An editorial comment for the special series "Upper-Tract Urothelial Carcinoma: Current State and Future Directions".
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SUBMITTER: Knoedler JJ
PROVIDER: S-EPMC7475657 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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An editorial comment for the special series "Upper-Tract Urothelial Carcinoma: Current State and Future Directions".
Knoedler John J JJ Raman Jay D JD
Translational andrology and urology 20200801 4
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Project description:Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas. In particular, it has been reported that UTUC harbored a higher level of FGFR3 alterations associated with a T-cell depleted immune microenvironment. The therapeutic landscape in urothelial carcinoma is rapidly evolving, with immune checkpoint inhibitors forming part of the standard of care. A greater understanding of the molecular alterations and immune microenvironment leads to the development of new treatment combinations and targeted therapy. This review summarizes the available evidence concerning the use of immune checkpoint inhibitors and the biological rationale underlying their use in high-grade UTUC.
| S-EPMC8431384 | biostudies-literature
Project description:Upper urinary tract urothelial carcinoma (UTUC) accounts for 5% to 10% of urothelial carcinomas and two-thirds are high-grade at the time of diagnosis. The gold standard management of high-grade UTUC is radical nephroureterectomy (RNU). Despite primary treatment, disease recurrence involves the bladder in 22% to 47% of cases. Single dose, postoperative intravesical chemotherapy (pIVC) is an adjunct to RNU to decrease bladder recurrences that is currently recommended in guidelines from the European Association of Urology, National Cancer Center Network, and American Urological Association. Two clinical trials, using single dose, postoperative intravesical mitomycin C or pirarubicin, have provided level 1 evidence to support the formation of these guidelines. Despite this evidence, pIVC utilization is reportedly low among urologists, ranging from 12% to 55% among three studies, with non-utilizers citing lack of supporting evidence, safety concerns, and clinical infrastructure as leading rationale. In the past 10 years, no additional trials on single dose pIVC have been completed and validated in systematic reviews or meta-analyses. Utilization of pIVC still has room for improvement and further studies on this subject are warranted to overcome the barriers to implementation. Herein, we describe the critical literature that supports guideline recommendations for single dose pIVC after RNU to understand efficacy, safety, practice patterns, and discuss the future directions of this treatment adjunct.
| S-EPMC10719762 | biostudies-literature
Project description:Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for firstline platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.
| S-EPMC5332938 | biostudies-literature
Project description:IntroductionUpper tract urothelial carcinoma (UTUC) is a relatively uncommon urologic malignancy for which there has not been significant improvement in survival over the past few decades, highlighting the need for optimal multi-modality management.MethodsA non-systematic review of the latest literature was performed to include relevant articles up to June 2019. It summarizes the epidemiologic risk factors associated with UTUC, including smoking, carcinogenic aromatic amines, arsenic, aristolochic acid, and Lynch syndrome. Molecular pathways underlying UTUC and potential druggable targets are outlined.ResultsSurgical management for UTUC includes kidney-sparing surgery (KSS) for low-risk disease and radical nephroureterectomy (RNU) for high-risk disease. Endoscopic management of UTUC may include ureteroscopic or percutaneous resection. Topical instillation therapy post-KSS aims to reduce recurrence, progression and to treat carcinoma-in-situ; this may be achieved retrogradely (via ureteric catheterization), antegradely (via percutaneous nephrostomy) or via reflux through double-J stent. RNU, which may be performed via open, laparoscopic or robot-assisted approaches, is the gold standard treatment for high-risk UTUC. The distal cuff may be dealt with extravesical, transvesical or endoscopic techniques. Peri-operative chemotherapy and immunotherapy are increasingly utilized; level 1 evidence exists for adjuvant chemotherapy, but neoadjuvant chemotherapy is favored as kidney function is better prior to RNU. Immunotherapy is primarily reserved for metastatic UTUC but is currently being investigated in the perioperative setting.ConclusionThe optimal management of UTUC includes a firm understanding of the epidemiological factors and molecular pathways. Surgical management includes KSS for low-risk disease and RNU for high-risk disease. Peri-operative immunotherapy and chemotherapy may be considered as evidence mounts.
