Central-line-associated bloodstream infections, multi-drug-resistant bacteraemias and infection control interventions: a 6-year time-series analysis in a tertiary care hospital in Greece.

BACKGROUND: Central-line-associated bloodstream infections (CLABSIs) are serious healthcare-associated infections with substantial morbidity and hospital costs. AIM: To investigate the association between the incidence of CLABSIs, the implementation of specific infection control measures, and the incidence of multi-drug-resistant (MDR) bacteraemias in a tertiary care hospital in Greece from 2013 to 2018. METHODS: Analysis was applied for the following indices, calculated monthly: CLABSI rate; use of hand hygiene disinfectants; isolation rate of patients with MDR bacteria; and incidence of bacteraemias [total Gram-negative carbapenem-resistant Acinetobacter baumanii, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae; and Gram-positive meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci]. FINDINGS: The total number of bacteraemias from carbapenem-resistant Gram-negative pathogens was significantly correlated with an increased CLABSI rate for all (total) hospital departments [incidence rate ratio (IRR) 1.17, 95% confidence interval (CI) 1.05-1.31, P=0.006] and the adult intensive care unit (ICU) (IRR 1.37, 95% CI 1.07-1.75, P=0.013). In the adult ICU, every increase in the incidence of each resistant Gram-negative pathogen was significantly correlated with a decreased CLABSI rate (carbapenem-resistant A. baumanii: IRR 0.59, 95% CI 0.39-0.90, P=0.015; carbapenem-resistant K. pneumoniae: IRR 0.48, 95% CI 0.25-0.94, P=0.031; carbapenem-resistant P. aeruginosa: IRR 0.54, 95% CI 0.33-0.89, P=0.015). The use of hand disinfectants was correlated with a decreased CLABSI rate 1-3 months before the application of this intervention for all (total) hospital departments (IRR 0.80, 95% CI 0.69-0.93, P=0.005), and for scrub disinfectants in the current month for the adult ICU (IRR 0.34, 95% CI 0.11-1.03, P=0.057). Isolation of patients with MDR pathogens was not associated with the incidence of CLABSIs. CONCLUSION: Hand hygiene was associated with a significant reduction in the incidence of CLABSIs at the study hospital. Time-series analysis is an important tool to evaluate infection control interventions.

Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Epidemiology and diagnosis of pulmonary embolism in lung cancer patients: is there a role for age adjusted D-dimers cutoff?

Our knowledge about the incidence of pulmonary embolism (PE) and the performance of age adjusted D-dimers (Dd) cutoff amongst patients with lung cancer (LC) and suspected PE, remains limited. We retrospectively analyzed all clinically suspected patients who underwent computed tomography pulmonary angiography (CTPA) in a tertiary hospital during a 19 month period. Cancer diagnosis was established using ICD10 code. Eligible for Dd analysis were those tested up to 24 h prior to the scan. We analyzed 2549 patients (54.6% males, median age 68.8 years, IQR 57-78), 15.8% had active LC and 5.4% other cancers (oC), while 70% were scanned in the Emergency Department (ED) and the rest during hospitalization. Overall incidence of PE was 16%. LC, but not oC, increased significantly the risk for PE (OR 1.58, 95% CI 1.21-2.06). LC patients were less likely to have bilateral (aOR 0.16, 95% CI 0.07-0.4) or central PE (aOR 0.2, 95% CI 0.09-0.48). Amongst those diagnosed with PE in the ED, LC increased all-cause inhospital mortality (aOR 6.7, 95% CI 2.64-16.95). When age adjusted instead of conventional Dd cutoff was used for ruling out PE in the ED, specificity for LC patients increased (10.16% vs 3.91%) without false negative tests (negative likelihood ratio-NLR = 0). A higher cutoff of 1.13 mg/l raised specificity to 28.9%, with only one case missed (sensitivity: 97.4%, NLR: 0.09, 95% CI 0.01-0.64). LC increases the risk for PE and adversely affects prognosis. Age adjusted and probably an even higher, "LC adjusted" Dd cutoff, could increase the specificity of the test without compromising its sensitivity.

Inhibition of the Hedgehog pathway in lung cancer.

