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Background Microsatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.Methods This was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013 viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.Results Between August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+ T cells and HLA-DRhigh T cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.Conclusion In patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+ T cells systemically that was poorly sustained.Trial registration number NCT04166383.

Fibrolamellar carcinoma (FLC) is a rare cancer of the liver that most commonly affects children and young adults. There is no clear standard of care for the disease, whose response to treatment seems to be very different from that of hepatocellular carcinoma. We present a case of FLC in a patient in her mid 30s that recurred and persisted despite resection and multiple lines of treatment. Following transcriptomic analysis, a combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) led to complete remission, although common biomarkers for immune checkpoint blockade were all negative in this case. The patient is still in remission. Here, combined checkpoint blockade guided by novel transcriptomic analysis led to complete remission after failure of several lines of treatment.

ObjectiveDescribe the clinical characteristics and histopathology findings in a family with two siblings affected with deficiency of adenosine deaminase 2 (DADA2). Both patients presented in childhood with polyarthritis and developed significant neurological and gastrointestinal features of DADA2 in ear, including variable degrees of immunologic and hematologic manifestations.MethodsAdenosine Deaminase 2 (ADA2; also known as cat eye syndrome chromosome region, candidate 1 gene; CECR1) exon sequencing and serum ADA2 levels were performed to confirm the diagnosis of DADA2. Comparison of serum adenosine deaminase 2 levels was made to DADA2 patients, carriers, and healthy controls in Patient 2. Autopsy specimens from brain and liver tissues were submitted for analysis.ResultsBoth patients were found to carry a previously reported rare intronic missense mutation predicted to affect the transcript splicing (c.973-2A > G; rs139750129) and an unreported missense mutation p.Val458Asp (c.1373T > A; V458D). Both brothers started therapy with a tumor necrosis factor inhibitor following the molecular diagnosis of DADA2 with good response and were eventually tapered off prednisone. However, Patient 1 died 18 months later due to complications of end-stage liver disease. His autopsy showed evidence for nodular hyperplasia of the liver often seen in common variable immunodeficiency (CVID) and numerous small, old infarcts throughout the brain that had not been demonstrated on prior MRI/MRA imaging.ConclusionThese cases emphasize the importance of recognition of DADA2 in adults, compare CNS imaging modalities to pathologic findings and suggest similarities in liver pathology between DADA2 and CVID. MRI may not be most sensitive method to identify small subcortical infarcts in patients suspected to have DADA2.

The liver biopsy is frequently used as an adjunct diagnostic test in the evaluation of drug-induced liver injury (DILI). A biopsy may be performed to confirm the diagnosis, especially when there is a complex clinical differential diagnosis that includes DILI. A biopsy can also be used to stage the severity of hepatotoxicity so that a necessary agent may be continued. Alternatively, a drug or toxin may only be implicated after a biopsy is performed, particularly in the case of subacute or chronic liver injury. The pathologist should approach the biopsy systematically by first classifying the disease and then working with the clinician to include or exclude etiologies in the pathological differential diagnosis. This article outlines a practical approach to the diagnosis of DILI on liver biopsy, including the common patterns of injury observed in drug- and toxin-induced liver pathology and prognostic pathological features that may be associated with the outcome of patients with DILI. [ABSTRACT FROM AUTHOR]

Abstract  The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies. [ABSTRACT FROM AUTHOR]

Abstract  The control of intracellular microorganisms such as mycobacteria is largely dependent on the adaptive immune response, specifically the interaction of T helper cells and antigen presenting cells such as macrophages. The interferon gamma (IFN-γ) pathway activation is crucial for containment and killing of mycobacteria, as evidenced by the fact that defects in this pathway often result in profound infections with both tuberculous and non-tuberculous mycobacteria. We herein report a case of a child with autosomal recessive IFN-γ receptor 2 (IFN-γR2) deficiency who developed hepatic venopathy secondary to disseminated Mycobacterium avium complex (MAC) infection. [ABSTRACT FROM AUTHOR]

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in neutropenic, nonneutropenic, and other immunocompromised patients. We therefore compared the patterns of infection and inflammation among 3 cohorts of immunocompromised patients with profound neutropenia, nonneutropenic immunosuppression, and hematopoietic stem cell transplantation. Lesions of IPA in neutropenic patients and hematopoietic stem cell transplant (HSCT) recipients were similar and consisted predominantly of angioinvasion and intraalveolar hemorrhage. The frequency of these histologic findings in neutropenic patients and HSCT recipients differed significantly from those of nonneutropenic patients (P < .05). It is noteworthy that even if HSCT recipients have normal peripheral blood neutrophil counts, there may be no influx into sites of infection. In the nonneutropenic cohort, lesions of IPA consisted mainly of neutrophilic and monocytic infiltrates and inflammatory necrosis. Thus, the status of innate host defenses contributes significantly to the histologic patterns observed in IPA. [ABSTRACT FROM AUTHOR]