RESUMEN
Fibroblast growth factor receptor (FGFR)-2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Compuestos de Fenilurea , Quinolinas , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Conductos Biliares Intrahepáticos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patologíaRESUMEN
The host microbiome is polymorphic, compartmentalized, and composed of distinctive tissue microbiomes. While research in the field of cancer immunotherapy has provided an improved understanding of the interaction with the gastrointestinal microbiome, the significance of the tumor-associated microbiome has only recently been grasped. This article provides a state-of-the-art review about the tumor-associated microbiome and sheds light on how local tumor microbiota shapes anticancer immunity and influences checkpoint immunotherapy outcome. The direct route of interaction between cancer cells, immune cells, and microbiota in the tumor microenvironment is emphasized and advocates a focus on the tumor-associated microbiome in addition to the spatially separated gut compartment. Since the mechanisms underlying checkpoint immunotherapy modulation by tumor-associated microbiota remain largely elusive, future research should dissect the pathways involved and outline strategies to therapeutically modulate microbes and their products within the tumor microenvironment. A more detailed knowledge about the mechanisms governing the composition and functional quality of the tumor microbiome will improve cancer immunotherapy and advance precision medicine for solid tumors.
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Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Inmunoterapia , Neoplasias/terapia , Microambiente TumoralRESUMEN
Herpes simplex virus 1 (HSV-1) is a frequently unrecognized, yet deadly cause of acute liver failure (ALF). We, therefore, analysed three cases of fatal HSV-1-induced ALF. All patients shared clinical (extremely elevated transaminases, LDH and AST/LDH ratio < 1) and virological characteristics (ratio of viral load in plasma versus throat swabs: 60-700-fold, lack of anti-HSV-1-IgG antibodies or low IgG-avidity during primary infection), which may help to identify patients at risk. Additionally, in vitro chemosusceptibility assays revealed high efficacy of the helicase-primase inhibitors (HPI), pritelivir and drug-candidate IM-250 compared to acyclovir (ACV) using HSV-1-isolates from two patients; hence, ACV/HPI-combinations might offer new therapeutic options for HSV-induced ALF.
Asunto(s)
Herpesvirus Humano 1 , Fallo Hepático Agudo , Aciclovir/farmacología , Aciclovir/uso terapéutico , Antivirales/efectos adversos , ADN Helicasas , ADN Primasa , Humanos , Inmunoglobulina G , Fallo Hepático Agudo/inducido químicamente , Piridinas/efectos adversosRESUMEN
BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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Carcinoma Hepatocelular/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/fisiopatología , Femenino , Alemania , Humanos , Inmunoterapia/métodos , Inmunoterapia/estadística & datos numéricos , Italia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Suiza , Resultado del TratamientoRESUMEN
Intrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.
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Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.
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Cranio-cervico-facial tumors are rare. While ultrasound is the gold-standard method for diagnosing these anomalies, three-dimensional ultrasound and prenatal magnetic resonance imaging are complementary tools for reaching a precise diagnosis. Hemangiomas, meningoceles, proboscis lateralis, skin appendages and other fetal tumors are the main differential diagnoses. The prenatally assumed diagnosis of these malformations can change postnatally, with the ready identifcation of additional clinical features. We present a case of prenatally suspected proboscis lateralis. This diagnosis was revised postnatally to a facial hemangioma. The tumor did not regress with ß-blocker therapy for 5â¯months, and so a biopsy was then performed, which showed it was a granular cell tumor (GCT). This was later successfully excised, with clear margins. This case is important because there has been only one reported case of neonatal GCT, and because it shows that even with technologically advanced prenatal diagnostic methods, reaching the correct diagnosis can still be challenging.
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Recent studies identified the SLC26A9 Cl(-) channel as a modifier and potential therapeutic target in cystic fibrosis (CF). However, understanding of the regulation of SLC26A9 in epithelia remains limited and cellular models with stable expression for biochemical and functional studies are missing. We, therefore, generated Fisher rat thyroid (FRT) epithelial cells with stable expression of HA-tagged SLC26A9 via retroviral transfection and characterized SLC26A9 expression and function using Western blotting, immunolocalization, whole cell patch-clamp, and transepithelial bioelectric studies in Ussing chambers. We demonstrate stable expression of SLC26A9 in transfected FRT (SLC26A9-FRT) cells on the mRNA and protein level. Immunolocalization and Western blotting detected SLC26A9 in different intracellular compartments and to a lesser extent at the cell surface. Whole cell patch-clamp recordings demonstrated significantly increased constitutive Cl(-) currents in SLC26A9-FRT compared with control-transduced FRT (Control-FRT) cells (P < 0.01). Similar, transepithelial measurements showed that the basal short circuit current was significantly increased in SLC26A9-FRT vs. Control-FRT cell monolayers (P < 0.01). SLC26A9-mediated Cl(-) currents were increased by cAMP-dependent stimulation (IBMX and forskolin) and inhibited by GlyH-101, niflumic acid, DIDS, and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), as well as RNAi knockdown of WNK1 implicated in epithelial osmoregulation. Our results support that these novel epithelial cells with stable expression of SLC26A9 will be a useful model for studies of pharmacological regulation including the identification of activators of SLC26A9 Cl(-) channels that may compensate deficient cystic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) secretion and serve as an alternative therapeutic target in patients with CF and potentially other muco-obstructive lung diseases.
