Endocrine Immune-Related Adverse Events Are Independent Predictors of Survival in Patients with Lung Cancer.

Lung cancer (LC) is a serious health problem worldwide. Survival outcomes have improved over time due to the widespread use of novel therapeutic agents, including immune checkpoint inhibitors (ICIs). Endocrine immune-related adverse events (e-irAEs) are common in LC patients treated with ICIs. We performed a retrospective study of patients with LC who received treatment with ICIs at a tertiary referral center between January 2014 and October 2023. In total, 983 LC patients were included in the study. E-irAEs presented at a median time of 4.1 months and included hypothyroidism (15.6%), hyperthyroidism (4.3%), adrenal insufficiency (0.4%), hypophysitis (0.4%), and diabetes mellitus (0.2%). These toxicities were not related to the duration of treatment or the type of ICIs. Most (97.6%) e-irAEs were mild (grade 1-2). Median overall survival (OS) was higher in LC patients who experienced e-irAEs (31.6 months) compared to those who did not (10.8 months). The difference remained statistically significant in the 3-month (HR: 0.42) and 6-month landmark analysis (HR: 0.51). The OS advantage was observed in both patients with NSCLC (HR: 0.36) and SCLC (HR: 0.27). Additional research is needed to validate the role of e-irAEs as an independent predictor of survival outcomes in patients with LC.

Molecular Diagnostics and Treatment Patterns in Metastatic Non-small Cell Lung Cancer Patients: Real World Evidence from Greece: LACHESIS Study.

BACKGROUND/AIM: Lung cancer, primarily non-small cell lung cancer (NSCLC), is the leading cause of cancer deaths globally. In Greece in 2020, 8,960 new cases were reported. NSCLC's 5-year survival rates range from 54% (stage I) to less than 2% (stage IV); however, innovative therapies like immune check points inhibitors (ICIs) and targeted treatments have notably enhanced outcomes. The aim of this study was to assess the 1st and 2nd line treatment patterns with the introduction of new treatment modalities. Additionally, we evaluated biomarker testing approaches in NSCLC. PATIENTS AND METHODS: LACHESIS was a retrospective multinational study, collecting and analyzing data from adult patients from Russia, Bulgaria, and Greece with metastatic NSCLC either newly diagnosed or relapsed from earlier stages, who had the option to undergo biomarker testing (genetic alterations/programmed death-ligand 1 protein expression levels, PD-L1), and who received 1st line treatment for squamous (SQ) or non-squamous (N-SQ) NSCLC. Subsequent lines of therapy were also reported. RESULTS: The Greek site registered retrospective data from 250 NSCLC patients, of whom 206 were newly diagnosed (ND) metastatic NSCLC patients and 44 were patients relapsed from earlier stages. Seventy-two had SQ NSCLC and 169 had N-SQ NSCLC. For these patients, treatment patterns including immunotherapy±chemotherapy combinations were recorded. Biomarker testing patterns, including genetic alterations and PD-L1 expression levels were also documented. CONCLUSION: LACHESIS provides treatment patterns and biomarker testing data. Greek patients were treated according to international guidelines, with immunotherapy as a viable option, particularly for PD-L1 levels over 50%. Biomarker testing, crucial for non-squamous (N-SQ) cases, should yield timely results for driver mutations, prioritizing patient benefits.

The safety and potential efficacy of exosomes overexpressing CD24 (EXO-CD24) in mild-moderate COVID-19 related ARDS.

INTRODUCTION: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier. METHODS: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 109 or 1010 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria. RESULTS: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO2) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group. CONCLUSIONS: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo.

Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma virus (KRAS) is the most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC). For many years, KRAS was considered "undruggable" due to its structure and difficult targeting. However, the discovery of the switch II region in the KRAS-G12C-mutated protein has changed the therapeutic landscape with the design and development of novel direct KRAS-G12C inhibitors. Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. Despite promising results, the efficacy of these novel inhibitors is limited by mechanisms of resistance. Ongoing studies are evaluating combination strategies for overcoming resistance. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.

Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets.

Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are continuously explored; these include ATR inhibitors, which target the ATR kinase involved in the DNA damage response (DDR) pathway, and CHK1/2 inhibitors, which target the Checkpoint Kinase 1/2 (CHK1/2) involved in cell cycle arrest and DNA repair. ATR and CHK1/2 inhibitors show potential as prospective treatments for TNBC by focusing on the DDR and interfering with cell cycle regulation in cancer cells. Preliminary preclinical and clinical findings suggest that when combined with chemotherapy, ATR and CHK1/2 inhibitors demonstrate significant anti-proliferative efficacy against TNBC. In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed.

Robotic Bronchoscopy in Lung Cancer Diagnosis.

BACKGROUND: The widespread use of chest CT has increased the number of detected pulmonary nodules. Nodules with intermediate risk of malignancy warrant further evaluation with PET-CT or sampling. Although sampling with conventional bronchoscopy presents lower complication rates compared to transthoracic needle biopsy (TTNB), it is limited by the inability to reach distal airways. To overcome this shortcoming, a new bronchoscopic technique named robotic bronchoscopy (RB) has emerged. METHODS: A literature review was used to clarify the rationale behind RB emergence, describe RB procedure, and summarize data regarding its efficacy and safety. RESULTS: The FDA has approved three RB platforms for clinical use. RB is safe, presenting a mortality and complication rate of 0% and 0-8.1%, respectively. Common complications include pneumothorax (0-5.7%) and minor bleeding (0-3.2%). However, its diagnostic yield remains lower than that of TTNB. CONCLUSIONS: RB is a promising bronchoscopic technique that aims to overcome the limitations of conventional bronchoscopy and improve upon the current techniques of guided bronchoscopy for the investigation of pulmonary nodules. Despite the lower complication rate, current evidence suggests a lower diagnostic yield compared to TTNB. Additional studies are required to adequately evaluate the role of RB in the diagnosis of pulmonary nodules.

Lung Cancer Proteogenomics: Shaping the Future of Clinical Investigation.

BACKGROUND: Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes. METHODS: A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis. RESULTS: As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets. CONCLUSIONS: An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer.

The Gap of Health Inequalities Amongst Lung Cancer Patients of Different Socioeconomic Status: A Brief Reference to the Greek Reality.

Lung cancer treatment and patient care are constantly improving, but it remains doubtful whether this applies equally to all socioeconomic groups. It is nowadays well established that there are socioeconomic inequalities regarding lung cancer incidence, screening, effective treatment, overall survival, and prognosis. One of the key contributing factors to low socioeconomic status is low education. Low educational level is correlated with several factors, such as smoking habits, bad lifestyle behaviors, lower paid and unhealthier occupations, polluted neighborhoods, and genetic-familial risk, that lead to increased lung cancer incidence. The disparities regarding lung cancer care are further enhanced by stigma. On this basis and inspired by the gap in health equality among the Greek population, the Greek Society of Lung Cancer initiated a campaign, "MIND THE GAP", to help increase awareness and minimize the gap associated with lung cancer, both in Greece and across Europe. The aim of this review is to explore the gap of health inequalities regarding lung cancer incidence and prognosis between patients of different SES and its root of causality. Key pivotal actions towards bridging this gap are reviewed as well.

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes.

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

Utilizing nullomers in cell-free RNA for early cancer detection.

Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99.

Lung Cancer Related Thrombosis (LCART): Focus on Immune Checkpoint Blockade.

Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors.

Dietary Approach of Patients with Hormone-Related Cancer Based on the Glycemic Index and Glycemic Load Estimates.

Hormone-related cancers, namely breast, endometrial, cervical, prostate, testicular, and thyroid, constitute a specific group of cancers dependent on hormone levels that play an essential role in cancer growth. In addition to the traditional risk factors, diet seems to be an important environmental factor that partially explains the steadily increased prevalence of this group of cancer. The composition of food, the dietary patterns, the endocrine-disrupting chemicals, and the way of food processing and preparation related to dietary advanced glycation end-product formation are all related to cancer. However, it remains unclear which specific dietary components mediate this relationship. Carbohydrates seem to be a risk factor for cancer in general and hormone-related cancers, in particular, with a difference between simple and complex carbohydrates. Glycemic index and glycemic load estimates reflect the effect of dietary carbohydrates on postprandial glucose concentrations. Several studies have investigated the relationship between the dietary glycemic index and glycemic load estimates with the natural course of cancer and, more specifically, hormone-related cancers. High glycemic index and glycemic load diets are associated with cancer development and worse prognosis, partially explained by the adverse effects on insulin metabolism, causing hyperinsulinemia and insulin resistance, and also by inflammation and oxidative stress induction. Herein, we review the existing data on the effect of diets focusing on the glycemic index and glycemic load estimates on hormone-related cancers.

