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Panagiotis A Konstantinopoulos

Publications and source records attributed to Panagiotis A Konstantinopoulos.

At least 19 recordsLinked to original sources
PubMed2026

Toward precision prognosis: Predicting recurrence-free survival in high-grade serous ovarian cancer patients using multi-time point clinical and computed tomography radiomics data.

OBJECTIVE: To evaluate the predictive value of clinical, genomic, and radiomics features in estimating recurrence-free survival (RFS) in patients with high-grade serous ovarian carcinoma (HGSOC) treated with neoadjuvant chemotherapy (NACT). METHODS: This single-center, retrospective study included 91 patients with HGSOC who underwent treatment with NACT followed by surgery, and who had portal venous phase contrast enhanced CT imaging at baseline and after NACT. First-order texture features based on 2D segmentation were extracted from baseline and post-NACT CT images for selected disease sites using commercially available texture software. Multivariate Cox models assessed the prognostic significance of features at baseline, after NACT, and post-surgery time points, and model performance in predicting RFS was evaluated using C-statistics. RESULTS: A model including only baseline clinical data had C-statistic 0.53, while a model including both clinical and radiomics features at baseline had C-statistic 0.63. After NACT, a model including all baseline data plus the change in radiomics features between baseline and post-NACT had C-statistic 0.63. Post-surgery, a model including all baseline data plus surgical outcome had C-statistic 0.69. Incorporating changes in radiomic features between time points did not measurably enhance model performance in the post-surgery data set (C-statistic 0.7). Age, residual disease at surgery, and kurtosis were individually associated with shorter RFS. CONCLUSIONS: Radiomic features extracted from CT imaging may offer additive prognostic value for predicting RFS in HGSOC when integrated with clinical and genetic data. Our results support the potential integration of radiomic analysis with clinical data to improve outcome prediction in HGSOC.

Humans↗
PubMed2026

Mirvetuximab soravtansine plus pembrolizumab in recurrent folate receptor alpha-positive uterine serous carcinoma: a phase II trial.

Immune checkpoint inhibitors (ICI) synergize preclinically with antibody drug conjugates (ADC), harboring anti-tubulin maytansinoid payloads. We conducted an investigator-initiated, single-arm, phase 2 trial of mirvetuximab soravtansine (MIRV), a folate receptor alpha (FOLR1/FRα)-targeting ADC with the maytansinoid payload, DM4, combined with pembrolizumab in female patients with recurrent FOLR1-expressing serous endometrial cancer (EC, NCT03835819). Co-primary objectives include objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6); secondary objectives include PFS, overall survival, duration of response and safety. Exploratory objectives include correlation of tumor genomics and immunoprofiling with clinical activity. Eighteen patients initiated protocol therapy [MIRV 6 mg/kg adjusted ideal body weight IV and pembrolizumab 200 mg IV every 3 weeks]. Confirmed ORR is 28% (1 complete and 4 partial responses, 95% CI:10-53%), Kaplan Meier estimate of PFS6 is 24.4% (95% CI:7.7-46.1%) with 4 patients progression free at 6 months; trial was closed early for feasibility (planned sample size of 35 patients not reached) and hence these results are considered preliminary. G3 treatment-related adverse effects were rare with no grade ≥4 toxicities. We report a population of high FOLR1-expressing tumor-associated macrophages (CD163 + FOLR1 + ), suggesting potential on-target, off-tumor immune editing by MIRV. A composite biomarker score derived in this cohort correlates with objective response to MIRV and pembrolizumab.

Adult↗
PubMed2007

The role of STATs in lung carcinogenesis: an emerging target for novel therapeutics.

The signal transducer and activator of transcription (STAT) proteins are a family of latent cytoplasmic transcription factors, which form dimers when activated by cytokine receptors, tyrosine kinase growth factor receptors as well as non-receptor tyrosine kinases. Dimeric STATs translocate to the nucleus, where they bind to specific DNA-response elements in the promoters of target genes, thereby inducing unique gene expression programs often in association with other transcription regulatory proteins. The functional consequence of different STAT proteins activation varies, as their target genes play diverse roles in normal cellular/tissue functions, including growth, apoptosis, differentiation and angiogenesis. Certain activated STATs have been implicated in human carcinogenesis, albeit only few studies have focused into their role in lung tumours. Converging evidence unravels their molecular interplays and complex multipartite regulation, rendering some of them appealing targets for lung cancer treatment with new developing strategies.

Animals↗
PubMed2006

Multilevel modulation of the mevalonate and protein-prenylation circuitries as a novel strategy for anticancer therapy.

The important role of the mevalonate and protein-prenylation circuitries in the process of carcinogenesis is increasingly being recognized. Accordingly, several enzymes within these pathways have been pharmacologically targeted for anticancer drug development. Despite promising activity in a plethora of preclinical models, clinical evaluation of these agents as monotherapy against various malignancies has been disappointing. Appropriate combinations of inhibitors of isoprenoid biosynthesis, inhibitors of prenylation and postprenylation modifications might be a more clinically effective strategy for anticancer therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Morphologic and immunophenotypic evidence of in-situ Kaposi's sarcoma.

BACKGROUND: The spectrum of Kaposi's sarcoma (KS) has been expanded to include pre-KS lesions. CASE PRESENTATION: We report, for the first time, a case providing direct histological evidence of the development of early (in-situ) KS from mediastinal lymphatic vessels in the setting of chronic lymphedema in an HIV-positive patient. Spindle-shaped and endothelial cells in these early KS-appearing lesions were immunoreactive for HHV8, D2-40 and CD34. CONCLUSION: Our findings suggest that HHV8-infected spindle-shaped cells associated with lymphangiogenesis that evolve into KS lesions, acquire from the outset an aberrant mixed vascular and lymphatic endothelial cell phenotype.

Journal Article↗
PubMed2006

NF-kappaB/PPAR gamma and/or AP-1/PPAR gamma 'on/off' switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression.

BACKGROUND AND AIMS: Several studies indicate that peroxisome proliferator-activated receptor gamma (PPAR gamma) represses activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) transcriptional activity and this negative cross-talk occupies an important role in carcinogenesis. The present study evaluated the differential expression profile of AP-1 constituents (c-FOS and phosphorylated-active pc-JUN), p-I kappaB-alpha (phosphorylated I kappaB-alpha, a signaling intermediate of NF-kappaB pathway), PPAR gamma, cyclic AMP-response element binding-binding protein (CBP, a known AP-1, NF-kappaB, and PPAR gamma transcriptional coactivator), epidermal growth factor receptor (EGF-R), p53, and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells. MATERIALS AND METHODS: Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinomas. A molecular profile was created for each patient and the induction or down-regulation of each pathway from normal to cancer cells was documented. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman's rho correlation coefficient and validated by nonparametric Kruskal-Wallis test. RESULTS/FINDINGS: P-I kappaB-alpha (P<0.001), CBP (P<0.001), c-FOS (P=0.047), pc-JUN (P=0.047), and EGF-R (P<0.001) were up-regulated in colon adenocarcinomas while PPAR gamma (P<0.001) was concomitantly down-regulated. p-I kappaB-alpha, CBP, pc-JUN, EGF-R, and p53 expression all correlated positively with COX-2 while PPAR gamma expression correlated inversely with COX-2. INTERPRETATION/CONCLUSION: NF-kappaB/PPAR gamma and/or AP-1/PPAR gamma expressional 'on/off' switches are common molecular events during colorectal carcinogenesis. Down-regulation of PPAR gamma and induction of the CBP transcriptional coactivator can augment NF-kappaB and AP-1 transcriptional activities leading to up-regulation of COX-2 expression in colon adenocarcinoma cells. p-I kappaB-alpha, pc-JUN, and CBP could potentially provide the basis for future molecular-targeted anticancer therapies.

Adenocarcinoma↗
PubMed2006

FK228 (depsipeptide): a HDAC inhibitor with pleiotropic antitumor activities.

PURPOSE: The fundamental role of epigenetic events in carcinogenesis has resulted in the evolution of epigenetic targeting as a new paradigm in anticancer therapeutics. Aberrant histone deacetylase (HDAC) activity has been documented in many human malignancies resulting in the repression of tumor suppressor genes and promotion of tumorigenesis. FK228, also known as depsipeptide, is a novel, natural, bicyclic tetrapeptide with significant antitumor properties which are mostly mediated by inhibition of HDACs. RESULTS: FK228 induces the expression of genes linked to the inhibition of cell growth, induction of cell differentiation, promotion of apoptotic cell death and inhibition of angiogenesis. CONCLUSION: Its multitargeting properties, its ability to act on non-histone targets, its clinical activity and its acceptable side-effect profile render FK228 a very promising novel anticancer agent.

Antibiotics, Antineoplastic↗
PubMed2006

The potential of proteasome inhibition in the treatment of colon cancer.

Proteasome inhibition is an entirely novel approach to the treatment of malignant disease. By interfering with the ubiquitin-proteasome degradation system, proteasome inhibitors affect numerous cellular processes that are commonly deregulated in cancer cells including gene transcription, cell-cycle regulation, apoptosis, cell migration and DNA repair. This review outlines the physiology of the ubiquitin-proteasome pathway, discusses preclinical and clinical data regarding the activity of proteasome inhibitors against colon cancer and evaluates the rationale for the use of proteasome inhibitors as monotherapy or in combination with other anticancer therapies (i.e., chemotherapy, radiation therapy and other molecular-targeted therapies) in colon cancer.

Colonic Neoplasms↗
PubMed2006

Higher prevalence of monoclonal gammopathy of undetermined significance in African Americans than whites--the unknown role of underlying HIV infection.

