Predominant Liver Involvement Research Articles

Abstract CT096: Phase 1 study of RO7119929 (TLR7 agonist prodrug) in patients (pts) with advanced primary or metastatic liver cancers

Abstract Background Agonists for TLR7, a major regulator of the innate immune response, have been tested in oncology across several nonclinical and clinical investigations due to their ability to stimulate T-cell mediated cancer cell killing. The orally available TLR7 agonist prodrug RO7119929 is converted to active drug predominantly in the liver. It was hypothesized to effectively reprogram the local immune microenvironment and thus enhance anti-tumor activity in liver tumors. Methods In this phase 1, first-in-human, open-label, dose-escalation study (NCT04338685), eligible pts had histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement. Pts received oral RO7119929 weekly in 3-week cycles in Part A (dose-escalation: Flat dosing [FD][A1], step-up dosing [SUD][A2] or FD with tocilizumab pre-treatment [A3]) and Part B (FD dose expansion with paired biopsies). Participants received treatment until disease progression, unacceptable toxicity or withdrawal. Primary endpoints were maximum tolerated dose (MTD) and/or optimal biologic dose and safety. Results At data cut-off (22 April 2022), 55 pts were enrolled (A1: n=27; A2: n=9; A3: n=1; B1: n=18). Median age: 58 years; 76% male; 51% Asian; 52% received ≥3 prior lines of therapy; 31% HCC as primary tumor type. Most pts discontinued treatment due to disease progression (75%). Among 17 HCC pts, a durable complete response was observed in one pt and 10 (59%) pts had stable disease. Treatment-related AEs were reported in 91% of pts, most common event was CRS (87%). Fever following drug administration was generally reported as CRS, and most CRS events were Grade 1 (fever). With FD, Grade 2 CRS occurred in 20 (44%) pts and Grade 3 CRS in 6 (13%) pts. With SUD, Grade 2 CRS occurred in one (11%) pt and no Grade 3 CRS was reported. The incidence and severity of CRS events was dose-dependent. Events generally had a predictable onset within 12h post-dosing. All events resolved, the majority within 1-2 days. CRS events of Grade 2/3 commonly occurred in Cycle 1, with later events rarely exceeding Grade 1. Increases in the TLR7-related peripheral pharmacodynamic (PD) biomarkers IFNα, ISG15 and IL6 were associated with higher doses, with particularly IL6 correlating with CRS severity. With SUD, high levels of IFNα and ISG15 levels were maintained while IL6 levels were reduced compared with FD. Pharmacokinetics (PK) of the active TLR7 agonist drug appeared linear (Cmax, AUC) and time-independent with a short effective t1/2 of approximately 5h on average. PK, PD and safety modeling-informed dose decisions. Conclusion CRS was identified as a dose-limiting safety risk, the incidence and severity of CRS appeared dose-dependent, and events were predictable and manageable. SUD reduced the risk of CRS whilst maintaining mode of action relevant PD effects. Combination therapy with a checkpoint inhibitor may be needed to leverage the pro-inflammatory potential of RO7119929 and further increase anti-tumor activity. Citation Format: Changhoon Yoo, Helena Verdaguer, Chia-Chi Lin, Camilla Qvortrup, Thomas Yau, Do-Youn Oh, Felix Lichtenegger, Izolda Franjkovic, Nicole Kratochwil, Juliana Bessa, Eva Rossmann, Elia Hall, Congqi Dai, Oliver Krieter, Audrey Yeo Te-Ying, Michael Cannarile, Christina Schiff, Bruno Sangro. Phase 1 study of RO7119929 (TLR7 agonist prodrug) in patients (pts) with advanced primary or metastatic liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT096.

A Case of Primary Amyloidosis Involving Liver, Stomach, Intestines, and Heart without Evident Kidney Involvement

Aim. Systemic amyloidosis caused by the synthesis and deposition of immunoglobulin light chains (AL amyloidosis) is a relatively rare disease that involves heart, kidneys, peripheral nervous system, gastrointestinal tract, and has a large number of various clinical manifestations. We present a clinical case of systemic AL amyloidosis with a predominant involvement of liver, stomach, intestines, and heart in a Caucasian female.Key points. A Caucasian woman presented to clinic with severe general weakness, abdominal pain, diarrhea, sudden weight loss, and palpitation. Initial examination revealed a duodenal bulb ulcer complicated by bleeding and polyps in the retrobulbar part of duodenum. Decreased hemoglobin levels, elevated levels of alkaline phosphatase, gamma-glutamyltransferase, and N-terminal prohormone of brain natriuretic peptide, signs of heart failure with preserved ejection fraction, and hepatomegaly became the basis for a clinical suspicion of AL amyloidosis and puncture liver biopsy. Histochemical and immunohistochemical studies of liver, stomach, and duodenum biopsy specimens confirmed AL amyloidosis. Timely diagnosis made it possible to conduct a specific therapy with melphalan plus dexamethasone, get a satisfactory response and improve the patient’s condition.Conclusion. A thorough examination of patients along with a pathomorphological and immunohistochemical study of the biopsy specimens is the basis for confirming the diagnosis of AL amyloidosis, selecting the proper therapy, improving the condition of patients and their survival.

