NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment. METHODS: NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 µg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000-1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60-75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266). FINDINGS: Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1-24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2-9·9] in the NGR-hTNF group vs 8·0 months [6·6-8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75-1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related. INTERPRETATION: The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis. FUNDING: MolMed.

Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study.

BACKGROUND: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. METHODS: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing. FINDINGS: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. INTERPRETATION: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. FUNDING: Merck and Pfizer.

Use of Intravenous Tranexamic Acid in Patients Undergoing Plastic Surgery: Implications and Recommendations per a Systematic Review and Meta-Analysis.

With increasing interest in aesthetic plastic procedures, the event of blood loss has compromised patients' safety and satisfaction. Tranexamic acid (TXA) is a drug used for the reduction of blood loss during surgical procedures. This systematic review aims to evaluate the clinical efficacy and safety of TXA in aesthetic plastic surgery for the reduction of bleeding and related complications. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Electronic databases PubMed, EMBASE, Cochrane Library, and Google Scholar were searched. The medical subject headings (MeSH) keywords used for data extraction were ("TXA," OR "tranexamic acid,") AND ("plastic surgery," OR "aesthetic surgery," OR "rhinoplasty," OR "blepharoplasty,") AND ("blood loss" OR "bleeding" OR "TBL") AND ("Edema" OR "ecchymosis"). A combination of these MeSH terms was used in the literature search. The timeline of research was set from 2015 to January 2024. A total of 7380 research articles were identified from the above-mentioned databases, and only 13 research articles met the inclusion criteria. There was a significant difference in total blood loss (TBL) among patients who had undergone plastic surgery procedures while on TXA as compared to a placebo (mean difference = -6.02; Cl: -1.07 to -0.16; p > 0.00001), and heterogeneity was found (degrees of freedom (df) = 9; I2 = 97%). Only two studies reported the average ecchymosis scores after TXA among interventions in comparison to the placebo group. This review provides evidence that TXA lowers TBL, ecchymosis, edema, and anemia during cosmetic surgery without significantly increasing thromboembolic consequences.

A Comparative Analysis of the Advances in Stem Cell Therapy in Plastic Surgery: A Systematic Review of Current Applications and Future Directions.

Stem cell (SC) therapy is revolutionizing the field of plastic surgery by harnessing the regenerative abilities of SCs derived from adipose tissue and bone marrow to boost tissue repair and enhance aesthetic outcomes. This groundbreaking method enhances results in procedures such as fat grafting, facial rejuvenation, and wound healing. As studies advance, SC therapy shows potential for more sophisticated uses in both reconstructive and cosmetic surgery. The objective of this review is to comprehensively examine the advances in SC therapy within the field of plastic surgery, highlighting its current applications and exploring future directions. The systematic review was conducted on SC therapy in plastic surgery adhering to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and specific search criteria. This systematic review highlights these main outcomes, and SC therapy in plastic surgery enhances tissue repair and aesthetic outcomes by utilizing mesenchymal SCs such as adipose-derived SCs (ADSCs) and bone marrow-derived SCs (BMSCs), with platelet-rich plasma (PRP) providing additional support. Techniques such as scaffolds and cellular reprogramming are employed to guide SC growth, enabling tailored tissue engineering for complex regenerative procedures. This innovative approach accelerates healing, reduces scarring in reconstructive surgeries, improves skin texture, and ensures the natural integration of treated areas, ultimately yielding enhanced aesthetic results and transforming facial rejuvenation processes. SC therapy in plastic surgery holds great promise, but challenges such as protocol standardization, cost, and regulations still need to be addressed. SC therapy is leading innovative advancements in plastic surgery, offering superior outcomes and improved quality of life for patients. Interestingly, the future of plastic surgery is focused on integrating SC therapy for personalized and transformative treatments. Furthermore, interdisciplinary collaboration among bioengineers, clinicians, and regulatory bodies is essential for overcoming challenges and advancing SC research into clinical practice.

A Comparative Analysis of the Advances in Scar Reduction: Techniques, Technologies, and Efficacy in Plastic Surgery.