Exploring the Use of a Digital Platform for Cancer Patients to Report Their Demographics, Disease and Therapy Characteristics, Age, and Educational Disparities: An Early-Stage Feasibility Study.

INTRODUCTION: The increasing burden of cancer, the development of novel therapies, and the COVID-19 pandemic have made cancer care more complex. Digital innovation was then pushed toward developing platforms to facilitate access to cancer care. Age, education, and other disparities were, however, shown to limit the use of the digital health innovation. The aim of this early-stage feasibility study was to assess whether Greek cancer patients would register at CureCancer and self-report their demographics, disease and therapy characteristics, and socioeconomic issues. The study was organized by the Hellenic Society of Medical Oncology. METHODS: Patients from nine cancer centers were invited to register on the CureCancer platform and complete an anonymous questionnaire on demographics, disease and therapy characteristics, and socioeconomic issues. Patients were also encouraged to upload, in a secure area for them, their medical files and share them with their physicians. They were then asked to comment on their experience of registration and how easy it was to upload their medical files. RESULTS: Of the 159 patients enrolled, 144 (90.56%) registered, and 114 of those (79.16%) completed the questionnaire, suggesting that the study is feasible. Users' median age was 54.5 years, and 86.8% of them were university and high school graduates. Most patients (79.8%) reported their specific type of cancer diagnosis, and all reported their therapy characteristics. Breast and lung cancers were the most common. A total of 87 patients (76.3%) reported being on active cancer therapy, 46 (40.4%) had metastatic disease, and 51 (44.7%) received supportive care medications. Eighty-one (71.05%) patients received prior cancer therapies, and twenty-seven recalled prior supportive care medications. All patients reported visiting non-oncology Health Care Professionals during the study. Nineteen of 72 (26.39%) patients who worked prior to cancer diagnosis changed work status; 49 (42.98) patients had children under 24 years; and 16 (14%) patients lived alone. Nine (7.9%) patients were members of patient associations. Registration was "much/very much" easy for 98 (86.0%) patients, while 67 (58.8%) had difficulties uploading their files. Patients commented on the well-organized data access, improved communication, feeling safe, medication adherence, interventions from a distance, and saving time and money. Over 80% of patients "preferred the digital way". DISCUSSION: A total of 114 patients succeeded in registering on the digital platform and reporting their demographics, disease and therapy characteristics, and socioeconomic issues. Age and educational disparities were disclosed and highlighted the need for educational programs to help older people and people of lower education use digital innovation. Health care policy measures would support patients' financial burden associated with work changes, living alone, and children under 24 years old at school or college. Policy actions would motivate patients to increase their participation in patient associations. According to the evidence DEFINED framework, the number of patients, and the focus on enrollment, engagement, and user experience, the study fulfills actionability level criterion 1.

Deep computational image analysis of immune cell niches reveals treatment-specific outcome associations in lung cancer.

The tumor immune composition influences prognosis and treatment sensitivity in lung cancer. The presence of effective adaptive immune responses is associated with increased clinical benefit after immune checkpoint blockers. Conversely, immunotherapy resistance can occur as a consequence of local T-cell exhaustion/dysfunction and upregulation of immunosuppressive signals and regulatory cells. Consequently, merely measuring the amount of tumor-infiltrating lymphocytes (TILs) may not accurately reflect the complexity of tumor-immune interactions and T-cell functional states and may not be valuable as a treatment-specific biomarker. In this work, we investigate an immune-related biomarker (PhenoTIL) and its value in associating with treatment-specific outcomes in non-small cell lung cancer (NSCLC). PhenoTIL is a novel computational pathology approach that uses machine learning to capture spatial interplay and infer functional features of immune cell niches associated with tumor rejection and patient outcomes. PhenoTIL's advantage is the computational characterization of the tumor immune microenvironment extracted from H&E-stained preparations. Association with clinical outcome and major non-small cell lung cancer (NSCLC) histology variants was studied in baseline tumor specimens from 1,774 lung cancer patients treated with immunotherapy and/or chemotherapy, including the clinical trial Checkmate 057 (NCT01673867).

