Advances in diagnosis and treatment of bladder cancer

BMJ, Journal Year: 2024, Volume and Issue: unknown, P. e076743 - e076743

Published: Feb. 12, 2024

Abstract Bladder cancer remains a leading cause of death worldwide and is associated with substantial impacts on patient quality life, morbidity, mortality, cost to the healthcare system. Gross hematuria frequently precedes diagnosis bladder cancer. Non-muscle-invasive (NMIBC) managed initially transurethral resection tumor (TURBT), followed by risk stratified approach adjuvant intravesical therapy (IVe), an overall survival 90%. However, cure rates remain lower for muscle invasive (MIBC) owing variety factors. NMIBC MIBC groupings are heterogeneous have unique pathological molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers luminal basal subtypes distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) gold standard high grade reduce or prevent both recurrence progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. gene combination chemotherapy recently been completed, promising results. localized MIBC, essential goals improving care reducing morbidity following cystectomy preserving strategies. In metastatic disease, advances in understanding genomic landscape microenvironment led implementation inhibitors, targeted treatments, antibody-drug conjugates. Defining better selection criteria identify patients most likely benefit from specific urgent need.

Language: Английский

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The 2022 revision of the World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges

Human Pathology, Journal Year: 2022, Volume and Issue: 136, P. 123 - 143

Published: Sept. 6, 2022

Language: Английский

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Precision Medicine in Bladder Cancer: Present Challenges and Future Directions

Journal of Personalized Medicine, Journal Year: 2023, Volume and Issue: 13(5), P. 756 - 756

Published: April 28, 2023

Bladder cancer (BC) is characterized by significant histopathologic and molecular heterogeneity. The discovery of pathways knowledge cellular mechanisms have grown exponentially may allow for better disease classification, prognostication, development novel more efficacious noninvasive detection surveillance strategies, as well selection therapeutic targets, which can be used in BC, particularly a neoadjuvant or adjuvant setting. This article outlines recent advances the pathology BC with understanding deeper focus on deployment promising biomarkers avenues that soon make transition into domain precision medicine clinical management patients BC.

Language: Английский

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Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer

Cancer Immunology Immunotherapy, Journal Year: 2023, Volume and Issue: 72(7), P. 1971 - 1989

Published: March 16, 2023

Abstract Bladder cancer (BC) can be divided into two subgroups depending on invasion of the muscular layer: non-muscle-invasive bladder (NMIBC) and muscle-invasive (MIBC). Its aggressiveness is associated, inter alia, with genetic aberrations like losses 1p, 6q, 9p, 9q 13q; gain 5p; or alterations in p53 p16 pathways. Moreover, there are reported metabolic disturbances connected poor diagnosis—for example, enhanced aerobic glycolysis, gluconeogenesis haem catabolism. Currently, primary way treatment method transurethral resection tumour (TURBT) adjuvant Bacillus Calmette–Guérin (BCG) therapy for NMIBC radical cystectomy MIBC combined chemotherapy immunotherapy. However, intravesical BCG immunotherapy immune checkpoint inhibitors not efficient every case, so appropriate biomarkers needed order to select proper options. It seems that success depends mainly microenvironment (TME), which reflects molecular tumour. TME consists specific conditions hypoxia local acidosis different populations cells including tumour-infiltrating lymphocytes, natural killer cells, neutrophils B responsible shaping response against neoantigens crucial pathways PD-L1/PD-1 axis. In this review, we summarise holistically impact system, changes key factors success. These findings should enable better understanding complexity case causes failures current therapies.

Language: Английский

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Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype

Cancers, Journal Year: 2023, Volume and Issue: 15(7), P. 2149 - 2149

Published: April 4, 2023

This study evaluated a panel including the molecular taxonomy subtype and expression of 27 genes as diagnostic tool to stratify bladder cancer patients at risk aggressive behavior, using well-characterized series non-muscle invasive (NMIBC) well muscle-invasive (MIBC). The was conducted novel NanoString nCounter gene analysis. technology allowed us identify analyze bladder-cancer-related selected through recent literature search. differential correlated with clinicopathological variables, such subtypes (luminal, basal, null/double negative), histological (conventional urothelial carcinoma, or carcinoma variant histology), clinical (NMIBC MIBC), tumor stage category (Ta, T1, T2–4), grade, PD-L1 (high vs. low expression), categories (low, intermediate, high very high). multivariate analysis 19 significant for cancer-specific survival in our cohort identified TP53 (p = 0.0001), CCND1 MKI67 < 0.005) independent predictors. A scoring system based on signature TP53, CCND1, used assessment. score ranging from 0 (best prognosis) 7 (worst obtained into two (low [score 0–2] 3–7], model A) three intermediate 3–4] 5–7], B) different characteristics. Mean longer (122 + 2.7 months) low-risk than intermediate-risk (79.4 9.4 high-risk (6.2 0.9 0.0001; A); (58 8.3 B). In conclusion, assessment model, reported here, might be better select appropriate management cancer.

