Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer

Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.

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Intramedullary spinal cord tumors: a review of current and future treatment strategies

Neurosurgical FOCUS ◽

10.3171/2015.5.focus15158 ◽

2015 ◽

Vol 39 (2) ◽

pp. E14 ◽

Cited By ~ 57

Author(s):

Matthew K. Tobin ◽

Joseph R. Geraghty ◽

Herbert H. Engelhard ◽

Andreas A. Linninger ◽

Ankit I. Mehta

Keyword(s):

Spinal Cord ◽

Treatment Options ◽

Treatment Strategies ◽

Incidence Rates ◽

Subtotal Resection ◽

Spinal Cord Tumors ◽

Intramedullary Spinal Cord ◽

Low Incidence ◽

New Research ◽

Localized Drug Delivery

Intramedullary spinal cord tumors have low incidence rates but are associated with difficult treatment options. The majority of patients with these tumors can be initially treated with an attempted resection. Unfortunately, those patients who cannot undergo gross-total resection or have subtotal resection are left with few treatment options, such as radiotherapy and chemotherapy. These adjuvant treatments, however, are associated with the potential for significant adverse side effects and still leave patients with a poor prognosis. To successfully manage these patients and improve both their quality of life and prognosis, novel treatment options must be developed to supplement subtotal resection. New research is underway investigating alternative therapeutic approaches for these patients, including directed, localized drug delivery and nanomedicine techniques. These and other future investigations will hopefully lead to promising new therapies for these devastating diseases.

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„The German- Registry” of Incidental gallbladder cancer and the GAIN- phase III trial – transformation from a registry to treatment platform due to a trial in trial concept

Zeitschrift für Gastroenterologie ◽

10.1055/s-0038-1668964 ◽

2018 ◽

Vol 56 (08) ◽

pp. e318-e318

Author(s):

TO Goetze ◽

V Paolucci ◽

SE Al-Batran

Keyword(s):

Gallbladder Cancer ◽

Phase Iii ◽

Phase Iii Trial ◽

Incidental Gallbladder Cancer ◽

German Registry

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TBE in Italy

Tick-borne encephalitis - The Book ◽

10.33442/26613980_12b15-3 ◽

2020 ◽

Keyword(s):

Surveillance System ◽

Ad Hoc ◽

National Level ◽

Case Series ◽

Incidence Rates ◽

Mountainous Regions ◽

North East ◽

The North ◽

Tick Borne Encephalitis ◽

Low Incidence

Italy is considered a low-incidence country for tick-borne encephalitis (TBE) in Europe.1 Areas at higher risk for TBE in Italy are geographically clustered in the forested and mountainous regions and provinces in the north east part of the country, as suggested by TBE case series published over the last decade.2-5 A national enhanced surveillance system for TBE has been established since 2017.6 Before this, information on the occurrence of TBE cases at the national level in Italy was lacking. Both incidence rates and the geographical distribution of the disease were mostly inferred from endemic areas where surveillance was already in place, ad hoc studies and international literature.1

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The Role of Diabetes Mellitus in Diseases of the Gallbladder and Biliary Tract

Current Diabetes Reviews ◽

10.2174/1573399816666200305094727 ◽

2020 ◽

Vol 16 (9) ◽

pp. 931-948

Author(s):

Benjamin Rahmani ◽

Jason Gandhi ◽

Gunjan Joshi ◽

Noel L. Smith ◽

Inefta Reid ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Diabetic Neuropathy ◽

Gallbladder Cancer ◽

Biliary Tract ◽

Treatment Approach ◽

Database Search ◽

Heavy Burden ◽

Prevalence Of Diabetes Mellitus

Background: The increasing prevalence of diabetes mellitus worldwide continues to pose a heavy burden. Though its gastrointestinal impact is appropriately recognized, the lesser known associations may be overlooked. Objective: We aim to review the negative implications of diabetes on the gallbladder and the biliary tract. Methods: A MEDLINE® database search of literature was conducted with emphasis on the previous five years, combining keywords such as "diabetes," "gallbladder," and "biliary". Results: The association of diabetes to the formation of gallstones, gallbladder cancer, and cancer of the biliary tract are discussed along with diagnosis and treatment. Conclusion: Though we uncover the role of diabetic neuropathy in gallbladder and biliary complications, the specific individual diabetic risk factors behind these developments is unclear. Also, in addition to diabetes control and surgical gallbladder management, the treatment approach also requires further focus.

