postoperative day with a duration of 2.25\ub11.54 days. Cosmetic result was 2.42\ub10.79 on a 3-point scale. Conclusions: Uniportal VATS esophagectomy seems to be a safe, feasible and effective alternative to multiportal VATS in terms of operative time, postoperative mortality, hospital stay and oncological outcomes. Less postoperative pain and better cosmetic results seem to be some advantages in favor of Uniportal VATS, however further studies with longer follow-up are claimed

Chronic chest pain and paresthesia after video-assisted thoracoscopy for primary pneumothorax

Background: This study aims to identify clinical and surgical risk factors for chronic chest pain and paresthesia after video thoracoscopic surgery for primary spontaneous pneumothorax.Methods: We retrospectively collected the data of 1,178 consecutive patients &lt;40-years-old undergoing video thoracoscopic surgery for primary spontaneous pneumothorax in 9 Italian centers in 2007-2017. Cases with &lt;2-month follow-up were excluded, leaving 920 patients [80% male; median age: 21 (IQR, 18-27) years] for statistical analysis. The following risk factors for chronic chest pain and chronic paresthesia were assessed by univariable and multivariable Cox regression model: age, gender, cannabis smoking, video thoracoscopy ports number, pleurodesis technique (partial pleurectomy/pleural electrocauterization/pleural abrasion/talc poudrage), chest tube size (24/28 F), postoperative chest tube stay.Results: Blebs/bullae resection with pleurodesis was performed in 732 (80%) cases; pleurodesis alone in 188 (20%). During a median follow-up of 68 (IQR: 42-95) months, chronic chest pain developed in 8% of patients, chronic chest paresthesia in 22%; 0.5% of patients regularly assumed painkillers. Chronic chest pain was independently associated with partial pleurectomy/pleura abrasion (P&lt;0.001) and postoperative chest tube stay (P=0.019). Chronic chest paresthesia was independently associated with pleurodesis by partial pleurectomy (P&lt;0.001), chest tube stay (P=0.035) and 28 F chest tube (P&lt;0.001).Conclusions: After video thoracoscopic surgery for primary spontaneous pneumothorax, the incidence of chronic chest pain and paresthesia was significantly lower when pleurodesis was performed by pleural electrocauterization or talc poudrage, and chest tube was removed early. A 24 F chest tube was associated with lower risk of chronic chest paresthesia