Language: Английский

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Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation

British Journal of Cancer, Journal Year: 2023, Volume and Issue: 130(3), P. 369 - 379

Published: Dec. 15, 2023

Abstract Background Bladder cancer is one of the most common types worldwide. Generally, research relies on invasive sampling strategies. Methods Here, we generate bladder organoids directly from urine (urinoids). In this project, establish 12 urinoid lines 22 patients with non-muscle and muscle-invasive tumours, an efficiency 55%. Results The histopathological features urinoids accurately resemble those original tumours. Genetically, there a high concordance single nucleotide polymorphisms (92.56%) insertions & deletions (91.54%) between tumours patient 4. Furthermore, these show sensitivity to drugs, similar their tissue-derived organoid counterparts. Genetic analysis longitudinally generated tumoroids receiving systemic immunotherapy, identify alterations that may guide choice for second-line therapy. Successful treatment adaptation was subsequently demonstrated in setting. Conclusion Therefore, can advance precision medicine as non-invasive platform tumour pathogenesis, longitudinal drug-response monitoring, therapy adaptation.

Language: Английский

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Immunohistochemistry subtyping of urothelial carcinoma is feasible in the daily practice

Virchows Archiv, Journal Year: 2022, Volume and Issue: 481(2), P. 191 - 200

Published: June 22, 2022

Language: Английский

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Clinical utility of checkpoint inhibitors against metastatic bladder cancer: overcoming challenges to find a way forward

Expert Opinion on Biological Therapy, Journal Year: 2023, Volume and Issue: 23(5), P. 407 - 418

Published: April 10, 2023

Introduction Cisplatin-based chemotherapy is currently considered the gold-standard treatment for metastatic urothelial carcinoma (mUC). Nevertheless, most mUC patients develop resistance to chemotherapy. Immune checkpoint inhibitors (ICI) have emerged as a therapeutic option mUC. ICI are used both first- and second-line therapy with but also maintenance following durable responses may be expected in these settings.Areas covered Patients who experience progression after platinum-based regimens, those cisplatin-ineligible positive PD-L1 expression, platinum-ineligible, regardless of status, target population. The role monotherapy or drug combinations newer proposals reviewed. current status biomarkers guide treatments provided, focusing on PD-L1, tumor mutational load, liquid biopsies using ctDNA.Expert opinion Current challenges improve could summarized i) development better drugs; ii) advances drug-combinations schemes; iii) novel techniques select this treatment; iv) providing drugs optimal clinical setting; v) promoting trials covering more demographic heterogeneity (i.e. wider age range, gender, diverse representation).

Language: Английский

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Clinical and Biological Differences between Upper Tract Carcinoma and Bladder Urothelial Cancer, Including Implications for Clinical Practice

Cancers, Journal Year: 2023, Volume and Issue: 15(23), P. 5558 - 5558

Published: Nov. 23, 2023

Upper tract urothelial carcinoma (UTUC) is a rare disease included, along with the much more frequent bladder cancer (BUC), in family of carcinomas (UCs). However, while UTUCs and BUCs share several features, their epidemiological, clinical, pathological, biological differences must be considered to establish an optimal therapeutic strategy. This review examines clinical between UTUC BUC, as well main results obtained by molecular screening two diseases. The findings trials, performed peri-operative metastatic settings assessing systemic treatments UC, are summarised. A comparison data for BUC suggests improved approaches, both regards routine practice future drug development.

Language: Английский

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Erdafitinib for tumors with FGFR3 mutation: A promising targeted therapy

Cancer Research Statistics and Treatment, Journal Year: 2023, Volume and Issue: 6(2), P. 288 - 295