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A Population-Based Retrospective Study of Biliary Tract Cancers in Alberta, Canada

Current Oncology ◽

10.3390/curroncol28010044 ◽

2021 ◽

Vol 28 (1) ◽

pp. 417-427

Author(s):

Carissa Beaulieu ◽

Arthur Lui ◽

Dimas Yusuf ◽

Zainab Abdelaziz ◽

Brock Randolph ◽

...

Keyword(s):

Biliary Tract ◽

Demographic Data ◽

Performance Status ◽

Single Agent ◽

Eastern Cooperative Oncology Group ◽

Intrahepatic Bile Duct ◽

Population Based ◽

Phase Iii ◽

First Line ◽

Biliary Tract Cancers

Background: Biliary tract cancers (BTC) are uncommon malignancies and are underrepresented in the literature. Methods: We performed a retrospective population-based review of adult patients with biopsy-confirmed BTC in Alberta from 2000 to 2015. Demographic data, risk factors, symptoms, treatment, and staging data were collected and analyzed. Survival analyses were completed. Results: A total of 1604 patients were included in our study, of which 766 (47.8%) were male. The median age at diagnosis was 68 (range 19–99). There were 374 (23.3%) patients with resectable tumors at diagnosis versus 597 (37.2%) with unresectable tumors. Of the patients, 380 (21.5%) received chemotherapy (CT) and 81 (5.0%) underwent radiation therapy. There was a clear trend with worsening stage and performance status associated with shorter median overall survival (OS). Ampulla of Vater tumors had the best median OS (25.69 months), while intrahepatic bile duct cancers had the worst (5.78 months). First-line palliative CT regimens included gemcitabine+cisplatin (OS 14.98 months (mo), n = 212), single agent gemcitabine (OS 12.42 mo, n = 22), capecitabine (OS 8.12 mo, n = 8), and capecitabine+gemcitabine (OS 6.93 mo, n = 13). Patients with advanced or metastatic disease who received first-line gemcitabine+cisplatin had a median OS of 11.8 months (n = 119). Conclusion: BTCs have poor survival. Worse outcomes occur in higher stage and poorer Eastern Cooperative Oncology Group (ECOG) performance status patients across all tumor subtypes. Tumor resectability at diagnosis was associated with better OS. Our study supports the use of gemcitabine+cisplatin as a combination first-line palliative CT, as patients treated in Alberta have a comparable OS to that reported in the ABC-02 phase III study.

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Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease

Gut ◽

10.1136/gutjnl-2020-323888 ◽

2021 ◽

pp. gutjnl-2020-323888

Author(s):

Stephan Urban ◽

Christoph Neumann-Haefelin ◽

Pietro Lampertico

Keyword(s):

Hepatitis B ◽

Hepatitis B Surface Antigen ◽

Treatment Strategies ◽

Phase Iii ◽

Interferon Α ◽

T Cell Epitopes ◽

The European Union ◽

Hepatitis D ◽

Hepatitis D Virus

Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5–10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.

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Renal Complications Related to Checkpoint Inhibitors: Diagnostic and Therapeutic Strategies

Diagnostics ◽

10.3390/diagnostics11071187 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1187

Author(s):

Julie Belliere ◽

Julien Mazieres ◽

Nicolas Meyer ◽

Leila Chebane ◽

Fabien Despas

Keyword(s):

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Kidney Injury ◽

Immunosuppressive Drugs ◽

Peripheral Tolerance ◽

Electrolyte Disorders ◽

Glomerular Diseases ◽

Renal Complications ◽

Lower Baseline ◽

Low Incidence

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are associated with the occurrence of immune-related adverse events. Despite their low incidence, renal complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, identify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored immunosuppressive drugs when renal response is not achieved.

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