Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

Various clinical scenarios of primary melanoma of the esophagus: A retrospective 20-year analysis from two university thoracic surgery centers.

BACKGROUND: Primary melanoma of the esophagus (PME) represents a rare type of gastrointestinal malignancy with an exceptionally poor diagnosis. So far, only few descriptions of PME which satisfactorily summarize their clinical characteristics and prognosis have been published. OBJECTIVES: The aim of our study was to summarize our experience with PME patients. MATERIAL AND METHODS: In a group of 1387 patients who underwent esophagectomy due to neoplastic process in the years 2000-2020 in 2 high-volume university thoracic surgery centers, we identified those with confirmed PME diagnosis. Subsequently, their clinical characteristics, imaging and histopathological results were compared. The data regarding the long-term survival were obtained from the Polish National Death Registry. RESULTS: The PME was identified in 4 (0.29%) patients. Three of them (75%) were males. The mean age on admission was 64.3 ±17.5 years. The main symptom in all patients was dysphagia. In 1 patient with the most advanced PME, the clinically relevant weight loss was noted. In 3 patients, Ivor Lewis esophagectomy was performed, and 1 patient underwent McKeown resection. Histopathologic examination revealed a metastasis of lymph nodes only in 1 patient. The average maximum size of tumor was 6.9 ±4.7 cm and all tumors were located in distal part of the esophagus. Two out of those 4 patients are still alive and the longest survival time is 17 years. One patient died due to postoperative massive gastrointestinal bleeding complicated with cardiac arrest and the other one due to progression of PME systemic dissemination 6 months after surgical treatment. CONCLUSION: The PME is an extremely rare diagnosis. A long-term survival can be achieved with the complete resection. Clinical scenarios of surgically treated PME patients may significantly differ.

Influence of bilateral mediastinal lymph node dissection on survival in non-small cell lung cancer patients - Randomized study.

OBJECTIVES: This study aimed to analyze the effect of bilateral mediastinal lymphadenectomy (BML) on survival of non-small cell lung cancer (NSCLC) patients. The hypothesis was: BML offers survival benefit as compared with SLND. METHODS: A randomized clinical trial including stage I-IIIA NSCLC patients was performed. All patients underwent anatomical lung resection. BML was performed during the same operation via additional cervical incision (BML group). In the control group, standard lymphadenectomy (systematic lymph node dissection, SLND) was performed. RESULTS: In total, 102 patients were randomized. No significant difference was found in the type of lung resection, blood loss, chest tube output, air leak, pain, and complications (p = 0.188-0.959). In the BML group, the operative time was longer (318 vs 223 min, p < 0.001) with higher number of removed N2 nodes (24 vs 14, p < 0.001). The 5-year survival rate was 72 % in the BML group vs 53 % in the SLND group (OR 2.33, 95 % CI 0.95-5.69, p = 0.062). Separate comparisons for different lobar locations of the tumor have shown no significant difference in survival for the right lung tumors and left upper lobe tumors. For the left lower lobe tumors, survival time was longer in the BML group (p = 0.021), and the 5-year survival rate was 90.9 % vs 37.5 %, (OR 16.66, 95 % CI 1.36-204.04, p = 0.0277). CONCLUSIONS: In patients with NSCLC located in the left lower lobe, bilateral lymph node dissection may be associated with better survival. The invasiveness of BML is comparable to that of SLND.

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer. METHODS: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival. RESULTS: The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group. CONCLUSIONS: Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).

Characterization of Partially Covered Self-Expandable Metallic Stents for Esophageal Cancer Treatment: In Vivo Degradation.