The study provides a comprehensive analysis of the latest methodologies and treatments aimed at improving scar management. Scar formation results from the replacement of normal skin with fibroblasts, leading to a structured unidirectional collagen bundle, as opposed to the collagen sheet matrix found in healthy skin. This review categorizes scars into hypertrophic scars and keloids, each with distinct pathophysiological characteristics. It highlights the importance of consistent scar assessment using scales such as the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale, emphasizing the need for standardized evaluation methods. The study systematically reviews various scar management techniques, ranging from traditional surgical methods to innovative treatments. Conventional approaches such as pressure garments and silicone gel sheeting are explored, noting their roles in maintaining hydration and occlusion. The efficacy of intralesional corticosteroid injections and laser therapies is discussed, with particular attention given to their combined use for optimal outcomes. The review also covers advanced techniques such as microneedling, platelet-rich plasma therapy, and stem cell-based treatments, detailing their mechanisms and potential benefits in scar remodelling. Additionally, the study underscores the emerging role of botulinum toxin A in both preventive and corrective scar treatments, offering promising results in reducing movement-induced scar exaggeration. The systematic review includes a thorough examination of existing literature, clinical trials, and meta-analyses to evaluate the effectiveness of these interventions. It concludes by calling for further research to refine these techniques and enhance their application in clinical practice, aiming to achieve better aesthetic and functional outcomes for patients with scars.

Advances in Tissue Engineering and Its Future in Regenerative Medicine Compared to Traditional Reconstructive Techniques: A Comparative Analysis.

Tissue engineering represents a revolutionary approach in regenerative medicine, offering promising alternatives to traditional reconstructive techniques. This systematic review explores recent advances in tissue engineering, comparing their efficacy, postoperative outcomes, and patient satisfaction to conventional methods. A comprehensive literature search was conducted across PubMed, Cochrane Library, and Google Scholar, covering studies published from 2000 to 2024. Fourteen studies were selected for final analysis based on inclusion criteria focusing on outcomes such as scar quality, postoperative pain, and patient satisfaction. The review demonstrated that tissue engineering techniques consistently provided superior cosmetic outcomes with minimal scarring compared to traditional methods. Patients undergoing tissue-engineered procedures experienced mild-to-moderate postoperative pain with rapid resolution, whereas traditional techniques resulted in moderate to severe pain requiring extended management. Furthermore, patients treated with tissue engineering reported high satisfaction rates due to improved cosmetic and functional outcomes. Despite challenges such as ensuring adequate vascularization, controlling scaffold degradation, and overcoming regulatory and cost barriers, ongoing research and development are essential to fully realize the potential of these innovative therapies. Tissue engineering offers significant advantages over traditional reconstructive techniques and has the potential to profoundly improve patient care in regenerative medicine.

A Systematic Review of the Optimal Management of Pediatric Distal Radius Displacement Fractures: Open Reduction and Internal Fixation Versus Cast Placement.

Distal radius fractures are among the most common pediatric injuries, affecting thousands of children each year. These fractures often require clinical intervention to reduce displacement and ensure the proper healing of the growth plate and wrist bone. The primary objective of this comprehensive analysis is to compare the effectiveness of open reduction and internal fixation (ORIF) versus cast placement in the treatment of pediatric distal radius fractures, with the aim of identifying the optimal treatment approach. Therefore, a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted on pediatric distal radius displacement fractures using extensive database searches from 2000 to 2024 for specific keywords, ensuring transparency and reproducibility. Our findings indicate that higher displacement necessitates ORIF to minimize long-term complications and ensure better functional outcomes for pediatric patients. Rare studies comparing ORIF and cast placement are analyzed, emphasizing the advantages and limitations of each approach. The document concludes that the choice between ORIF and casting depends on factors such as fracture severity, patient's age, and specific characteristics of the injury to ensure optimal outcomes in pediatric distal radius fracture management. In conclusion, our data suggests that ORIF and cast placement each have pros and cons for pediatric distal radius fractures, with the best treatment depending on fracture specifics and patient factors, but neither method is clearly superior for long-term outcomes.

Advantages and Disadvantages of Reconstructive and Preservation Rhinoplasty: Surgical Techniques, Outcomes, and Future Directions.

Reconstructive rhinoplasty, a specialized surgical procedure, aims to restore both the form and function of the nose, particularly after trauma, congenital defects, or prior surgeries. This review evaluates the advantages and disadvantages of various surgical techniques used in reconstructive and preservation rhinoplasty. The study focuses on the outcomes of commonly employed methods such as cartilage grafting, flap techniques, and alloplastic materials, assessing both functional and aesthetic results. Recent advancements, including 3D imaging, tissue engineering, and artificial intelligence, are discussed as potential future directions that could enhance surgical precision, safety, and patient care. The review systematically examines clinical studies from the past decade, highlighting the evolving landscape of rhinoplasty and its impact on patient outcomes.

Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

Circulating tumour cells and circulating cell-free DNA in patients with lung cancer: a comparison between thoracotomy and video-assisted thoracoscopic surgery.