Published: April 1, 2023

CASE SUMMARY History and examination A 77-year-old gentleman, with no prior comorbidities or a family history of malignancy, presented in October 2021 to the outpatient department Tata Memorial Hospital, Mumbai, India, complaints loss appetite unintentional weight (of approximately 12 kgs) over past 5 months. In May 2021, he experienced an episode acute urinary retention, which required catheterization. He was prescribed tablet tamsulosin for this. view persistent repeated lower tract symptoms (burning micturition increased frequency), patient underwent further evaluation. At time presentation had Eastern Cooperative Oncology Group Performance Status 1 systemic revealed significant findings. Investigations diagnosis The undergone ultrasonography kidney bladder (USG KUB) consultation his general physician, heterogeneous echotexture left few hypoechoic areas associated cystic lesion third peripheral rim calcifications (maximum diameter 2.4 cm), grade 2 prostatomegaly [Figure 1]. then referred our center. Repeat USG at center diffusely measuring 8.6 × 4.9 cm echogenic endophytic causing distention proximal ureter, infiltration renal pelvis. Contrast-enhanced computed tomography (CECT) thorax, abdomen pelvis (TAP) [Figures 3] heterogeneously hypoenhancing mass interpolar region pole perinephric fat stranding extending into upper ureter. There were least four hypodensities segments VIII, VII, VI liver (largest 1.1 multiple enlarged enhancing irregular lesions both lungs right lobe 6.5 5.6 pre- paratracheal, hilar subcarinal nodes paratracheal node 1.8 cm).Figure 1: Ultrasonography showing (arrow) size cmFigure 2: stranding. – Anterior, P Posterior, R Right, L - LeftFigure 3: New onset exophytic soft tissue response contrast enhanced CT scan done December 2022 on erdafitinib therapyThe CT-guided biopsy lung November reported histopathology as carcinoma squamous differentiation. Immunohistochemistry (IHC) showed diffuse positivity p40, GATA binding protein 3 (GATA-3); it negative thyroid transcription factor (TTF1) paired-box gene 8 (PAX8). pathological metastatic urothelial differentiation considered. Additional IHC markers estrogen (ER), progesterone (PR), androgen receptors (AR) negative. tumor cells programmed death ligand (PD-L1) antibody by SP263 Ventana clone. sent next-generation sequencing (NGS). After thorough clinical, radiological histopathological evaluation, final (with differentiation) liver, non-regional nodal metastases made. Next-generation excerpts from discussion molecular board NGS using targeted panel (SOPHiA solid plus solution),[1] identified single nucleotide variants (SNVs), indels 44 genes, 139 ribonucleic acid (RNA) fusions, amplification events 24 genes microsatellite instability (MSI) status (6 unique loci). test has been standardized validated pathology laboratory institution. data analyzed annotation sources: dbSNP (Version 1), 1000 genomes ClinVar 4), COSMIC 3), EXAC 1).[2] Extracted deoxyribonucleic (DNA) RNA subjected library preparation, followed paired-end synthesis technology Illumina MiSeq platform.[3] Data analysis performed SOPHiA data-driven medicine (DDM) software. mutations according American College Medical Genetics Genomics (ACMG) guidelines, 2018, Human Genome Variation Society (HGVS) nomenclature. Genes < 500X coverage not interpreted. paraffin block (reports available February 2022, Table Tier I mutation Fibroblast Growth Factor Receptor (FGFR3) [Tier c.746C>G, p.(Ser249Cys) amino change, variant allele frequency (VAF)= 11.20] II likely pathogenic phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) [c.1633G>A p.(Glu545Lys) VAF=11.40]. FGFR3 S249C[4] is highly activating type seen carcinoma. This oncogenic sensitive tyrosine kinase inhibitors (TKI), hence considered I. Targeted therapy erdafitinib[5] recommended. Other possible options discussed infigratinib,[6] rogaratinib,[7] pemigatinib.[8]PIK3CA also targetable resistance mechanism FGFR inhibitors, but clinical rates PIK3CA inhibition have disappointing patients non-breast cancer (objective ([ORR] 3-6%, and, median progression-free survival [PFS] 3.4-5.5 months), recommended be used after exhaustion standard lines if rapid progression inhibition.[9] incidence 25% per Cancer Atlas (TCGA), 18% having hotspot alleles.[10]Table Next generation report 2021Treatment While awaiting results NGS, planned chemotherapy. evaluation frailty means geriatric assessment, started reduced dose chemotherapy (three-weekly gemcitabine 75% [days 8] carboplatin dosed area under free plasma concentration versus curve [AUC] 4).