European Epidemiology of Pleural Mesothelioma-Real-Life Data From a Joint Analysis of the Mesoscape Database of the European Thoracic Oncology Platform and the European Society of Thoracic Surgery Mesothelioma Database.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with increasing prevalence and poor prognosis. Real-life data are a unique approach to reflect the reality of PM epidemiology, treatment, and prognosis in Europe. METHODS: A joint analysis of the European Thoracic Oncology Platform Mesoscape and the European Society of Thoracic Surgeons (ESTS) databases was performed to better understand the characteristics and epidemiology of PM, including histologic subtype, staging, and treatment. Overall survival (OS) was assessed, adjusting for parameters of clinical interest. RESULTS: The analysis included 2766 patients (Mesoscape: 497/10 centers/ESTS: 2269/77 centers). The primary histologic subtype was epithelioid (71%), with 57% patients on stages III to IV. Within Mesoscape, the patients received either multimodality (59%) or palliative intention treatment (41%). The median follow-up was 47.2 months, on the basis of 1103 patients (Mesoscape: 491/ESTS: 612), with 823 deaths, and median OS was 17.4 months. In multivariable analysis, female sex, epithelioid subtype, and lower stage were associated with longer OS, when stratifying by cohort, age, and Eastern Cooperative Oncology Group Performance Status. Within Mesoscape, multimodality treatment including surgery was predictive of longer OS (hazard ratio = 0.56, 95% confidence interval: 0.45-0.69), adjusting for sex, histologic subtype, and Eastern Cooperative Oncology Group Performance Status. Overall, surgical candidates with a macroscopic complete resection had a significantly longer median OS compared with patients with R2 (25.2 m versus 16.4 m; log-rank p < 0.001). CONCLUSIONS: This combined European Thoracic Oncology Platform/ESTS database analysis offers one of the largest databases with detailed clinical and pathologic outcome. Our finding reflects a benefit for selected patients that undergo multimodality treatment, including macroscopic complete resection, and represents a valuable resource to inform the epidemiology and treatment options for individual patients.

Takotsubo Cardiomyopathy in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Summary of Included Cases.

BACKGROUND: There are emerging reports of Takotsubo syndrome (TTS) in cancer patients treated with immune checkpoint inhibitors (ICIs); however, the association of the two remains uncertain. METHODS: A systematic literature review was performed in the PubMed database and web sources (Google Scholar) according to the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. Case reports/series or studies including cancer patients treated with ICIs and presenting with TTS were considered. RESULTS: Seventeen cases were included in the systematic review. Most patients were males (59%) with median age of 70 years (30-83). Most common tumor types were lung cancer (35%) and melanoma (29%). Most patients were on first-line immunotherapy (35%) and after the first cycle (54%) of treatment. The median time on immunotherapy at the time of TTS presentation was 77 days (1-450). The most used agents were pembrolizumab and the combination of nivolumab-ipilimumab (35%, respectively). Potential stressors were recognized in 12 cases (80%). Six patients (35%) presented with concurrent cardiac complications. Corticosteroids were used in the management of eight patients (50%). Fifteen patients (88%) recovered from TTS, two patients (12%) relapsed, and one patient died. Immunotherapy was reintroduced in five cases (50%). CONCLUSION: TTS may be associated with immunotherapy for cancer. Physicians should be alert for TTS diagnosis in any patient with myocardial infarction-like presentation under treatment with ICIs.

Efficacy of Tocilizumab in Severely Ill COVID-19 Patients With Rapid Respiratory Deterioration: A Single Center Experience During the Third Pandemic Wave in Greece.

