Konstantinos Zarogoulidis

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): current literature review

Asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases, very common in general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma, but is progressive and irreversible in COPD. Asthma and COPD may overlap and converge, especially in older people [overlap syndrome-asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS)]. Although ACOS accounts approximately 15-25% of the obstructive airway diseases, is not well recognised because of the structure of clinical trials. COPD studies exclude asthma patients and asthma studies exclude COPD patients, respectively. It is crucial to define asthma, COPD and overlap syndrome (ACOS), as notable clinical entities, which they share common pathologic and functional features, but they are characterized from differences in lung function, acute exacerbations, quality of life, hospital impact and mortality.

Inhaled chemotherapy in lung cancer: future concept of nanomedicine.

Regional chemotherapy was first used for lung cancer 30 years ago. Since then, new methods of drug delivery and pharmaceuticals have been investigated in vitro, and in animals and humans. An extensive review of drug delivery systems, pharmaceuticals, patient monitoring, methods of enhancing inhaled drug deposition, safety and efficacy, and also additional applications of inhaled chemotherapy and its advantages and disadvantages are presented. Regional chemotherapy to the lung parenchyma for lung cancer is feasible and efficient. Safety depends on the chemotherapy agent delivered to the lungs and is dose-dependent and time-dependent. Further evaluation is needed to provide data regarding early lung cancer stages, and whether regional chemotherapy can be used as neoadjuvant or adjuvant treatment. Finally, inhaled chemotherapy could one day be administered at home with fewer systemic adverse effects.

Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. METHODS In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. FINDINGS Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). INTERPRETATION Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. FUNDING GlaxoSmithKline Biologicals SA.

Treatment of non-small cell lung cancer (NSCLC)

Radical surgery is the standard of care for fit stage I non-small cell lung cancer (NSCLC) patients. Adjuvant treatment should be offered only as part of an investigation trial. Stage II and IIIA adjuvant cisplatin-based chemotherapy remains the gold standard for completely resected NSCLC tumors. Additionally radiotherapy should be offered in patients with N2 lymph nodes. In advanced stage IIIB/IV or inoperable NSCLC pts, a multidisciplinary treatment should be offered consisted of 4 cycles of cisplatin-based chemotherapy plus a 3(rd) generation cytotoxic agent or a cytostatic (anti-EGFR, anti-VEGFR) drug.

Right heart failure post left ventricular assist device implantation

Right heart failure (RHF) is a frequent complication following left ventricular assist device (LVAD) implantation. The incidence of RHF complicates 20-50% (range, 9-44%) of cases and is a major factor of postoperative morbidity and mortality. Unfortunately, despite the fact that many risk factors contributing to the development of RHF after LVAD implantation have been identified, it seems to be extremely difficult to avoid them. Prevention of RHF consists of the management of the preload and the afterload of the right ventricle with optimum inotropic support. The administration of vasodilators designed to reduce pulmonary vascular resistance is standard practice in most centers. The surgical attempt of implantation of a right ventricular assist device does not always resolve the problem and is not available in all cardiac surgery centers.

Interleukin-8 and interleukin-17 for cancer.

Pro-inflammatory cytokines have been associated with chronic inflammation and inflammatory diseases. Increased levels of interleukins (ILs) have been associated with inflammatory disease exacerbation. ILs levels have been observed to be associated with advance stage cancer for several types of cancer and a poor prognostic maker for malignant disease. Moreover; increased levels of cytokines induce tumorigenesis. There are several paradigms such as the hepatocellular carcinoma induced from chronic inflammation of an underlying hepatitis. In the current review, we will focus on IL-8 and -17. These two ILs as in the case of others, induce neo-angiogenesis through activation of the vascular endothelial growth (VEGF) factor pathway. Additionally, they enhance the activity of matrix metalloproteinase-2 and –9 (MMP-2,-9) which in turn increase the metastatic activity of the underlying malignancy. Inhibition of cytokine production could be a potential treatment both for chronic inflammatory diseases and tumor modulation. Local microenvironment modulation could be applied in surgery resected patients as in the case of lung cancer in order to enhance the local immune activity.

Catamenial pneumothorax: a rare entity? Report of 5 cases and review of the literature

OBJECTIVE Spontaneous recurrent pneumothorax during menstruation is reported as catamenial pneumothorax. It is encountered in 3-6% of spontaneous pneumothorax cases among menstruating women. The percentage among women referred for surgery is significantly higher (25-30%). Although it usually involves the right-side (85-95%) it can be left-sided or bilateral. It is associated with diaphragmatic perforations and/or thoracic endometriosis. There is pelvic endometriosis in up to 30-51% of cases. The lesions that are not always found may present as small or larger holes at the central tendon of the diaphragm, as red, blueberry, brown spots or larger nodules at the diaphragm, the visceral or parietal pleura. Lesion histology may reveal endometriosis. We present 5 cases of catamenial pneumothorax treated surgically during the last 6 years. PATIENTS AND METHODS Five women, with a mean age of 34+/-9.9 years (median 38, range, 19-45 years) presented with right-sided recurrent catamenial pneumothorax. In 3 patients diaphragmatic perforation(s) were found; perforation suturing (n=1), and diaphragmatic plication reinforced with bovine pericardial patch (n=1) were performed. All patients underwent atypical resection of upper and/or middle lobe segments of lung parenchyma that appeared abnormal (haemorrhagic/emphysematous or blebs). Four patients underwent pleurodesis and 1 patient underwent pleurectomy. Four interventions were performed through video assisted thoracoscopic surgery, while diaphragmatic plication was performed through a video assisted mini-thoracotomy. Histology did not reveal endometriosis tissue. RESULTS The postoperative course was uneventful. The patients were extubated in theatre and were discharged home at a mean of 7+/-4 days (median 6 days, range, 4-14 days). Two of them received hormonal therapy [Gonadotropin Releasing Hormone (GnRH) analogue] postoperatively. At a follow-up of 14.16 patient-years (mean 2.83+/-1.08 years, range, 1.33-3.83 years) there was recurrence, 6.5 months postoperatively, in one patient that had not undergone closure of a tiny diaphragmatic hole and had not received hormonal treatment postoperatively. She was treated medically (amenorrhea for 6 months with GnRH analogue) and had no further recurrences (in 3.3 years). CONCLUSIONS Surgery is the treatment of choice of catamenial pneumothorax. It should aim to complete management of all lesions. The most common complication is recurrence. Early diagnosis and multidisciplinary treatment including hormonal therapy may be beneficial in high risk patients.

Extrapelvic endometriosis: a rare entity or an under diagnosed condition?

Endometriosis is a clinical entity characterized by the presence of normal endometrial mucosa abnormally implanted in locations other than the uterine cavity. Endometriosis can be either endopelvic or extrapelvicdepending on the location of endometrial tissue implantation. Despite the rarity of extrapelvic endometriosis, several cases of endometriosis of the gastrointestinal tract, the urinarytract, the upper and lower respiratory system, the diaphragm, the pleura and the pericardium, as well as abdominal scars loci have been reported in the literature. There are several theories about the pathogenesis and the pathophysiology of endometriosis. Depending on the place of endometrial tissue implantation, endometriosis can be expressed with a wide variety of symptoms. The diagnosis of this entity is neither easy nor routine. Many diagnostic methods clinical and laboratory have been used, but none of them is the golden standard. The multipotent localization of endometriosis in combination with the wide range of its clinical expression should raise the clinical suspicion in every woman with periodic symptoms of extrapelvic organs. Finally, the therapeutic approach of this clinical entity is also correlated with the bulk of endometriosis and the locum that it is found. It varies from simple observation, to surgical treatment and treatment with medication as well as a combination of those.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1968087883113362.