Management of Children with Glycogen Storage Disease (Liver Involvement Forms). Best Practice Guidelines

Glycogen storage disease is the hereditary carbohydrate metabolism pathology which is caused by mutations in various genes encoding enzymes responsible for glycogenesis and glycogenolysis. Excessive glycogen deposition in various tissues cells (mostly in liver and muscles) occurs due to enzyme defects. The authors present recent epidemiological data and features of glycogen storage disease etiology and pathogenesis. Clinical characteristics of different types of this disease are also presented. The data on laboratory-instrumental and morphological signs of glycogen storage disease in children, as well as data on its treatment methods is provided in accordance with the developed clinical guidelines. The article provides relevant information on disease types with predominant liver involvement, besides the variety of clinical forms of glycogenosis.

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis.

Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ–inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.

Langerhans cell histiocytosis involving the liver

Langerhans cell histiocytosis is a group of disorders caused by proliferation of the histiocytes. This is a rare neoplastic disease with multisystem involvement. We present a case of an adult male with intermittent fever, recurrent jaundice suggestive of predominant liver involvement. He had undergone multiple courses of anti-tuberculosis treatment with no improvement. Biopsy of the lymph node in our hospital showed Langerhan's cell histiocytosis and liver biopsy showed bridging fibrosis. This case report highlights liver involvement in Langerhans cell histiocytosis with lung and lymph node involvement occurring later, which is an uncommon presentation of this rare disease.

Hepatic arterial infusion therapy in advanced cancer and liver-predominant disease: the MD Anderson Experience.

Liver metastases in patients with cancer are associated with a poor prognosis. We assessed the clinical outcomes in patients with advanced cancer and predominant liver involvement treated on hepatic arterial infusion (HAI chemotherapy protocols. We retrospectively analyzed the outcomes of patients referred to the Phase I Clinical Trials Program between April 2004 and September 2009. Overall, 202 consecutive patients were identified. Of 189 evaluable patients, the rates of partial response (PR) and stable disease (SD) >4 months were 6.3% and 23%, respectively. In patients with hepatocellular carcinoma or cholangiocarcinoma (n = 15), 5 (33%) had SD ≥ 4 months. In patients with colorectal cancer (n = 67) treated with HAl oxaliplatin or irinotecan combination therapy, the rates of PR and SD ≥ 4 months were 7.5% and 34.3%, respectively. In patients with breast cancer (n = 17) treated with HAI cisplatin-based therapy, the rates of PR and SD -4 months were 17.6% and 35.3%, respectively. The median survival of patients with PR and SD ≥ 4 months was 11.6 months. Independent factors predicting shorter survival were male gender; decreased albumin and hemogloblin; and elevated bilirubin, lactate dehydrogenase and alanine aminotransferase. HAI combination therapies have antitumor activity in selected heavily pretreated patients with certain tumor types and liver involvement.

Anti-convulsant Hypersensitivity Syndrome with Predominant Liver Involvement

Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life threatening syndrome that develops in genetically susceptible individuals following exposure to aromatic antiepileptic drugs (AED’s) like phenytoin. It is characterized by fever, rash and internal organ involvement. AHS should be recognized at the earliest because continuation of the culprit drug can lead to fatal outcome. We present severe phenytoin hypersensitivity syndrome with predominant hepatic involvement that improved with drug withdrawal and other supportive treatment. JMS 2011;14(1):22-24

Hepatic response after high-dose melphalan and stem cell transplantation in patients with AL amyloidosis associated liver disease

High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. In this retrospective study, we evaluated clinical and hematologic responses in 69 patients with predominant liver involvement who were treated with high-dose intravenous melphalan and autologous stem cell transplantation from 1998 to 2006. Nine patients (13%) died from treatment-related mortality, similar to patients without hepatic involvement. The overall survival was 81% at one year and 61% at five years, by Kaplan-Meier estimates. A hematologic complete response was achieved by 53% (31/58) of patients at one year. A hepatic response occurred in 57% (33/58) at one year after high-dose intravenous melphalan and autologous stem cell transplantation and 63% (19/30) at two years after high-dose intravenous melphalan and autologous stem cell transplantation. In conclusion, hepatic disease improves in almost 2/3 patients treated with high-dose intravenous melphalan and autologous stem cell transplantation who have a complete or partial hematologic response to treatment.

Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence.

To investigate if fibrin (or fibrinogen), immunoglobulins and complement were present in the liver of patients with toxemia of pregnancy, we performed immunofluorescence studies on needle biopsies of pre-eclamptic women. Fibrin (or fibrinogen) outlining the hepatic sinusoids was found in all 12 cases; in two of them there were also large nodular deposits of fibrin (or fibrinogen) and to a lesser extent of IgG, IgM and C3 in areas of necrosis. Immunofluorescence study of 13 control liver biopsies, six from pregnant women, was negative. Our findings suggest that the factors involved in glomerular and hepatic injury are similar. To explain the predominant involvement of liver and kidney, we propose that in these organs, the vasospasm characteristic of toxemia is more severe; this enhanced severity, in the presence of a systemic yet mild blood hypercoagulability, would create adequate local conditions for the precipitation of fibrin-fibrinogen.