INTRODUCTION: The type of lung cancer surgery impacts on tumour manipulation during surgery and may drive dissemination of cancer cells into the vasculature, thus facilitating metastatic spread. The aim of this study was to investigate the impact of surgically induced trauma using peripheral blood from preoperative and postoperative patients with non-small cell lung cancer (NSCLC) undergoing thoracotomy or video-assisted thoracoscopic surgery (VATS) resection. METHODS: Imaging flow cytometry was used to measure circulating cancer-associated cells (CCs). Circulating cell-free DNA (ccfDNA) isolation was performed using Promega dsDNA HS Assay Kit. DNA integrity measurements were calculated by the ALU247 to ALU115 ratio and cytokine levels measured using the Luminex screening assay. RESULTS: CCs were increased in postoperative blood samples in 54 patients with NSCLC. Patients who underwent thoracotomy instead of VATS had higher numbers of EpCAM (p=0.004) and PanCK-labelled (p=0.03) CCs postoperatively. ccfDNA and DNA integrity index were also significantly increased in postoperative samples (p=0.0009 and p=0.04), with concomitant increase in interleukin 6 and interleukin 10 levels in the same cohorts (p=0.0004 and p=0.034, respectively). CONCLUSIONS: In this study we have shown the potential clinical utility of several biomarkers from liquid biopsies to guide perioperative management, as well as provide a snapshot of the type of surgical resection in terms of circulating tumour cell release. Obtaining reliable readouts from blood can provide crucial information for disease progression, as well as being of prognostic value monitoring patients' response to treatment.

COVID­19 and SARS­CoV­2 host cell entry mediators: Expression profiling of TMRSS4 in health and disease.

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV­2), the causative viral agent for the ongoing COVID­19 pandemic, enters its host cells primarily via the binding of the SARS­CoV­2 spike (S) proteins to the angiotensin­converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin­1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS­CoV­2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID­19 symptomatology as another SARS­CoV­2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.

Avelumab Versus Docetaxel in Patients With Platinum-Treated Advanced NSCLC: 2-Year Follow-Up From the JAVELIN Lung 200 Phase 3 Trial.

INTRODUCTION: In the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data. METHODS: Patients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 1:1 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay). RESULTS: Of 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumab versus docetaxel were 29.9% (24.5%-35.5%) versus 20.5% (15.6%-25.8%); in greater than or equal to 50% PD-L1+ subgroups, 2-year OS rates were 36.4% (29.1%-43.7%) versus 17.7% (11.8%-24.7%) and in the greater than or equal to 80% subgroup were 40.2% (31.3%-49.0%) versus 20.3% (12.9%-28.8%), respectively. Median duration of response (investigator assessed) was 19.1 months (95% CI: 10.8-34.8) versus 5.7 months (95% CI: 4.1-8.3). Safety profiles for both arms were consistent with the primary analysis. CONCLUSIONS: Although the JAVELIN Lung 200 primary analysis (reported previously) revealed that avelumab did not significantly prolong OS versus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%).

Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer.

Gefitinib (Iressa) is a specific and effective epidermal growth factor receptor inhibitor. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-epidermal growth factor receptor therapies and provide information for overcoming gefitinib resistance. In this study, we investigated the role and regulation of FOXM1 in response to gefitinib treatment in breast cancer. Using the gefitinib-sensitive breast carcinoma cell lines BT474 and SKBR3 as well as the resistant lines MCF-7, MDA-MB-231, and MDA-MB-453, we showed that gefitinib represses the expression of the transcription factor FOXM1 in sensitive, but not resistant, cells. FOXM1 repression by gefitinib is associated with FOXO3a activation and is mediated at the transcriptional level and gene promoter level. These results were verified by immunohistochemical staining of biopsy samples from primary breast cancer patients obtained from a gefitinib neoadjuvant study. We also showed that ectopic expression of an active FOXO3a represses FOXM1 expression, whereas knockdown of FOXO3a expression using small interfering RNA can up-regulate FOXM1 and its downstream targets polo-like kinase, cyclin B1, and CDC25B and rescue sensitive BT474 cells from gefitinib-induced cell proliferative arrest. These results suggest that gefitinib represses FOXM1 expression via FOXO3a in breast cancer. We further showed that overexpression of a wild-type FOXM1 or a constitutively active FOXM1, DeltaN-FOXM1, abrogates the cell death induced by gefitinib, indicating that FOXM1 has a functional role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib. In summary, our study defined FOXM1 as a cellular target and marker of gefitinib activity in breast cancer.

In Silico and In Vitro Analysis of lncRNA XIST Reveals a Panel of Possible Lung Cancer Regulators and a Five-Gene Diagnostic Signature.