Partially covered self-expandable metallic esophageal stent (SEMS) placement is the most frequently applied palliative treatment in esophageal cancer. Structural characterization of explanted 16 nitinol-polyurethane SEMS (the group of 6 females, 10 males, age 40-80) was performed after their removal due to dysfunction. The adverse bulk changes in the polymer structure were identified using differential scanning calorimetry (DSC), differential mechanical thermal analysis (DMTA), and attenuated total reflectance infrared spectroscopy (ATR-IR) and discussed in terms of melting point shift (9 °C), glass-transition shift (4 °C), differences in viscoelastic behavior, and systematic decrease of peaks intensities corresponding to C-H, C═O, and C-N polyurethane structural bonds. The scanning electron and confocal microscopic observations revealed all major types of surface degradation, i.e., surface cracks, peeling off of the polymer material, and surface etching. The changes in the hydrophobic polyurethane surfaces were also revealed by a significant decrease in wettability (74°) and the corresponding increase of the surface free energy (31 mJ/m2). To understand the in vivo degradation, the in vitro tests in simulated salivary and gastric fluids were performed, which mimic the environments of proximal and distal ends, respectively. It was concluded that the differences in the degradation of the proximal and distal ends of prostheses strongly depend on the physiological environment, in particular stomach content. Finally, the necessity of the in vivo tests for SEMS degradation is pointed out.

Early chemotherapy de-escalation strategy in patients with advanced-stage Hodgkin lymphoma with negative positron emission tomography scan after 2 escalated BEACOPP cycles.

INTRODUCTION Escalated BEACOPP (escBEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) significantly improves overall response rates (ORRs) and prolongs progression­free survival (PFS) in patients with advanced­stage Hodgkin lymphoma (HL). However, 6 to 8 cycles of escBEACOPP are associated with increased acute toxicity and late complications. OBJECTIVES We aimed to determine the role of early positron emission tomography-computed tomography (PET­CT) response assessment in a de­escalation strategy. PATIENTS AND METHODS We retrospectively analyzed 188 consecutive patients with advanced­stage HL treated at diagnosis. Patients received 2 cycles of escBEACOPP followed by an early PET­CT response assessment performed after 2 cycles of chemotherapy (PET2). Patients with an active disease continued therapy with escBEACOPP, while those with negative PET2 were de­escalated to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Radiotherapy was allowed in patients with stage IIBX. RESULTS PET2 allowed for de­escalation of therapy in 141 patients (75%). Their ORR was 92.2%, with a complete remission (CR) rate of 91.5%; 10­year PFS and overall survival (OS) were 87.2% and 95%, respectively. In the whole cohort, ORR was 87.8% (CR, 85.6%), while the 10­year PFS and OS were 79.3% and 89.4%, respectively. Hematological and thromboembolic complications were significantly more frequent in patients treated with 6 escBEACOPP cycles, including febrile neutropenia (25 patients, [53.2%] vs 7 [5%]), serious anemia (35 [74.5%] vs 11 [7.8%]), or thrombocytopenia (16 [34%] vs 7 [5%]) (P <0.001 for all comparisons with de­escalation strategy) as well as pulmonary embolism (3 [6.4%] vs 0) (P = 0.02). CONCLUSIONS The early de­escalation strategy allows for effective treatment of advanced HL, with a comparable efficacy to that of 6 to 8 cycles of escBEACOPP, but with significantly reduced toxicity.

Safety and efficacy of airway stenting in patients with malignant oesophago-airway fistula.

BACKGROUND: Close anatomical relationships between the oesophagus and the bronchial tree can lead to the formation of oesophageal fistula particularly in patients with advanced lung or oesophageal carcinoma. Stenting is a most often used treatment in such patients, but data regarding the relative value of unilateral (US) vs. double stenting (DS) are scarce. METHODS: Retrospective analysis of hospital records of patients with oesophageal fistula who underwent stenting between 2008 and 2016. In those in whom airway stenosis was >30%, double stenting (oesophagus and bronchial tree) was performed, whereas in those with lesser airway stenosis unilateral stenting (i.e., oesophagus only) was performed. In all patients, the degree of dysphagia, the degree of dyspnoea and the quality of life were assessed before and after the stenting. RESULTS: There were 46 patients, analysed, including 26 who underwent DS and 20 patients who underwent US. Both, DS and US resulted in significant improvement of dysphagia (2.72 vs. 1.2, P=0.0001 and 2.65 vs. 1.0, P=0.0001), dyspnoea (2.89 vs. 0.34, P=0.0001 and 1.71 vs. 0.09, P=0.0001) and performance score (53.2 vs. 66.3, P=0.0001 and 54.3 vs. 62.38, P=0.0001). Neither fistula type, nor stenting method, weight loss and gain, and BMI, had an effect on survival (P=0.34). Disease progression and recurrence of fistula requiring re-intervention occurred in 9 patients (19.5%). CONCLUSIONS: Double and unilateral stenting is an effective measure to alleviate dysphagia and dyspnoea in patients treated with malignant oesophageal fistula. In those with airway stenosis of ≤30%, stenting of the oesophagus only, instead of DS, is a safe method of treatment.