Inhibitors of the hedgehog pathway are effective in patients with basal cell carcinoma and a subgroup of patients with medulloblastoma with active hedgehog signaling. Despite preclinical work suggesting otherwise, clinical trials in solid tumors of epithelial origin have not shown added benefit with these drugs. Here, we review the preclinical and clinical data of hedgehog pathway inhibition in the most common histologic types of lung cancer. We focus on highlighting areas of uncertainty, where further research might define a niche for hedgehog pathway inhibition in patients with lung cancer.

Lung cancer patients' journey from first symptom to treatment: Results from a Greek registry.

BACKGROUND: To map the patients' journey from symptoms onset to treatment initiation for the most frequent histological types of lung cancer in Greece and describe the initial treatment that patients receive. METHODS: The primary data source was a Greek hospital-based registry. Demographic, anthropometric, lifestyle, and diagnostic-related characteristics as well as treatment-related data were extracted from the registry for patients diagnosed with Adenocarcinoma, Squamous and Small Cell Lung Cancer (SCLC). The time intervals from symptoms onset to diagnosis (StD), diagnosis to treatment initiation (DtT), symptoms onset to treatment initiation (StT) and surgery to post-surgery treatment (SRGtT) were estimated. RESULTS: 231, 120 and 122 patients were diagnosed with Adenocarcinoma, SCLC and Squamous, respectively. The percentage of patients diagnosed at stage III/IV ranged from 75% in Adenocarcinoma to 97.5% in SCLC (p < 0.001). The median (IQR) StD was 52 (28-104) days and no difference was detected across the three histological types (p = 0.301). Cough as first symptom was the only determinant of StD (p = 0.001). The median (IQR) DtT was 23 (13-36) days, with this time interval being shorter among patients with SCLC compared to patients with Adenocarcinoma and Squamous (p < 0.001). The median (IQR) StT was 81 (51-139) days. Almost one third of patients with Adenocarcinoma and Squamous were subjected first to surgery and the median (IQR) SRGtT was 42 (34-55) days. CONCLUSIONS: Our results indicate that time interval from symptoms onset to treatment initiation in Greece is substantially prolonged, highlighting the need for strategies to expedite lung cancer diagnosis and access to evidence-based treatment.

Cutaneous toxicities of antineoplastic agents: data from a large cohort of Greek patients.

PURPOSE: Cutaneous toxicities from novel anticancer treatments are an emerging problem in dermato-oncology. However, the prevalence of those toxicities and necessity of skin consultations are currently unknown. The purpose of our study was to perform an epidemiologic analysis of cutaneous toxicities that were referred to our cutaneous toxicity clinic in Athens, Greece. METHODS: All patients examined at the oncodermatology department over a 42-month period were included. Gender, age, type of cancer, type of antineoplastic treatment, and type of toxicity were recorded and analyzed. RESULTS: Four hundred fifty-nine patients (182 males, 277 females) with mean age (SD) 60.6 years (13.05) were included in the analysis. Six hundred seventy-two cutaneous toxicities were recorded. Chemotherapy-induced toxicities were the most commonly recorded incidents, with taxanes being the most commonly involved agent. Immune-related adverse events (IRAEs) have steadily increased over the past 3 years. Treatment modifications due to skin toxicities were more common in patients treated with targeted agents and immune checkpoint inhibitors than in those treated with chemotherapy. The toxicities that led to the most treatment modifications were acneiform eruptions and perionychias. The most common IRAEs recorded were psoriasis in 11 patients, followed by pruritus, macular rash, and lichenoid-type eruptions. In addition, 4 interesting cases of IRAEs are discussed. CONCLUSION: Antineoplastic treatments can lead to a wide range of cutaneous toxicities. Our study underlines the need for a multidisciplinary approach in oncologic patients. The dermatologists' role is crucial in effectively managing those reactions and preventing antineoplastic drug dose adjustments or discontinuation of treatment.

Anti-PD1/PDL1 induced psoriasis.

BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the treatment of late-stage malignancies. Despite its important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects known as immune-related adverse events. Skin toxicities are the most frequent immune-related adverse events during anti-PD1 blockade therapies. Among them, rare cases of psoriasis exacerbation have been reported. METHODS: We present the clinical characteristics of exacerbated psoriasis in 5 patients under anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4 males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1 (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a strong related family history (3/5 siblings). Four out of 5 patients experienced guttate lesions, though the most severe exacerbation was noted in the durvalumab group. Four out of 5 patients managed to continue treatment after close dermatologic monitoring, whereas 1 patient under durvalumab was forced to treatment delays owing to the severity of the skin reactions. Skin rashes appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS: Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although more severe flares were noted in patients treated with durvalumab. Not only personal but also related family history of psoriasis are significant risk factors and need to be outlined before treatment initiation. If such related history exists, strict skin surveillance can lead to the early diagnosis and treatment of any psoriatic exacerbations that could otherwise severely affect quality of life or even compromise therapeutic protocols and final prognosis.

Incidence and implications of chemotherapy related hand-foot syndrome.

INTRODUCTION: Hand-foot syndrome (HFS) is a well-established cutaneous adverse event of certain chemotherapeutic agents, mainly capecitabine, continuously infused 5-fluorouracil, docetaxel and pegylated liposomal doxorubicin. Erythema, dysesthesia, pain, cracking and desquamation located on palms and soles are the most characteristic manifestations. Although HFS is a reversible and non-life-threatening clinical condition, it can often affect patient's quality of life significantly, hence necessitating therapeutic modifications or even treatment discontinuation. Areas covered: This is review article on current data regarding the clinical characteristics, grading and management of HFS. Special focus has been given to recent literature studying novel therapeutic strategies. Expert opinion: Early recognition, patient education and supportive measures are considered as the key elements in the management of HFS. Up to date, treatment interruption and dose intensity reduction are the mainstay of HFS management. Many topical formulations and systemic treatment regimens have been proposed, with COX-2 inhibitors being the most promising agents. Nevertheless, large prospective randomized controlled trials are needed in order to agree on solid, evidence-based treatment algorithms.

Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma? A report of two cases.

INTRODUCTION: Basal cell carcinomas (BCCs) are the most common skin cancers in the Caucasian population. BCCs are in the majority of cases adequately managed with surgical excision, however a small subset of these tumours exhibit resistance to conventional therapies and progress to become locally advanced or even metastatic. Although Hedgehog inhibitors have been successfully used during the last few years in the treatment of locally advanced or metastatic BCCs, resistance to treatment remains an issue. Until this point, no biomarkers or clinical markers of drug resistance for Hedgehog inhibitors have been identified. METHODS AND RESULTS: We report two patients, a female patient with Gorlin syndrome and a male patient with locally advanced BCC, which received treatment with the Hedgehog inhibitor Vismodegib. These patients responded adequately to treatment and they both developed Hedgehog inhibitor-induced alopecia as an adverse event. However, after 2.5 and 1.5 years of treatment, respectively, the patients exhibited progressive disease that was accompanied by reversal of the Hedgehog inhibitor-induced alopecia, although still under treatment with Vismodegib. CONCLUSION: Although alopecia is a well-known adverse event associated with the administration of Hh inhibitors, data associated with the appearance and/or clinical severity of alopecia and the treatment efficacy of Hedgehog inhibitors are limited. The Hedgehog pathway plays an important role in the normal cycling of the hair follicles in adults and, therefore, the pathomechanism of Hedgehog inhibitor-induced alopecia is considered unique for this drug class. Based on the fact that Hh inhibitor resistance is associated with partial reactivation of the Hh pathway, it would not be illogical to suggest that reversal of Hh inhibitor-induced alopecia in patients under treatment with Hh inhibitors could serve as a clinical marker of drug resistance. However, this observation, as reported in this paper, is only limited in two patients and therefore more information is needed in order to assess its actual clinical importance.

PO-53 - Prospective evaluation of risk assessment models and biological markers of hypercoagulability for the identification of high VTE risk patients with lung adenocarcinoma. The ROADMAP study.