[11] three cycles interval increase number 2.3 1.5 segment VII), decrease 4.8 2.2 lobe), mediastinal cm) suggestive disease Response Evaluation Criteria Solid tumors version (RECIST, v1.1). Based (February 3, 2022), that point, India only compassionate basis platinum-based therapy. As patient's progressed + chemotherapy, treatment planned. Erdafinitib tolerance starting mg orally once daily, developed Grade hyperphosphatemia, correction close monitoring serum phosphate levels. there minimal reduction levels despite use oral binders, 7 September 2022. Patient could tolerate either hand-foot syndrome (HFS) temporarily withheld conservative management given. Erdafitinib restarted daily Progression CECT new 2.1 3], bilobar 4.7 3.3 cm, 4]), para-aortic lymph (measuring 1.3 patchy opacities Figure nodules bilateral parenchyma, paratracheal/subcarinal location), focal short segmental eccentric wall thickening involving sigmoid colon maximal thickness mm adjacent meso-colonic mesenteric nodes.Figure 4: contrast-enhanced therapy, well hepatic metastasisDue progressive disease, weekly paclitaxel 80 mg/m2 intravenously January 2023, continued. decision continue one, interruptions while solely attributed development (sub-optimal therapeutic exposure). One presence mutation. However, receiving second cycle paclitaxel, hospitalization mucositis HFS, following permanently discontinued. recovery, continued agent alone. Early 2023 lesions, changed atezolizumab, however, lost follow up subsequently. timeline shown 5.Figure 5: Timeline course mutations; = growth receptor Phosphatidyl inositol-4,5-bisphophate alpha, AUC Area curve, Generation Sequencing, Contrast-Enhanced Computed Tomography, TAP Thorax, Abdomen PelvisDISCUSSION Introduction FGFR3, belonging family, exhibits high expression chondrocytes osteoblasts, thereby playing critical role processes osteogenesis bone maintenance. Its governed gene, located chromosome 4.[12,13] Germline this are linked various disorders, including achondroplasia, chondrodysplasia, thanatophoric dysplasia.[14] These paternally inherited increasing paternal age.[12,15] signaling pathway fibroblast factors (FGF) FGF implicated tumoral epithelial-to-mesenchymal transition (EMT). overlaps mitogen-activated (MAPK) PI3-AKT pathways, influencing cellular such proliferation, differentiation, angiogenesis, metabolism, mobility, invasion.[16] protein, acts kinase, transmembrane single-pass structure. It consists immunoglobulin-like domains (IgI, IgII, IgIII) its extracellular region, domain intracellular domain.[17] Dimerization leads transphosphorylation sites, subsequently recognized src homology-2 (SH2) phosphotyrosine (PTB) adaptor proteins.[16,18,19] phosphorylation event triggers proteins, initiating downstream through major cascades: MAPK pathway, PI3K/AKT phospholipase C gamma signal transducer activator (STAT) pathway. carcinogenesis alterations transformation resulting genetic abnormalities. hyperactivation promotes cell metastasis, drug resistance.[20] context advanced carcinomas, detected 20% cases.[21-24] most commonly occurring cancers missense in-frame fusions transforming coiled coil (FGFR3-TACC3), occur 2% cases cancers.[22] Mutations Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) proteins responsible recurrent mutation, S249C (TCC→TGC). other types demonstrating APOBEC signature raising possibility target APOBEC-mediated ability generate clinically relevant driver mutations.[25] potential observed pre-translational level, circular (circRNA) product known Has_circ_0068871. circRNA proliferation migration.[26] Furthermore, tumors, antisense transcript FGFR3-AS1 stabilizes mRNA. This, turn, invasiveness, motility.[26,27] Bladder involves FGFR, EGFR, PI3/AKT/mTOR, RAS-MAPK, checkpoints, DNA damage repair. TCGA classified 4 subtypes as: Luminal cluster (consisting 30-35% total carcinomas) express FGFR3; (comprising carcinomas), HER2-, ER pattern; Basal III, similar basal-like breast carcinoma, head-and-neck carcinomas (20–25% carcinomas); IV, III 10–15% additional features surrounding stroma muscle).[27] clusters GATA3 whereas KRT5/6 IHC. double phenotype exists small proportion (4%) neither Tumors aggressive higher activation EMT early metastasis.[28] Treatment particularly directed towards luminal I, TCGA. Of note, subtype lowest anti PD-L1 atezolizumab nivolumab when compared lack immune marker expression.[29] classification prognostic value[30] non-muscle-invasive (associated conventional morphology), less expression, favorable outcomes terms overall survival. basal greater muscle invasive (variant histology), checkpoint inhibitor (ICI) mortality related cancer. Immunomodulatory effect study conducted genetically engineered p53 mutated mouse model statistically improvement (OS, OS 19.7 weeks vs 13.4 weeks, ≤ 0.01) combined immunotherapy (10 mg/kg, Bio X Cell, RMP1-14) Prior exposure, micro-environment cold immunosuppressive abundance i.e. T-regulatory (Tregs). Following exposure erdafitinib, CD4+ CD8+ T-cell noted can deduced study, monotherapy immunomodulatory potentiating benefit combination.