Preoperative thrombocytosis in surgically treated patients with non-small cell lung cancer.

Introduction Lung cancer is the most common cause of cancer­related death. Accurate and easy­to­use prognostic factors are necessary. Increased platelet count might be a potential prognostic factor. Objectives We aimed to investigate the relationship between thrombocytosis and stage of lung cancer and to assess the frequency and clinical importance of thrombocytosis in this patient group. Patients and methods We retrospectively analyzed hospital records of consecutive patients with non-small cell lung cancer (NSCLC) who underwent curative­intent pulmonary resections. Results Of 323 patients, 285 patients with NSCLC were selected (mean [SD] age, 66.55 [8.52] years; men, 63.86%). Squamous cell carcinoma was diagnosed in 130 patients (45.61%); adenocarcinoma, in 128 (44.91%); large cell carcinoma, in 16 (5.61%); and adenosquamous carcinoma, in 11 (3.86%). The prevalence of preoperative thrombocytosis in the whole sample was 10.18% (n = 29). Anemia was more common in patients with thrombocytosis compared with those without thrombocytosis (65.52% vs 30.08%; P <0.001). Thrombocytosis was found in 22.41% of patients with stage III+IV cancer and in 3.82% of those with stage I (P <0.001). Moreover, in patients with no metastases (N0, M0 according to the 7th edition of the TNM classification), thrombocytosis was more frequent in the group with stage II than in that with stage I cancer (3.85% vs 20.00%; P = 0.002). Thrombocytosis was also more frequent in patients with N2 than with N1 disease (9.76% vs 23.81%; P = 0.09). Conclusions Thrombocytosis is often observed in patients with NSCLC and is significantly associated with the higher stage of disease.

Safety and efficacy of oesophageal stenting with simultaneous percutaneous endoscopic gastrostomy as a supplementary feeding route in unresectable proximal oesophageal cancer.

INTRODUCTION: Proximally located oesophageal cancer poses an especially difficult problem in terms of restoration of patency and the stenting procedure. Supplementary percutaneous endoscopic gastrostomy (PEG) may be useful in these patients. AIM: To assess the safety of the stenting procedure in the proximal oesophagus in patients with unresectable upper oesophageal cancer, performed simultaneously with PEG insertion. MATERIAL AND METHODS: Patients with obstructing upper oesophageal tumours were scheduled for an oesophageal stenting procedure and simultaneous PEG insertion. Degree of dysphagia, body weight loss, daily energy requirement, body mass index and performance status before and after the stenting procedure as well as complications were assessed. RESULTS: Forty-five patients aged 19-88 years were included in the study. Six of them had a fistula to the trachea and underwent stenting of the oesophagus or both the oesophagus and the airway. The technical success rate was 100%. Following the procedure all patients were able to swallow fluids and semi-liquids, and PEG was used as the primary feeding route. Body mass index increased from 20.4 to 21.1 (p = 0.0001), body weight gain improved from -10.1 to +2.0 kg and metabolic requirements improved (p = 0.0001). Also, the Karnofsky score improved significantly (56.7 vs. 65.1, p = 0.0001). Mean survival time was 133 days (range: 36-378). CONCLUSIONS: Stenting of the proximal oesophagus with simultaneous PEG is a safe procedure, allowing the patients to resume oral intake of liquids whilst improving nutritional status and general performance, with an acceptable rate of complications.

Stenting in Palliation of Unresectable Esophageal Cancer.