INTRODUCTION: In patients with lung adenocarcinoma (LA), metastasis (MTS), advanced stage and chemotherapy (CTx) are risk factors for thromboembolism (VTE). Routine thromboprophylaxis is not recommended but individualized risk assessment is encouraged. AIM: The selection of the most relevant hypercoagulability biomarkers (HB) for incorporation into the risk assessment models (RAM) for VTE. MATERIALS AND METHODS: Patients with documented LA eligible for CTx at distance of at least 3months from surgery or hospitalization were included. They were either CTx naive (NG) or had received CTx (OTG). Control group (CG) consisted of 30 healthy age & sex-matched individuals. We assessed them for thrombin generation (TG), P-Selectin, heparanase (HPA), procoagulant phospholipids (PPL), factor VIIa, D-Dimers (DDi) and Tissue Factor activity (TFa). RESULTS: Patients showed significantly shortened PPL and higher levels of TFa, DDi and HPA as compared to the CG. FVIIa levels were lower in patients compared to CG. The NG showed significantly shorter lag-time and lower ETP as compared to the OTG. It also showed significantly higher levels of HPA as compared to the OTG.The increase of TG and of HPA, P-Selectin, FVIIa was associated with the stage. Patients with MTS had higher levels of P-Selectin, TFa, DDi, FVIIa, TGT and HPA than those with localized or advanced disease.Patients with VTE had higher baseline levels of DDi, TGT, shorter PPL and lower levels of HPA as compared to those without. Patients who died within 3-months had higher baseline levels of DDi and lower HPA levels as compared to those who were alive. CONCLUSIONS: Increased PPL, TF pathway up regulation, DDi and HPA increase is a universal phenomenon in LA. CTx has an impact on TGT and HPA levels. Baseline values of TGT, PPL, HPA, DDi were related with mortality and thrombosis. The incorporation of HB in VTE-RAMs might improve their predictive value. This concept is being studied on an ongoing trial.

A phase II, open-label trial of bortezomib (VELCADE(®)) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: Bortezomib is a selective reversible proteasome inhibitor with proapoptotic effects. Preclinical and phase I clinical data suggest activity of bortezomib in NSCLC, either as monotherapy or in combination with chemotherapeutic agents including gemcitabine and cisplatin. METHODS: Chemotherapy-naïve patients with inoperable stage IIIB or IV NSCLC were administered bortezomib 1 mg/m(2) i.v. on days 1 and 8, and starting on day 21 (cycle 2), bortezomib (days 1 and 8) in combination with gemcitabine 1000 mg/m(2), (days 1 and 8), and cisplatin 70 mg/m(2) (day 1) in cycles of 21 days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity. RESULTS: Fifty-three patients [median age 66 years; 79.2 % male; 96.2 % stage IV; performance status (ECOG) 0/1 73.6/26.4 %; adenocarcinoma 45.3 %, squamous cell carcinoma 41.5 %] were enrolled. All patients were evaluable for toxicity and 43 for efficacy. Grade 3-4 hematologic toxicity consisted of neutropenia (22.6 %) and thrombocytopenia (17 %). Grade 2-4 non-hematologic adverse events were fever (9.4 %), fatigue (20.8 %), infection (18.9 %), and dyspnea (15.1 %). There was no >grade 2 neurotoxicity. Febrile neutropenia occurred in two (1.9 %) patients, and there were three possibly treatment-related deaths (5.4 %). In the intention-to-treat population, the objective response rate was 17 % (95 % CI 6.9-27.1 %). No difference in response rate was observed for squamous versus other histology (18.2 vs. 16.1 %, p = 0.845). The median progression-free survival was 2.5 months, the median overall survival 10.6 months and the 1-year survival rate 38.1 %. CONCLUSION: The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

Venous Thromboembolism in Patients Diagnosed With Lung Cancer.