BACKGROUND/AIM: Immunomodulatory therapy with Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 receptor-alpha, has been endorsed by the World Health Organization and other major regulatory bodies, as part of the standard-of-care therapy for severe or critical COVID-19 cases despite discordant trial outcomes. The aim of the present study was to report the experience of our center regarding TCZ routine use in severely ill COVID-19 patients who were hospitalized during the third pandemic wave in Greece. PATIENTS AND METHODS: From March 2021 to December 2021, we retrospectively analyzed COVID-19 patients with radiological findings of pneumonia and signs of rapid respiratory deterioration that were treated with TCZ. The primary outcome included the risk of intubation or/and death in TCZ-treated patients compared to matched controls. RESULTS: TCZ administration was neither predictive of intubation and/or death [OR=17.5 (95% CI=0.47-652.2; p=0.12)] or associated with fewer events (p=0.92) in multivariate analysis. CONCLUSION: Our single-center real-life experience is in line with recently published research, revealing no benefit from TCZ routine use in severely or critically ill patients with COVID-19.

Clinical Outcomes Beyond 1L EGFR-TKI Progression in mNSCLC: Final Results of the Real-World Study 'LUNGFUL'.

BACKGROUND/AIM: Real-world data on the EGFR mutational profile upon progression after first/second-generation EGFR-TKI treatment in patients with advanced non-small-cell lung cancer (NSCLC) and treatment strategies employed thereon are needed. PATIENTS AND METHODS: This observational study was conducted in 23 hospital-based lung cancer Centers in Greece (protocol code: D133FR00126). Ninety-six eligible patients were consecutively enrolled between July-2017 and September-2019. Re-biopsy was performed in 18 of 79 patients who tested T790M-negative in liquid biopsy after progression in the first-line (1L) setting. RESULTS: Of the study population, 21.9% tested T790M-positive, while 72.9% proceeded to 2L treatment, mainly comprising of a third-generation EGFR-TKI (48.6%), a switch to chemotherapy (30.0%), or chemo-immunotherapy (17.1%). The objective response rate (ORR) in 2L was 27.9% in T790M-negative and 50.0% in T790M-positive patients. Of evaluable patients, 67.2% experienced disease progression; median progression-free survival (PFS) was 5.7 and 10.0 months among T790M-negative and positive patients, respectively. Among T790M-negative patients, longer median PFS and post-progression survival were observed with third-generation EGFR-TKI treatment. CONCLUSION: Mutational status and treatment strategy were identified as critical determinants of clinical outcomes in the 2L-setting of EGFR-mutated NSCLC patients in real-world settings in Greece, with early diagnosis, appropriate molecular testing and high-efficacy treatments at first lines positively affecting ORR and PFS.

Presepsin as a diagnostic and prognostic biomarker of severe bacterial infections and COVID-19.

We aimed to develop presepsin as a marker of diagnosis of severe infections of either bacterial and viral origin. The derivation cohort was recruited from 173 hospitalized patients with acute pancreatitis or post-operative fever or infection suspicion aggravated by at least one sign of the quick sequential organ failure assessment (qSOFA). The first validation cohort was recruited from 57 admissions at the emergency department with at least one qSOFA sign and the second validation cohort from 115 patients with COVID-19 pneumonia. Presepsin was measured in plasma by the PATHFAST assay. Concentrations more than 350 pg/ml had sensitivity 80.2% for sepsis diagnosis in the derivation cohort (adjusted odds ratio 4.47; p < 0.0001). In the derivation cohort, sensitivity for 28-day mortality prognosis was 91.5% (adjusted odds ratio 6.82; p: 0.001). Concentrations above 350 pg/ml had sensitivity 93.3% for the diagnosis of sepsis in the first validation cohort; this was 78.3% in the second validation cohort of COVID-19 aiming at the early diagnosis of acute respiratory distress syndrome necessitating mechanical ventilation. The respective sensitivity for 28-day mortality was 85.7% and 92.3%. Presepsin may be a universal biomarker for the diagnosis of severe infections of bacterial origin and prediction of unfavorable outcome.

Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond.

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC.