Abstract:Gallbladder cancer (GBC) is a rare, highly aggressive malignancy with a 5-year survival rate of 5–10% in advanced cases, highlighting the need for more effective therapies. The aim of this study was to identify potentially actionable therapeutic targets for GBC. Specimens and clinicopathological data of 642 GBC patients, diagnosed between 2000 and 2019 were collected using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry. All cases were histologically reviewed and a subset was subjected… Show more
“…The etiology of cholecystitis is complex and constitutes an independent risk factor for the incidence of extrahepatic biliary tract malignancies, including gallbladder cancer (24). Given the unfavorable prognosis associated with gallbladder cancer, with an overall 5-year survival rate of less than 10% (25), proactive measures to prevent cholecystitis assume paramount importance in the prevention of gallbladder cancer. Numerous risk factors associated with cholecystitis in the general population have been identi ed, including prolonged fasting, rapid weight loss, total parenteral nutrition, and somatostatin(-analogue) treatment, which signi cantly increase the risk of developing the condition(26).…”
Background and aims: Overlapping symptoms of gastroesophageal reflux disease (GERD) and cholecystitis include belching, acid reflux, and heartburn. Nevertheless, the causal relationship between these two conditions remains uncertain. The study aimed to investigate the causal relationship between GERD and cholecystitis via the Mendelian randomization (MR) approach.Methods A two-sample MR analysis utilizing the inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods was conducted to assess the causal effects of GERD on the risk of cholecystitis. The genome-wide association studies (GWASs) for GERD (n = 602604) and cholecystitis (n = 361194) were obtained from the MR-base platform. The pleiotropy and heterogeneity were assessed using various techniques.Results A total of 77 single nucleotide polymorphisms from GWASs with GERD were selected as instrumental variables (IVs). The primary IVW method demonstrated a significant association between GERD and an elevated risk of cholecystitis [odds ratio (OR) = 1.004; 95% CI 1.003–1.005, p = 2.68×10− 9]. The absence of heterogeneity and pleiotropy in the data suggested that the results were dependable.Conclusion Our study demonstrated a positive correlation between GERD and the likelihood of developing cholecystitis. These findings may serve as a fundamental basis for comprehending the intricate interplay between GERD and cholecystitis. However, additional investigations are warranted to elucidate the precise underlying mechanisms of this plausible causal relationship.
“…The etiology of cholecystitis is complex and constitutes an independent risk factor for the incidence of extrahepatic biliary tract malignancies, including gallbladder cancer (24). Given the unfavorable prognosis associated with gallbladder cancer, with an overall 5-year survival rate of less than 10% (25), proactive measures to prevent cholecystitis assume paramount importance in the prevention of gallbladder cancer. Numerous risk factors associated with cholecystitis in the general population have been identi ed, including prolonged fasting, rapid weight loss, total parenteral nutrition, and somatostatin(-analogue) treatment, which signi cantly increase the risk of developing the condition(26).…”
Background and aims: Overlapping symptoms of gastroesophageal reflux disease (GERD) and cholecystitis include belching, acid reflux, and heartburn. Nevertheless, the causal relationship between these two conditions remains uncertain. The study aimed to investigate the causal relationship between GERD and cholecystitis via the Mendelian randomization (MR) approach.Methods A two-sample MR analysis utilizing the inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods was conducted to assess the causal effects of GERD on the risk of cholecystitis. The genome-wide association studies (GWASs) for GERD (n = 602604) and cholecystitis (n = 361194) were obtained from the MR-base platform. The pleiotropy and heterogeneity were assessed using various techniques.Results A total of 77 single nucleotide polymorphisms from GWASs with GERD were selected as instrumental variables (IVs). The primary IVW method demonstrated a significant association between GERD and an elevated risk of cholecystitis [odds ratio (OR) = 1.004; 95% CI 1.003–1.005, p = 2.68×10− 9]. The absence of heterogeneity and pleiotropy in the data suggested that the results were dependable.Conclusion Our study demonstrated a positive correlation between GERD and the likelihood of developing cholecystitis. These findings may serve as a fundamental basis for comprehending the intricate interplay between GERD and cholecystitis. However, additional investigations are warranted to elucidate the precise underlying mechanisms of this plausible causal relationship.
“…Most notably, two of the most common actionable genomic alterations with FDA-approved targeted therapies, IDH1 and FGFR2 alterations, occurring approximately 18% and 15% of iCCA, respectively, are rarely found in eCCA [ 15 , 25 •, 26 , 27 ]. Given that up to 50% of patients with BTC have an potentially actionable mutations [ 28 , 29 ] with targeted agents, guideline-recommended therapy should always include upfront molecular testing on patients with unresectable BTC [ 2 ]. Fig.…”
Section: Molecular Pathogenesis and Distinctive Molecular Characteris...mentioning
Opinion statementBiliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.
“…This approval was somewhat controversial [ 84 ] as many researchers called into question the generalizability of a universal TMB cutoff of 10 mutations/Mb to define high TMB across all tissue sites [ 80 , 85 ]. Further studies attempting to validate TMB as a predictive marker for response to immunotherapy in all cancer types were unable to prove differences in ORR based on TMB alone [ 86 ].…”
Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon.
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