Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.
- MeSH
- Ataxia Telangiectasia Mutated Proteins genetics MeSH
- Adult MeSH
- ErbB Receptors genetics MeSH
- Papillomavirus Infections MeSH
- Cyclin-Dependent Kinase Inhibitor p16 genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Penile Neoplasms * genetics mortality pathology virology MeSH
- Prognosis MeSH
- Telomere-Binding Proteins MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Shelterin Complex MeSH
- Carcinoma, Squamous Cell * genetics mortality pathology virology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.
- MeSH
- Chemotherapy, Adjuvant methods MeSH
- Immune Checkpoint Inhibitors * therapeutic use pharmacology MeSH
- Neoplasm Invasiveness MeSH
- Carcinoma, Transitional Cell drug therapy pathology MeSH
- Humans MeSH
- Urinary Bladder Neoplasms drug therapy pathology MeSH
- Network Meta-Analysis as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
Karcinom endometria je obvykle diagnostikován v časném stadiu a po primární operační a následné adjuvantní onkologické léčbě má relativně dobrou prognózu. V případě lokální či regionální recidivy v oblasti pánve lze často účinně aplikovat záchrannou léčbu, ať už operační, či léčbu zářením. Pokud ale karcinom endometria recidivuje tak, že jej nelze řešit lokální záchrannou léčbou, nebo pokud metastazuje do vzdálených lokalit, je situace už mnohem vážnější. Díky molekulárně genetickým poznatkům dnes dovedeme nádory endometria lépe kategorizovat a také lépe předpovědět léčebnou odpověď nejen na chemoterapii, ale především na stále rychleji se rozvíjející imunoterapii cílenou na receptor programované buněčné smrti 1 (programmed cell death protein 1, PD-1) a jeho ligandy. Dostarlimab je prvním plně hrazeným tzv. „checkpoint inhibitorem“ v první linii léčby pacientek s rekurentním či metastazujícím MMR (mismatch repair) deficientním karcinomem endometria.
Endometrial cancer is usually diagnosed at an early stage and has a relatively good prognosis after primary surgery and subsequent adjuvant oncological treatment. In the case of local or regional recurrence in the pelvic region, salvage treatment, either surgery or radiation therapy, can often be effectively applied. However, if the endometrial cancer recurs so that it cannot be managed with local salvage treatment, or if it metastasises to distant sites, the situation is much more serious. Thanks to molecular genetic knowledge, we can now better categorize endometrial tumors and more accurately predict the therapeutic response not only to chemotherapy, but also to the rapidly developing immunotherapy targeting the programmed cell death protein 1 (PD-1) receptor and its ligands. Dostarlimab is the first fully reimbursed “checkpoint inhibitor” in the first-line treatment of patients with recurrent or metastatic MMR (mismatch repair) deficient endometrial cancer.
Nivolumab je průlomový onkologický lék patřící mezi inhibitory kontrolních bodů, který cílí na receptor programované buněčné smrti 1 (programmed cell death protein 1, PD-1). Jeho účinnost byla prokázána jak v monoterapii, tak v kombinaci s chemoterapií u mnoha typů onkologických diagnóz, včetně uroteliálního karcinomu. V léčbě metastazujícího uroteliálního karcinomu se nivolumab ukázal jako významný doplněk ke standardní chemoterapii, zejména u pacientů s pozitivní expresí ligandu programované buněčné smrti 1 (programmed cell death-ligand 1, PD-L1) a postižením lymfatických uzlin, kde významně prodlužuje celkové přežití a dobu bez progrese onemocnění. V adjuvantní léčbě nivolumab přináší prokazatelný benefit u pacientů po radikální operaci s vysokým rizikem relapsu. Studie prokázaly jeho schopnost prodloužit dobu do přežití bez známek onemocnění (disease free survival, DFS) a bez vzdálených metastáz (distant metastasis free survival, DMFS), přičemž jeho účinek je nejvýraznější u PD-L1 pozitivních pacientů.
