Achilonu, Conrad C

Abstract Background Alveolar macrophages (AMs) are central to host defense against Pneumocystis, mediating organism clearance while also contributing to lung inflammation. EphA2, a transmembrane receptor that binds fungal β-glucans, has emerged as a regulator of host–pathogen interactions, but its role in AM responses during Pneumocystis pneumonia (PCP) is unknown. Methods We evaluated AM inflammatory responses to Pneumocystis β-glucans in the presence and absence of EphA2. In vivo studies used a CD4-depleted mouse model of PCP comparing wild-type and EphA2-deficient (EphA2−/−) mice. Lung cytokine responses and organism burden were assessed. Additionally, EphA2 signaling was pharmacologically inhibited using ALW-II-41-27 during trimethoprim-sulfamethoxazole treatment. Results EphA2 deficiency significantly reduced AM proinflammatory cytokine responses to Pneumocystis β-glucans. In CD4-depleted PCP mice, EphA2−/− animals demonstrated decreased lung inflammatory cytokines, but increased organism burden compared to controls. Pharmacologic inhibition of EphA2 during antimicrobial therapy significantly suppressed lung inflammation. Conclusions EphA2 signaling plays a critical role in AM-mediated host defense against Pneumocystis by promoting inflammatory responses necessary for organism control. However, this pathway also contributes to lung inflammation. Targeting EphA2 may represent a novel strategy to modulate inflammation during severe PCP while preserving antimicrobial defense.

Introduction. Aspergillus fumigatus phosphoglucomutase ( Af PGM) is a central enzyme in fungal carbohydrate metabolism that catalyses the interconversion of glucose-1-phosphate and glucose-6-phosphate, generating precursors such as uridine diphosphate glucose required for the synthesis of key cell wall polysaccharides. Hypothesis/Gap Statement. Although Af PGM has been implicated in fungal viability and cell wall integrity, further functional and molecular characterization is required to better define its role in cell wall-associated processes and to evaluate its potential as a selective antifungal target. Aim. This study aimed to further characterize the functional contribution of Af PGM to fungal growth, cell wall-related phenotypes, biofilm formation and enzymatic activity. Methodology. A conditional A. fumigatus P alcA ::pgm mutant was used to assess growth, soluble β -glucan levels and biofilm formation. Functional complementation was evaluated by heterologous expression of Afpgm in a Saccharomyces cerevisiae pgm2Δ strain. Enzymatic inhibition was examined using the isothiazolone compound ISFP10. Results. Reduced Af PGM activity was associated with impaired growth, altered cell wall-related phenotypes, decreased soluble β -glucan levels and diminished biofilm biomass. Expression of Afpgm restored growth and sedimentation defects in the yeast pgm2Δ mutant to WT levels, confirming functional conservation. ISFP10 inhibited Af PGM activity and disrupted associated fungal phenotypes. Conclusion. These findings further define the functional role of Af PGM in fungal carbohydrate metabolism and cell wall-associated biology. The selective inhibition of Af PGM relative to human phosphoglucomutase supports its potential as a promising target for the development of novel antifungal therapies.

Primary tumor resection and liver transplantation are the only curative treatment options for the management of cholangiocarcinoma (CCA). However, for patients with advanced or metastatic disease, palliative systemic therapy remains the only treatment option. The development of targeted therapeutics has begun to shift the treatment paradigm in CCA. Targets of interest in CCA include mutated isocitrate dehydrogenase-1 (mIDH-1), human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and fibroblast growth factor receptor 2 (FGFR2) fusion, in addition to less frequently observed targets such as BRAF V600E, deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and high tumor mutation burden (TMB-H). These targets are observed in varying frequency among patients with intrahepatic CCA and extrahepatic CCA. Multiple novel therapies have been developed to exploit each of these targets, with some having received United States Food and Drug Administration approval for use in the second-line setting. In the current review, we discuss targets of interest in CCA and summarize current evidence evaluating available therapies directed at these targets.

Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.

Biliary tract cancers are a diverse and aggressive malignancy that carry a poor chance for curative treatment and significant associated mortality. Current first-line treatment only extends median overall survival to roughly 1 year and is associated with a significant adverse event profile. Recently, advancements in genetic sequencing have opened new avenues of targeted treatment. In cholangiocarcinoma, FGFR2 alterations have been shown to be present in roughly 10–15% of intrahepatic cholangiocarcinoma. Pemigatinib, a FGFR1–4 inhibitor, has been shown to significantly extend survival in the second-line setting to over 20 months in patients who harbor FGFR2 fusions. Here, we outline the development and future direction of pemigatinib and other FGFR2 inhibitors in the field of advanced biliary tract cancers.

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.

Liver transplantation for cholangiocarcinoma has been an absolute contraindication worldwide due to poor results. However, in recent years and thanks to improvements of patient management and treatments of this cancer, this indication has been revisited. This consensus paper, approved by the International Liver Transplant Society, aims to provide a collection of expert opinions, consensus, and best practices surrounding liver transplantation for cholangiocarcinoma.