Review of mitral valve insufficiency: repair or replacement

Mitral valve (MV) dysfunction is the second-most common clinically significant form of valvular defect in adults. MV regurgitation occurs with the increasing frequency of degenerative changes of the aging process. Moreover, other causes of clinically significant MV regurgitation include cardiac ischemia, infective endocarditis and rhematic disease more frequently in less developed countries. Recent evidence suggests that the best outcomes after repair of severe degenerative mitral regurgitation (MR) are achieved in asymptomatic or minimally symptomatic patients, who are selected for surgery soon after diagnosis on the basis of echocardiography. This review will focus on the surgical management of mitral insufficiency according to its aetiology today and will give insight to some of the perspectives that lay in the future.

1173OMAGRIT, A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE III STUDY TO ASSESS THE EFFICACY OF THE RECMAGE-A3 + AS15 CANCER IMMUNOTHERAPEUTIC AS ADJUVANT THERAPY IN PATIENTS WITH RESECTED MAGE-A3-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC)

ABSTRACT Aim: Adjuvant chemotherapy (ACT) is the standard of care for Stage II and IIIA NSCLC, and for high risk Stage IB NSCLC. However, the 5-year disease-free survival remains poor (35-50%) and about half of the patients will not receive ACT for various reasons. This Phase III trial investigated whether the recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) as adjuvant therapy improved disease-free survival (DFS) in patients with resected NSCLC. Methods: MAGRIT was a randomized, double-blind, placebo-controlled trial in patients with completely resected MAGE-A3-positive NSCLC Stages IB, II, and IIIA (TNM version 6) and who did or did not receive ACT. Patients were randomly assigned (2:1) to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month (m) treatment period. The three co-primary endpoints were DFS in the overall and in the no-ACT population and DFS in patients with a potentially predictive gene signature (GS). Results: Out of 13,849 patients screened, 4,210 patients had a MAGE-A3 positive tumour sample and 2,272 patients were randomised and treated. Overall, 52% of the patients received ACT; 47%, 36% and 17% were Stage IB, II and IIIA, respectively. Median age was 63 years and 24% of patients were females. Mean relative dose intensity was above 98% in both groups throughout the treatment period. Median follow-up at the time of final analysis was 38.8m. Median DFS was 60.5m and 57.9m respectively for MAGE-A3 CI and placebo (HR 1.024, 95% CI 0.891-1.177; p = 0.7379). In patients who did not receive ACT, median DFS was 58.0m and 56.9m for MAGE-A3 CI and placebo groups, respectively (HR 0.970, 95% CI 0.797-1.179; p = 0.7572). The rate of grade ≥ 3 adverse events (16%) did not differ between treatment groups. Conclusions: Treatment of NSCLC patients with MAGE-A3 CI did not increase DFS compared to placebo in either the overall population or in patients who did not receive ACT. Due to the absence of treatment effect, a GS predictive of clinical benefit to MAGE-A3 CI could not be identified. Funding Source: GlaxoSmithKline Biologicals SA. Disclosure: J.F. Vansteenkiste: Pr Vansteenkiste received GSK fees as Primary investigator for the MAGRIT study; B. Cho: Dr Cho received consultancy fees from Novartis and Boehringer-ingelheim; T. De Pas: No conflicts of interest. Fee received from GSK as member of steering committee of the study; J. Jassem: Dr Jassem received grant and personal fees for Consultancy from GSK; M. Yoshimura: Pr Yoshimura received GSK fees as Primary investigator for the MAGRIT and PEARL study; H. Nakayama: Dr Nakayama received GSK fees as Primary investigator for the MAGRIT and PEARL study; T. Mitsudomi: Dr Mitsudomi received personal fees from GSK for an advisory role; B. Spiessens: Bart Spiessens is employee of GSK and do own stock options of GSK; V. Brichard: Dr Birchart is GSK employee and do own Stock options from GSK; C. Debruyne: Dr Debruyne is GSK employee and do own GSK stock options; P. Therasse: GSK employee and Stock options owner; N. Altorki: Dr Altorki received GSK fees for trial conduct of GSK studies. All other authors have declared no conflicts of interest.