BACKGROUND: The aim of this study was to analyze the safety and effectiveness of stenting using partially covered self-expandable stents in palliation of dysphagia in patients with unresectable esophageal cancer. METHODS: Retrospective analysis of hospital records of all patients who underwent esophageal stenting in the period 2008-2015 was performed. The study included patients with unresectable esophageal and esophagogastric cancer. RESULTS: There were 442 patients included. Mean age was 56 years (range 28-89), and 379 were males. In 40 (9.0%) patients, stenting was performed in the cervical, in 150 (39.3%)-in the middle thoracic, in 141 (31.9%)-in lower thoracic esophagus and in 111 (25.1%)-in the esophagogastric junction. Stenting resulted in significant alleviation of dysphagia grade (3.0 vs. 1.0, p = 0.00001). During the follow-up, 55 (12.4%) patients experienced recurrent dysphagia due to tumor or granulation tissue overgrowth, and in 18 (4.1%) patients, migration of the stent occurred, for which an independent risk factor was adjuvant chemo- and/or radiation therapy (p = 0.001). Minor complications included chest pain (54.5%), delayed complete stent expansion (12.0%), feeling of a foreign body (25.3%), hiccup (1.6%), gastroesophageal reflux (45.6%) and post-discharge pneumonia (2.5%). A feeling of a foreign body in the esophagus was significantly more common after stenting of the cervical esophagus (p = 0.0001), and hiccup was more common after stenting of the esophagogastric junction (p = 0.02). Major complications included bleeding (1.3%), respiratory insufficiency (0.7%), esophageal perforation (0.9%) and irregular heartburn (2.3%). Overall procedure-related mortality was 0.4%. The median survival time was 117.8 days (range 2-732). CONCLUSIONS: Stenting is an effective procedure in relieving dysphagia in patients with unresectable malignant esophageal stenosis and is associated with low rate of postoperative and long-term complications.

Residua of thymus in the mediastinum - clinical aspects - cadaveric study.

The main goal of this study was to investigate possible residua of thymic tissue in 100 adult cadavers with no thoracic pathology known before, by dissection of standard locations of thymic tissue in perithyroid, periaortic, peritracheal and retrotracheal spaces, as well as areas located next to the course of phrenic, vagus and left recurrent laryngeal nerves. Thus obtained tissue samples were studied by two pathologists independently. The remnants of the thymic tissue were found in 61 out of 100 specimens studied. It means that residua of ectopic thymic tissue is common, which may have a huge impact on the results of treatment of many diseases i.e. myasthenia gravis in course of thymoma.

A benchmarking project on the quality of previous guidelines about the management of malignant pleural effusion from the European Society of Thoracic Surgeons (ESTS) Pleural Diseases Working Group.

OBJECTIVES: In the European Society of Thoracic Surgeons (ESTS) survey about management of malignant pleural effusions (MPE), 56% of respondents are not informed of any relevant clinical guidelines and 52%, who are aware of the existence of guidelines, declared that they are in need of updating or revision. The ESTS Pleural Diseases Working Group developed a benchmarking project on quality of previous guidelines on the management of MPE. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument was used to assess each guideline. Each item was scored on a 7-point scale. Scores for each domain were calculated. Economic data for the nations which have issued the guidelines were collected from the Organisation for Economic Cooperation and Development health statistics database. RESULTS: Six guidelines fitted the inclusion criteria and were assessed. Five out of 6 guidelines were produced by a multinational collaboration. Observers would recommend only 2 guidelines with minimal modification. Two areas that received the best score were clarity of presentation and scope and purpose (objectives and health questions target population). The applicability of guideline domain had the lowest score. Multivariate analysis demonstrated that clarity of presentation, international guidelines and publication through medical journal were related to improved scores. A strong correlation was observed between the measures of economic status. CONCLUSIONS: The quality of guidelines assessed by the AGREE II criteria was found to be extremely variable. Guidelines achieving higher AGREE II scores were more likely to come from the European Union with the direct involvement of scientific societies in their development. It was also recognized that some fundamental unanswered questions remain about the management of MPE.

Endosonography­guided fine­needle aspiration in the diagnosis of sarcoidosis: a randomized study.