The age-adjusted prevalence rate of monoclonal gammopathy of undetermined significance (MGUS) is three-fold higher in African Americans than whites. Similarly, there is a higher preponderance of multiple myeloma (MM) in African-American patients. Since the risk of progression of MGUS to MM is equal in both races, identification of exogenous and genetic risk factors of MGUS [such as genetic pre-disposition; diet; and chronic antigenic exposure related to sexually transmitted diseases, including human immunodeficiency virus (HIV) infection] is essential for unraveling the etiology of the racial disparity for MM. HIV infection, a well-documented risk factor for MGUS, is more frequent in African-American patients. Future epidemiologic studies dealing with plasma cell disorders should carefully examine the relationship between race, HIV infection status, prevalence of MGUS and its ultimate progression to MM.

Black or African American↗
PubMed2005

PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas.

PURPOSE: Accumulated evidence indicates that carcinogenesis is closely associated with the transformation of normal stroma into a 'reactive' stromal phenotype. The present study investigated the role of PPARgamma, COX-2 and p-IkB-alpha--important molecular targets of colon cancer chemoprevention--in this stromal remodeling by evaluating and comparing the expression of these factors in stromal myofibroblasts, macrophages and endothelial cells that surround normal colonic mucosa and colon cancer. METHODS: Immunohistochemical methodology was employed on archived paraffin-embedded sections prepared from tumors and adjacent normal colon from 45 patients with colon adenocarcinomas. Double immunostaining with the universal marker for myofibroblasts (alpha-smooth muscle actin/alpha-SMA) as second primary antibody was also performed. RESULTS: Stromal macrophages and endothelial cells expressed these factors both in normal colonic mucosa and colon cancer. By contrast, stromal myofibroblasts expressed PPARgamma, COX-2 and p-IkB-alpha only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-alpha expressions were strongly correlated in these cells (P < 0.001). PPARgamma, COX-2 and p-IkB-alpha expression did not correlate with the stage or differentiation of the adenocarcinomas. CONCLUSIONS: NF-kB pathway is activated and COX-2 expression is upregulated in stromal myofibroblasts surrounding colon adenocarcinomas compared to normal colon. Induction of COX-2 expression is primarily induced by NF-kB. NSAIDs, selective COX-2 inhibitors and PPARgamma ligands may exert their chemoprophylactic properties through direct actions on these cells.

Adenocarcinoma↗
PubMed2005

The cardiovascular toxicity of selective and nonselective cyclooxygenase inhibitors: comparisons, contrasts, and aspirin confounding.

The premature suspension of the Alzheimer Disease Anti-inflammatory Prevention (ADAPT) and the Adenoma Prevention with Celecoxib (APC) trials prompted intense review of the cardiovascular safety profile of selective and nonselective cyclooxygenase (COX) inhibitors. This article reviews the current state of selective COX-2 inhibitors, discusses the mechanistic evidence underlying the cardiovascular risk associated with selective COX-2 inhibition, outlines the pharmacodynamics of aspirin effects on platelets and the interference of propionic acid derivatives (ibuprofen and naproxen) with these effects, and poses that aspirin confounding may have led to the erroneous conclusion of naproxen-associated adverse cardiovascular outcomes in the ADAPT trial. Finally, recommendations regarding selective COX-2 inhibitors and appropriate timing of aspirin coadministration with traditional NSAIDs are proposed in relevance to patient safety and future trial design.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

17-AAG: mechanisms of antitumour activity.

Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in three-dimensional folding, intracellular translocation and degradation of multiple key regulatory proteins. Accumulated evidence has indicated an important role of Hsp90 in several signal transduction pathways that are deregulated in carcinogenesis. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective inhibitor of Hsp90, is currently under clinical investigation in advanced malignancies in which Hsp90 client proteins are implicated. This article discusses the mechanistic evidence underlying 17-AAG's cytostatic, proapoptotic, antiangiogenic and anti-invasive properties that provide the basis for its antitumour activity and underscores its unique therapeutic potential as a multi-targeted agent, as opposed to most of the current-generation molecular therapeutics.

Animals↗
PubMed2005

Erythropoietin abuse and erythropoietin gene doping: detection strategies in the genomic era.

The administration of recombinant human erythropoietin (rhEPO) increases the maximum oxygen consumption capacity, and is therefore abused as a doping method in endurance sports. The detection of erythropoietin (EPO) abuse is based on direct pharmacological and indirect haematological approaches, both of which have several limitations. In addition, current detection methods cannot cope with the emerging doping strategies of EPO mimicry, analogues and gene doping, and thus novel detection strategies are urgently needed. Direct detection methods for EPO misuse can be either pharmacological approaches that identify exogenous substances based on their physicochemical properties, or molecular methods that recognise EPO transgenes or gene transfer vectors. Since direct detection with molecular methods requires invasive procedures, it is not appropriate for routine screening of large numbers of athletes. In contrast, novel indirect methods based on haematological and/or molecular profiling could be better suited as screening tools, and athletes who are suspect of doping would then be submitted to direct pharmacological and molecular tests. This article reviews the current state of the EPO doping field, discusses available detection methods and their shortcomings, outlines emerging pharmaceutical and genetic technologies in EPO misuse, and proposes potential directions for the development of novel detection strategies.

Doping in Sports↗