PURPOSE: Considering the high prevalence of lung cancer, our purpose was to summarize the existing literature to identify the several factors that contribute to the increased risk of venous thromboembolism (VTE) in patients with lung cancer and to analyze the current recommendations for thromboprophylaxis and treatment of VTE in those patients. METHODS: We searched the Medline and EMBASE databases from February 1985 to February 2014 to identify retrospective and prospective randomized controlled studies that investigate one or more risk factors for VTEs in patients with lung cancer. RESULTS: A VTE is a major complication for patients diagnosed with lung cancer. The risk factors for VTE events in patients with lung cancer consist of cancer-related (histological type and stage of cancer), treatment-related (surgery, chemotherapy, angiogenic agents, and supportive care agents), and patient-related factors (comorbidities, immobility, performance status, and prior thrombosis). Low-molecular-weight heparins are recommended for long-term treatment of cancer-associated thrombosis. Duration of anticoagulant therapy beyond 6 months should be based on individual clinical evaluation. Thromboprophylaxis for patients with lung cancer during hospitalization and immediate postoperative period is well established. CONCLUSIONS: Efforts to assess thrombotic risk in patients with lung cancer may improve therapeutic and preventive strategies in the future, with final goal to minimize the burden and consequences of thrombotic events in patients with lung cancer.

Successful rapid desensitization to glatiramer acetate in a patient with multiple sclerosis

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2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

Hormones of adipose tissue and their biologic role in lung cancer.

INTRODUCTION: Adipose tissue secretes numerous bioactive peptides, collectively termed "adipocytokines" or "adipokines". Adipokines act in a paracrine, autocrine, or endocrine manner and regulate several physiological and pathological processes. Increasing evidence indicates that adipokines are implicated also in several malignancies, including lung cancer as well. AIM: The aim of this study is to summarize data concerning adipokines in lung cancer pathogenesis, prognosis and survival; the role of adipokines in lung cancer cachexia is also examined. MATERIALS AND METHODS: A systematic literature search was performed in the electronic database of Medline. Several studies and review articles met the inclusion criteria. RESULTS: Leptin and adiponectin are the best studied adipokines. The majority of the relevant studies has investigated the potential correlations mainly between leptin, adiponectin, and sometimes also resistin, and nutritional status, systemic inflammation of lung cancer or lung cancer cachexia and have also assessed their prognostic significance. Few other studies have studied genetic variations in leptin, leptin receptor and adiponectin genes and their association with lung cancer susceptibility and prognosis. The ongoing list of adipokines associated with lung cancer also includes resistin, chemerin, and visfatin. CONCLUSIONS: Increasing evidence points to the involvement of certain adipocytokines in lung cancer development, progression and prognosis. No conclusive evidence exists so far with regards to the role of adipocytokines in lung cancer cachexia. Future, longitudinal studies are warranted in order to clarify the role of adipocytokines in lung cancer and also uncover adipocytokines as novel therapeutic targets.

Structure and function of the oncologic boards in Greece. Description of the institutional and scientific frame; objective problems and difficulties.

PURPOSE: Oncology boards should constitute a routine in all hospitals that are dealing with the care of cancer patients. Unfortunately the procedure which should be followed to deal with this health problem has some deficiencies. METHODS: A literature review has recently been attempted, searching Internet databases by using key words such as oncologic board, medical legislation and medical ethics. RESULTS: Current mentality suggests that hiding the truth from the patient is wrong and unethical. However, in the Greek society, this is not the case as it seems not right to adopt foreign practices, i.e. to disclose directly to the patient all information relevant to his health status, the intended therapy and possible outcome. Instead, ambiguous information pass onto relatives who in turn bear the burden of informing the patient. CONCLUSIONS: The best solution would be the integration of the positive elements of the patient's awareness and the beneficial effects of the involvement of the Greek family in the general care of the cancer patient.

Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC.

Improvements in our understanding of the molecular biology of cancer have shifted management of lung cancer toward molecular-guided, individualized treatment. Development of epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, represent the best example of this approach. Erlotinib was tested as second/third line treatment in unselected population of patients and demonstrated a statistically significant prolongation of overall survival, while gefitinib was shown to be non-inferior to docetaxel as second line treatment. The discovery of EGFR activating mutations facilitated the selection of patients most likely to benefit from erlotinib/gefitinib. These drugs in patients with EGFR activating mutations offer an increased progression free survival and significantly higher response rates compared to chemotherapy. The purpose of this paper is to present the relevant clinical data, describe the predictive markers available for TKIs treatment in NSCLC, and describe the mechanisms associated with resistance to treatment with these agents.