Nivolumab is a breakthrough cancer drug belonging to the class of checkpoint inhibitors that targets the programmed cell death protein 1 receptor (PD-1). Its efficacy has been demonstrated both in monotherapy and in combination with chemotherapy in many types of cancer, including urothelial carcinoma. In the treatment of metastatic urothelial carcinoma, nivolumab has proven to be an important adjunct to standard chemotherapy, particularly in patients with positive programmed cell death-ligand 1 (PD-L1) expression and lymph node involvement, where it significantly prolongs overall survival and progression free survival. In adjuvant therapy, nivolumab provides a demonstrable benefit in patients after radical surgery with a high risk of relapse. Studies have demonstrated its ability to prolong disease free survival (DFS) and distant metastasis free survival (DMFS), with its effect being most pronounced in PD-L1 positive patients.
Pembrolizumab je humanizovaná monoklonální protilátka proti receptoru programované buněčné smrti 1 (programmed cell death protein 1, PD-1). Kombinace pembrolizumabu a enfortumab vedotinu je novým standardem terapie pokročilého uroteliálního karcinomu. Kombinace pembrolizumabu a axitinibu a kombinace pembrolizumabu a lenvatinibu prokázaly protinádorovou aktivitu u dříve neléčeného pokročilého renálního karcinomu. Podání pembrolizumabu v adjuvanci u renálního karcinomu je spojeno s klinicky významným zlepšením celkového přežití.
xPembrolizumab is a humanized monoclonal antibody against programmed cell death protein 1 (PD-1). The combination of pembrolizumab and enfortumab vedotin is a new standard of therapy in advanced urothelial cancer. The combination of pembrolizumab and axitinib and combination pembrolizumab and lenvatinib showed antitumor activity in previously untreated advanced renal cell carcinoma. Adjuvant pembrolizumab in renal cell carcinoma is associated with clinically meaningful improvement in overall survival.
Karcinom plic je celosvětově nejčastěji diagnostikovaným nádorovým onemocněním. Pro pacienty s neresekabilním nemalobuněčným plicním karcinomem (non-smaii cell lung cancer, NSCLC) ve stadiu III je metodou volby radiochemoterapie (RCHT), a to konkomitantní nebo sekvenční. Použití konsolidační systémové léčby durvalumabem po konkomitantní RCHT u pacientů s NSCLC a přítomnou expresí ligandu programované buněčné smrti 1 (programmed cell death-ligand 1, PD-L1) je standardním přístupem, a nese také název podle registrační studie – PACIFIC režim. Tento článek se týká i dalších potenciálních klinických situací s možností použití konsolidační systémové léčby.
Lung cancer is the most commonly diagnosed cancer worldwide. For patients with unresectable stage III non-small cell lung cancer (NSCLC), radiochemotherapy (RCHT) is the treatment of choice, either concurrent or sequential. The use of consolidation systemic treatment with durvalumab after concurrent RCHT in patients with NSCLC and programmed cell death-ligand 1 (PD-L1) expression is the standard approach, and is also named after the registration study, the PACIFIC regimen. This article covers other potential clinical situations with the possibility of consolidation systemic therapy.
Enfortumab vedotin je inovativní cílená terapie uroteLiálního karcinomu, zejména v jeho pokročilých nebo metastatických stadiích. Klinické studie prokázaly výrazný přínos enfortumab vedotinu pro pacienty, u nichž selhala chemoterapie obsahující platinu a imunoterapie inhibitory receptoru programované buněčné smrti 1 (programmed cell death protein 1, PD-1) / ligandu programované buněčné smrti 1 (programmed cell death-ligand 1, PD-L1). Tato kazuistika popisuje případ pacienta s uroteliálním karcinomem horních močových cest s dominantním metastatickým postižením skeletu, který byl po selhání standardní chemoterapie a udržovací terapie avelumabem léčen enfortumab vedotinem. Přestože odpověď na enfortumab vedotin bývá u skeletálních metastáz ve srovnání s jinými lokalizacemi nižší, v tomto případě vedla terapie ke stabilizaci kostního postižení a regresi metastáz v plicích a retroperitoneálních uzlinách, což se odrazilo ve zlepšení klinického stavu pacienta.
Enfortumab vedotin is an innovative targeted therapy for urothelial carcinoma, particularly in its advanced or metastatic stages. Clinical studies have demonstrated a significant benefit of enfortumab vedotin for patients in whom platinum-based chemotherapy and immunotherapy with programmed cell death protein 1 (PD-1) / programmed cell death-ligand 1 (PD-L1) inhibitors have failed. This case report describes a patient with upper urinary tract urothelial carcinoma with predominant metastatic skeletal involvement who was treated with enfortumab vedotin after the failure of standard chemotherapy and maintenance therapy with avelumab. Although the response to enfortumab vedotin in skeletal metastases is generally lower compared to other metastatic sites, in this case, the therapy resulted in the stabilization of bone involvement and regression of metastases in the lungs and retroperitoneal lymph nodes, leading to an improvement in the patient's clinical condition.
A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- Apoptosis * drug effects MeSH
- Cell Cycle drug effects MeSH
- Histone Deacetylases metabolism MeSH
- Histone Deacetylase Inhibitors * pharmacology chemical synthesis chemistry MeSH
- Hydroxamic Acids * pharmacology chemical synthesis chemistry MeSH
- Coumaric Acids * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemical synthesis chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- THP-1 Cells MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.
BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) patients is correlated with the efficacy of immune checkpoint blockade therapy (ICB) targeting programmed cell death ligand 1 (PD-L1) or its cognate receptor (PD-1) on cancer cells or infiltrating immune cells. Analysis of PD-L1/PD-1 expression in tumor tissue represents a crucial step before PD-L1/PD-1 blocker usage. METHODS: We used directed evolution of protein variants derived from a 13 kDa Myomedin loop-type combinatorial library with 12 randomized amino acid residues to select high-affinity binders of human PD-L1 (hPD-L1). After the ribosome display, individual clones were screened by ELISA. Detailed analysis of binding affinity and kinetics was performed using LigandTracer. The specificity of Myomedins was assessed using fluorescent microscopy on HEK293T-transfected cells and cultured cancer cells in vitro, formalin-fixed paraffin-embedded (FFPE) sections of human tonsils, and FFPE tumor samples of NSCLC patients. RESULTS: Seven identified PD-L1 binders, called MLE, showed positive staining for hPD-L1 on transfected HEK293T cells and cultured MCF-7 cells. MLE031, MLE105, MLE249, and MLE309 exhibited high affinity to both human and mouse PD-L1-transfected HEK293T cells measured with LigandTracer. The diagnostic potential of MLE variants was tested on human tonsillitis tissue and compared with diagnostic anti-PD-L1 antibody DAKO 28-8 and PD-L1 IHC 22C3 pharmDx antibody. MLE249 and MLE309 exhibited an excellent overlap with diagnostic DAKO 28-8 (Pearson ́s coefficient (r) = 0.836 and 0.731, respectively) on human tonsils on which MLE309 exhibited also excellent overlap with diagnostic 22C3 antibody (r = 0.876). Using three NSCLC tissues, MLE249 staining overlaps with 28-8 antibody (r = 0.455-0.883), and MLE309 exhibited overlap with 22C3 antibody (r = 0.534-0.619). Three MLE proteins fused with Fc fragments of rabbit IgG, MLE249-rFc, MLE309-rFc and MLE031-rFc, exhibited very good overlap with anti-PD-L1 antibody 28-8 on tonsil tissue (r = 0.691, 0.610, and 0.667, respectively). Finally, MLE249-rFc, MLE309-rFc and MLE031-rFc exhibited higher sensitivity in comparison to IHC 22C3 antibody using routine immunohistochemistry staining system Ventana, which is one of gold standards for PD-L1 diagnosis. CONCLUSIONS: We demonstrated the development of MLE Myomedins specifically recognizing hPD-L1 that may serve as a refinement tool for clinical PD-L1 detection.