Long non-coding RNAs (lncRNAs) perform a wide functional repertoire of roles in cell biology, ranging from RNA editing to gene regulation, as well as tumour genesis and tumour progression. The lncRNA X-inactive specific transcript (XIST) is involved in the aetiopathogenesis of non-small cell lung cancer (NSCLC). However, its role at the molecular level is not fully elucidated. The expression of XIST and co-regulated genes TSIX, hnRNPu, Bcl-2, and BRCA1 analyses in lung cancer (LC) and controls were performed in silico. Differentially expressed genes (DEGs) were determined using RNA-seq in H1975 and A549 NSCLC cell lines following siRNA for XIST. XIST exhibited sexual dimorphism, being up-regulated in females compared to males in both control and LC patient cohorts. RNA-seq revealed 944 and 751 DEGs for A549 and H1975 cell lines, respectively. These DEGs are involved in signal transduction, cell communication, energy pathways, and nucleic acid metabolism. XIST expression associated with TSIX, hnRNPu, Bcl-2, and BRCA1 provided a strong collective feature to discriminate between controls and LC, implying a diagnostic potential. There is a much more complex role for XIST in lung cancer. Further studies should concentrate on sex-specific changes and investigate the signalling pathways of the DEGs following silencing of this lncRNA.

Liquid Biopsies in Lung Cancer: Four Emerging Technologies and Potential Clinical Applications.

Background: Liquid biopsies offer a promising alternative to tissue samples, providing non-invasive diagnostic approaches or serial monitoring of disease evolution. However, certain challenges remain, and the full potential of liquid biopsies has yet to be reached. Here we report several methodological approaches to interrogate liquid biopsies using circulating tumour cell (CTC) enumeration and characterisation, transcriptomics, Raman spectroscopy, and copy number instability (CNI) scores using blood samples of lung cancer (LC) patients. Methods: We choose LC; since it still is the most common cause of cancer-related mortality worldwide, and therefore there is a need for development of new non-invasive diagnostic/prognostic technologies. Changes in gene expression were assessed using RNA-seq, and in CTCs using ImageStream, an imaging flow-cytometer. CNI scores, from paired tissue/ctDNA were also explored. Raman spectroscopy was used to provide chemical fingerprints of plasma samples. Results: CTCs were detected in all LC patients (n = 10). We observed a significant increase in CTC levels in LC patients (n = 10) compared to controls (n = 21). A similar CNI was noted in the tissue and plasma of 2 patients, where higher CNI scores corresponded with poorer outcome. Significant changes in Raman spectra (carotenoid concentrations) were noted in LC patients (n = 20) compared to controls (n = 10). RNA-seq revealed differential expression of 21 genes between LC cases and controls in both LC tissue and blood samples. Conclusions: Liquid biopsies can potentially provide a more comprehensive picture of the disease compared to a single tissue biopsy. CTC enumeration is feasible and sensitive for LC patients. Molecular profiling of CTCs is also possible from total blood. CNI scores and Raman spectra require further investigation. Further work is being undertaken to explore these methods of detection in a larger LC cohort.

The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells.

Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib.

Squamous cell carcinoma of pancreas: an unusual site of relapse from early-stage lung cancer: 12-month postsurgery.

A 57-year-old man presented with abdominal pain and backache, weight loss of 10 kg and irregular bowel movements. He was previously diagnosed with Stage IB squamous cell carcinoma of lung and had undergone lobectomy 12 months previously. Investigations including imaging revealed a cystic mass in the body and tail of the pancreas which was biopsied and it was confirmed to be a recurrence of the squamous lung cancer involving the pancreas. He was treated with systemic chemotherapy and has shown a partial response on repeat imaging. This case illustrates a rare and unusual site of relapse in lung cancer after adjuvant therapy and a key message for follow-up surveillance for these patients.

A rare occurrence of biphasic pulmonary blastoma in an elderly male.

Pulmonary Blastoma (PB) is a rare primary lung malignancy usually occurring in young to middle aged adults. Surgery is the primary mode of treatment, but survival is poor with the mean 5-year survival being approximately 16%. We report on a case of PB arising in a 63-year-old man. Computed tomography, magnetic resonance imaging and positron emission tomography confirmed the mass to be of pulmonary origin. The morphological appearance combined with the immunoprofile of the tumour was consistent with a poorly-differentiated biphasic pulmonary blastoma. Two months after the surgical resection the patient relapsed with multiple sites of metastasis. The patient was treated with four cycles of cyclophosphamide-, doxorubicin- and vincristine-(CAV)-based chemotherapy, achieving a partial response to treatment. He is currently on a two-monthly review and is recovering from chemotherapy-related toxicities.