Background and purposeCombining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic proceduresWe used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findingsRegorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusionsJudicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

Immune checkpoint blockade combined with anti-angiogenic therapy induces vascular normalization and anti-tumor immunity and is efficacious in hepatocellular carcinoma (HCC). But whether and how initial immunotherapy affects the efficacy of subsequent anti-angiogenic therapy is unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-VEGF receptor multi-kinase inhibitor sorafenib after initial therapy with an anti-programmed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median OS of 12.1 months). To understand mechanisms of this benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8–9 mice per group, HR = 0.28, 95% CI: 0.09–0.91; p = .04). Anti-PD-1 therapy showed angio-protective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.

Hepatocellular carcinoma (HCC) remains as one of the major causes of cancer‐related mortality, despite the recent development of new therapeutic options. Regorafenib, an oral multikinase inhibitor, is the first systemic therapy that has a survival benefit for patients with advanced HCC that have a poor response to sorafenib. Even though regorafenib has been approved by the FDA, the clinical trial for regorafenib treatment does not show significant improvement in overall survival. The impaired efficacy of regorafenib caused by various resistance mechanisms, including epithelial–mesenchymal transitions, inflammation, angiogenesis, hypoxia, oxidative stress, fibrosis and autophagy, still needs to be resolved. In this review, we provide insight on regorafenib microenvironmental, molecular and cellular mechanisms and interactions in HCC treatment. The aim of this review is to help physicians select patients that would obtain the maximal benefits from regorafenib in HCC therapy.

Multikinase inhibitors (MKIs) have been the only first-line treatment for advanced hepatocellular carcinoma (HCC) for more than a decade, until the approval of immune checkpoint inhibitors (ICIs). Moreover, the combination regimen of atezolizumab (anti-programmed cell death protein ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) has recently been demonstrated to have superior efficacy when compared with sorafenib monotherapy. The remarkable efficacy has made this combination therapy the new standard treatment for advanced HCC. In addition to MKIs, many other molecularly targeted therapies are under investigation, some of which have shown promising results. Therefore, in the era of immuno-oncology, there is a significant rationale for testing the combinations of molecularly targeted therapies and ICIs. Indeed, numerous preclinical and clinical studies have shown the synergic antitumor efficacy of such combinations. In this review, we aim to summarize the current knowledge on the combination of molecularly targeted therapies and immune checkpoint therapies for HCC from both preclinical and clinical perspectives.

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The axillary lymph nodes are the primary group responsible for lymphatic drainage in the breast and, consequently, are the most common location for breast cancer metastasis. However, lymphatic pathways running from the breast, via intercostal spaces, to parasternal lymph vessels have also been identified. According to the American Joint Committee on Cancer eighth edition manual, regional lymph node metastasis normally travels to the ipsilateral axillary, supraclavicular, subclavicular, and internal mammary lymph nodes. The presence of intercostal metastasis is out the range of these regional lymph nodes. It is very rare for intercostal lymph nodes to be the extra-axillary site of metastasis in breast cancer, and it has been little reported on in the literature. Despite its rarity, it has the capacity to adversely affect the prognosis of breast cancer and drastically influence treatment choice. Here, we analyze such a case, with a patient receiving a radical mastectomy and metastatic intercostal lymph node dissection due to the presence of intercostal lymph node metastasis indicated via MRI. Furthermore, the potential application of preoperative 3-dimensional (3D) visualization and surgical planning is also discussed.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, andin vivoT-cell depletion and CD8+T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+T-cells. Depletion of CD8+but not CD4+T-cells compromised efficacy. Conversely, CD8+T-cell transfer from Cxcr3-/-versus Cxcr3+/+mice into Rag1-/-immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 ″priming″) with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

Pancreatic leiomyosarcoma (PL) is a very rare, malignant neoplasm with a very poor prognosis. Here, we examine a novel case of PL with schistosomiasis hematobia. The patient had been initially misdiagnosed by the first magnetic resonance imaging (MRI). The second imaging examination demonstrated an enlarged heterogeneous tumor mass in the body-tail of pancreas. Following image analysis, the patient underwent a pancreatectomy, splenectomy and lymph node dissections. Sixteen months after the tumor resection, follow-up computed tomography (CT) and MRI revealed tumor metastasis in the liver and lung. PL has non-specific clinical manifestations and imaging characteristics, making early diagnosis very challenging. When it is difficult to distinguish between benign and malignant pancreatic lesions, short-term imaging follow-up is preferred. In this case report, we discuss the relationship between PL and schistosomiasis hematobia.