INTRODUCTION    There are no widely accepted standards for the diagnosis of sarcoidosis. OBJECTIVES    The aim of this study was to assess the relative diagnostic yield of endobronchial ultrasound fine-needle aspiration (EBUS -FNA) and endoscopic ultrasound fine needle aspiration (EUS -FNA), and to compare them with standard diagnostic techniques such as endobronchial biopsy (EBB), transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA), and mediastinoscopy. PATIENTS AND METHODS    This was a prospective randomized study including consecutive patients with clinical diagnosis of stage I or II sarcoidosis. EBB, TBLB, and TBNA were performed at baseline in all patients. Subsequently, patients were randomized to group A (EBUS -FNA) or group B (EUS -FNA). Next, a crossover control test was performed: all patients with negative results in group A underwent EUS -FNA and all patients with negative results in group B underwent EBUS -FNA. If sarcoidosis was not confirmed, mediastinoscopy was performed. RESULTS    We enrolled 106 patients, of whom 100 were available for the final analysis. The overall sensitivity and accuracy of standard endoscopic methods were 64% each. When analyzing each of the standard endoscopic methods separately, the diagnosis was confirmed with EBB in 12 patients (12%), with TBLB in 42 patients (42%), and with TBNA in 44 patients (44%). The sensitivity and accuracy of each endosonographic technique were significantly higher than those of EBB+TBLB+TBNA (P = 0.0112 vs P = 0.0134). CONCLUSIONS    The sensitivity and accuracy of EBUS -FNA and EUS -FNA are significantly higher than those of standard endoscopic methods. Moreover, the sensitivity and accuracy of EUS -FNA tend to be higher than those of EBUS -FNA.

Current practices in the management of malignant pleural effusions: a survey among members of the European Society of Thoracic Surgeons.

Objectives: Malignant pleural effusion (MPE) commonly complicates advanced malignancy and their exact management is still undefined. We undertook a survey to determine the current practice among members of the European Society of Thoracic Surgeons (ESTS). Methods: A cross-sectional survey focused on the current practice of management of MPE was developed by the authors. The questions were outlined after a review of the literature and circulated in an Internet-based survey format. Results: Computed tomography (125, 92%) and chest X-ray (106, 78%) are the most common imaging modalities performed in the initial evaluation. Video-assisted thoracoscopic surgery for washout and pleurodesis (93, 68%) was reported as the preferred approach to patients with uncomplicated MPE. Sixty-one (45%) of the responding colleagues routinely use large bore chest tubes for draining malignant effusions. Forty-nine (35%) surgeons would not apply suction to the drainage system, whilst 50 (37%) would use -2 kPa or less. Talc (124, 91%) is the most commonly used sclerosing agent for pleurodesis in the context of malignant pleural effusion. The practice of 76 (56%) of the respondents is not informed by any clinical guidelines, whilst 60 (44%) reported adhering to the 2010 British Thoracic Society Pleural Disease Guideline. Seventy-one (52%) declared that the guidance was in need of updating or revision. Conclusions: This survey demonstrates the lacking adoption of the existing clinical guidance in this field, as well as the need for more contemporary guidelines for a better-informed practice. The ESTS Working Group on the management of MPE has been established for this purpose.

Surgical Treatment Results of Burn-Related Oesophageal Strictures.

BACKGROUND: Post-burn oesophageal stricture is a late complication, which may require surgical intervention. The aim of the study was to compare gastric and colonic conduits and to evaluate the safety, efficacy and complications of these techniques. METHODS: Retrospective analysis of all patients treated for burn-related oesophageal strictures between 1989 and 2013. Oesophagectomy was performed via laparotomy and right thoracotomy, and/or cervical incision. RESULTS: Forty-six patients, including 29 men, aged 17-67 years (mean: 41 years), had burn-related oesophageal strictures. The post-operative follow-up period ranged between 3 months and 30 years. Colonic transposition was used in 23 patients. In 21 patients, the oesophageal substitute was introduced through the posterior mediastinum, and in two patients the retrosternal route was used. Gastric conduit in was used in 21 patients and jejunal interposition in one patient. One patient underwent segmental oesophageal resection with end-to-end anastomosis. One patient had necrosis of the colonic conduit with anastomotic leakage, two patients had oesophago-colonic anastomosis leakage, five developed anastomotic stenosis, and two had respiratory insufficiency. Among patients with a gastric conduit, anastomotic leakage occurred in four, cervical anastomotic stenosis occurred in two, and respiratory insufficiency occurred in three, and one patient had impaired gastric emptying that required surgical re-intervention. Operative mortality was three patients (6.5%). CONCLUSIONS: The use of colonic and gastric conduit is an effective and safe method for restoring the continuity of the gastrointestinal tract, with an acceptable rate of post-operative complications. Patients who undergo oesophageal resection for post-burn stricture require post-operative systematic endoscopic control.