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Antiportadores de Cloruro-Bicarbonato/genética , Animales , Células Cultivadas , Antiportadores de Cloruro-Bicarbonato/biosíntesis , Clonación Molecular , Fibrosis Quística/tratamiento farmacológico , Células Epiteliales , Expresión Génica , Potenciales de la Membrana , Osmorregulación , Ratas Endogámicas F344 , Transportadores de SulfatoRESUMEN
OBJECTIVE: Multicystic dysplastic kidney (MCDK) is the most common antenatally diagnosed cystic renal pathology. It refers to the presence of multiple kidney cysts surrounded by dysplastic parenchymal tissue. The typical MCDK ultrasound finding shows multiple nonconnecting thin-walled cysts within an irregularly outlined kidney. We want to present our own cases as an addition to the relatively scarce literature about MCDK. METHOD: We retrospectively review 54 cases (21 bilateral and 33 unilateral) with antenatally diagnosed MCDK between the years 1998 and 2012. We compare our data with the published literature and discuss different parameters. RESULTS: Our findings show a male predominance of 1.8 : 1 and a left side/right side ratio of 0.73 : 1. Most of the cases were isolated findings, but 20.3% were associated with anomalies. One case was a Goldenhar syndrome. Of the bilateral MCDK cases, 14.3% had chromosomal defects. The mean gestational age at time of diagnosis was 20-21 weeks. Renal length was above the 90th normal percentile in 96.2% of the cases. CONCLUSION: Isolated unilateral MCDK has good prognosis. Bad prognosis is linked to association with other anomalies as well as to bilateral MCDK.
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Riñón Displástico Multiquístico/diagnóstico por imagen , Riñón Displástico Multiquístico/epidemiología , Segundo Trimestre del Embarazo , Ultrasonografía Prenatal/estadística & datos numéricos , Femenino , Edad Gestacional , Humanos , Incidencia , Recién Nacido , Riñón/anomalías , Riñón/diagnóstico por imagen , Riñón/patología , Masculino , Tamizaje Masivo/estadística & datos numéricos , Riñón Displástico Multiquístico/patología , Embarazo , Estudios RetrospectivosRESUMEN
OBJECTIVE: To determine if changes in natriuretic peptide levels [propeptide of atrial natriuretic peptide (proANP) and N-terminal propeptide of brain natriuretic peptide (NT-proBNP)] can be demonstrated in fetuses with serious growth restriction and Doppler ultrasonographic findings of hemodynamic compromise. METHOD: Natriuretic peptides of the umbilical vein (proANP and NT-proBNP), arterial and venous blood gases, as well as lactate levels of the umbilical vein were determined in 38 appropriate for gestational age (AGA) fetuses, and 24 intrauterine growth-restricted (IUGR) fetuses with absent (zero-flow) and 17 IUGR fetuses with reversed end-diastolic flow (reverse-flow) of the umbilical artery. RESULTS: A continuous increase in natriuretic peptides in the presence of progressive deterioration was shown. ANP concentrations were significantly lower in the AGA group (mean 818 fmol/mL; range 508-991 fmol/mL) than the zero-flow group (mean 19,680 fmol/mL; range 13,680-25,080 fmol/mL) and the reverse-flow group (mean 33,880 fmol/mL; range 24,365-41,786 fmol/mL). Significant differences were further demonstrated in BNP concentrations of the AGA group (mean 32 fmol/L; range 25-38 fmol/L), zero-flow group (mean 1191 fmol/L; range 908-1655 fmol/L), and reverse-flow group (mean 3063 fmol/L; range 1281-4968 fmol/L). Additionally, significant differences in lactate concentrations were observed for the three groups: AGA, 2.6 mmol/L (range 2-3 mmol/L); zero-flow group, 4.1 mmol/L (range 3.3-5 mmol/L); and reverse-flow group, 7.7 mmol/L (range 5.9-13.7 mmol/L). Increased ANP levels correlated with the arterial base excess and lactate concentrations, as well as with the flow velocities in the ductus venosus during atrial contraction (a-wave), and both ductus venosus indices (S-a)/D and (S-a)/V(mean). No correlations were established for BNP. CONCLUSIONS: As components of a compensatory mechanism, natriuretic peptides exert an influence on the cardiovascular function of the fetus.