[31] To strengthen hypothesis, ongoing phase Ib/II NORSE trial evaluating safety efficacy combination cetrelimab (immunoglobulin G4 monoclonal specific PD-1) cisplatin-ineligible participants locally select disease.[32,33] Previous vitro assays demonstrated enhancement function PD-1 mediated suppression reversal anti-PD-1 antibody. addition, drives clone expansion, microenvironment immunologic changes which, turn supports antitumor immunity survival.[26] Updated promising confirmed objective rate (ORR) 55% 11 evaluable control (including unconfirmed complete response, partial stable disease) 100%.[34] indicator Aberrations grades stages. Approximately 49–84% non-muscle muscle-invasive carcinomas.[35-37] Despite their association disease-specific rates.[30–32] Although more common T1 luminal-papillary cancers, currently evidence validate claim stage correlate phenotype. fact, aberrations chemotherapy.[29,38,39] Erdafitinib: pan-FGFR oral, (1-4) TKI potent all activity.[40] granted accelerated approval United States Food Drug Administration (FDA) second-line adults FGFR2/3 (mutations/fusions) whose one line platinum-containing approved based BLC2001 open-label, arm led 40% ORR (95% CI, 30–49) unresectable fusion.[5,41] follow-up months, PFS 5.5 months 4.2–6.0), 13.8 9.8–not reached). Given (mutations/fusions), trials different settings. Additionally, may heightened responses sensitivity interventions.[33] studies effects microenvironment, research solidify hypothesis.[33] beyond targets Alteration (FGFRalt), malignancies. single-arm called RAGNAR (NCT04083976): alterations," being investigated pre-treated adult pediatric harboring FGFRalt.[33,42] aims explore benefits broad range malignancies (beyond carcinoma) alterations. profile daily. two long remain below mg/dL. Hyperphosphatemia class 76 (77%) study.[5] toxicities included stomatitis (n 57; 58%), diarrhea 50; 51%), dry mouth 45; 46%). ≥ 10, 10%), hyponatremia 11; 11%) asthenia 7; 7%). 3% 2) enrolled subjects retinal pigment epithelium detachment, discontinuation drug.[33,42,43] Close phosphorus essential erdafitinib. plays pivotal regulation levels, hyperphosphatemia might lead mineralization, cutaneous calcinosis, non-uremic calciphylaxis, and/or vascular calcification. Increased Median documented 20 days (range, 8-116). Cutaneous calcification 0.3% patients. avoid concurrent agents potassium phosphate, vitamin D supplements, antacids, phosphate-containing enemas laxatives, medications excipients before initial (days 14-21) period. Phosphate intake should restricted 600-800 exceed mg/dL, binder until fall well, (tablet sevelamer carbonate 400 times day antacid syrup) added level 6.8 When did respond normalize, decreased mg. Our reductions due toxicities, namely, fatigue, mucositis, requiring in-patient hospital admission, parenteral nutrition, anti-mucositis measures, topical emollients, therefore never escalated full dose. sub-therapeutic blood reasons PFS. whom successfully 9 numerically 48.8%.[41] Central serous retinopathy (CSR) another important class-specific adverse inhibitors. disruption normal ocular FGFR–MAPK leading accumulation fluid between neural retina resultant epithelial dysfunction central retinopathy. first retinopathy/retinal detachment 50 days, resolution 13% CSR/retinal study. discontinued.[41,43,44] toxicity generally presents visual impairment , asymptomatic edema limited fovea. For (or any inhibitor), monthly ophthalmological examinations during visits ophthalmologist. Dry eyes about quarter patients, eye lubricants used. needs immediately discontinued worsening acuity than 20/40 (Grade Common Terminology Adverse Events v4.03).[45] date, pemigatinib FGFR-altered cholangiocarcinoma, respectively. marketed non-selective nintedanib, regorafenib (metastatic colorectal cancer, gastrointestinal stromal hepatocellular carcinoma), pazopanib sarcoma) sunitinib lieu selective CONCLUSION evolved alteration (mutation/fusion) positive however almost half prompt effects. Overall, represents advancement offering renewed hope improved previously scenario. With better understanding underlying mechanisms, will expected population. Declaration consent authors certify they obtained appropriate forms. form, given images information journal. understands name initials published, efforts made conceal identity, anonymity cannot guaranteed. Financial support sponsorship Nil. Conflicts interest Vanita Noronha, Anuradha Chougule, Kumar Prabhash members editorial Research, Statistics Treatment. such, access participated decisions perceived publication manuscript. recused themselves peer review, editorial, decision-making process manuscript, ensure content unbiased.

Language: Английский

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