| S-EPMC6954076 | biostudies-literature
Project description:Cancers of the biliary tree represent a rare group of diseases with a devastating impact on patients. Gallbladder cancer often is associated with cholelithiasis. Cholangiocarcinoma may arise in the setting of biliary inflammation, such as primary sclerosing cholangitis, but most commonly occurs in patients without a particular risk factor. Surgical removal of biliary cancer is essential for cure, but it is associated with a very high rate of recurrence and for many patients is not possible at the time of diagnosis. Although risk factors differ for each anatomic site, systemic treatment is generally similar. Various adjunctive therapies, such as radiation and embolization, have been investigated for biliary tract cancers with modest success and efforts are ongoing to understand how to optimize these tools. Retrospective series and pooled analysis suggest a benefit for adjuvant treatment following resection, but prospective data are limited. Ongoing and planned phase 3 trials should help to clarify the role of adjuvant chemotherapy and radiation. For advanced disease, chemotherapy improves quality of life and survival, and gemcitabine with cisplatin represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients.
| S-EPMC3769474 | biostudies-other
Project description:Though radical nephroureterectomy remains the gold standard treatment for high grade or invasive disease in upper tract urothelial cancer (UTUC), kidney-sparing surgery has become preferred for low risk disease, in order to minimize morbidity and preserve renal function. Many methods exist for endoscopic management, whether via an antegrade percutaneous or retrograde ureteroscopic approach, including electroresection, laser ablation, and fulguration. There has been an increase in use of adjuvant intracavitary therapy, predominantly using mitomycin and bacillus Calmette-Guerin (BCG), to reduce recurrence after primary endoscopic management for noninvasive tumors, although efficacy remains questionable. Intraluminal BCG has additionally been used for primary treatment of CIS in the upper tract, with around 50% success. Newer investigations include use of narrow band imaging or photodynamic diagnosis with ureteroscopy to improve visualization during diagnosis and treatment. Genomic characterization may improve selection for kidney-sparing surgery as well as identify actionable mutations for systemic therapy. The evolution in adjuvant management has seen strategies to increase the dwell time and the urothelial contact of intraluminal agents. Lastly, chemoablation using a hydrogel for sustained effect of mitomycin is under investigation with promising early results. Continued expansion of the armamentarium available and better identification and characterization of tumors ideal for organ-sparing treatment will further improve kidney preservation in UTUC.
| S-EPMC7475682 | biostudies-literature
Project description:Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor (FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a "precision medicine" strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.
| S-EPMC9400707 | biostudies-literature
Project description:Glucocorticoids are the most effective anti-inflammatory therapy for asthma yet are relatively ineffective in chronic obstructive pulmonary disease. Glucocorticoids suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to co-activator molecules and recruitment of histone deacetylase-2 to the activated inflammatory gene transcription complex (trans-repression). At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects (trans-activation). Glucocorticoids also have post-transcriptional effects and decrease stability of some pro-inflammatory mRNA species. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with chronic obstructive pulmonary disease. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve post-translational modifications of GR. Histone deacetylase-2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids and selective GR modulators which show improved trans-repression over trans-activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance.
| S-EPMC3085866 | biostudies-literature
Project description:BackgroundDespite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.ObjectiveTo investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Design, setting, and participantsTumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.Outcome measurements and statistical analysisWe described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Results and limitationsComparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.ConclusionsHigh-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Patient summaryComparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.
| S-EPMC4675454 | biostudies-literature
Project description:BackgroundUpper tract urothelial carcinoma (UTUC) is a rare disease with a potentially dismal prognosis. We systematically compared international guidelines on UTUC to analyze similitudes and differences among them.MethodsWe conducted a search on MEDLINE/PubMed for guidelines related to UTUC from 2010 to the present. In addition, we manually explored the websites of urological and oncological societies and journals to identify pertinent guidelines. We also assessed recommendations from the International Bladder Cancer Network, the Canadian Urological Association, the European Society for Medical Oncology, and the International Consultation on Bladder Cancer, considering their expertise and experience in the field.ResultsAmong all the sources, only the American Urologist Association (AUA), European Association of Urology (EAU), and the National Comprehensive Cancer Network (NCCN) guidelines specifically report data on diagnosis, treatment, and follow-up of UTUC. Current analysis reveals several differences between all three sources on diagnostic work-up, patient management, and follow-up. Among all, AUA and EAU guidelines show more detailed indications.ConclusionsDespite the growing incidence of UTUC, only AUA, EAU, and NCCN guidelines deal with this cancer. Our research depicted high variability in reporting recommendations and opinions. In this regard, we encourage further higher-quality research to gain evidence creating higher grade consensus between guidelines.
| S-EPMC10969327 | biostudies-literature