IMbrave152/SKYSCRAPER-14: a Phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma.

Atezolizumab plus bevacizumab is a standard of care, first-line therapy for advanced hepatocellular carcinoma (HCC). Myeloid and T regulatory cells are key immunosuppressive cell types within the hepatic tumor microenvironment associated with clinical resistance to atezolizumab and bevacizumab therapy for HCC and overall poor prognosis. Therapeutic targeting of TIGIT, which is highly expressed in these cells, with tiragolumab may overcome the immunosuppressive environment and improve clinical benefit, a hypothesis supported by positive efficacy signals in the Phase Ib/II MORPHEUS-Liver study. This paper describes the rationale and design of IMbrave152/SKYSCRAPER-14, a randomized, double-blind, placebo-controlled Phase III study comparing atezolizumab and bevacizumab with tiragolumab or placebo in patients with HCC and no prior systemic treatment.Clinical Trial Registration: NCT05904886 (ClinicalTrials.gov).

This research study is designed to test a new treatment combination for liver cancer, specifically for patients whose cancer cannot be removed with surgery or has spread. The treatment involves three medications: atezolizumab, bevacizumab and tiragolumab.Atezolizumab and bevacizumab are already used together as a standard treatment for liver cancer. Tiragolumab is designed to block the TIGIT receptor, which is normally involved in holding back the immune cells that would attack the tumor. Because tiragolumab may restore the immune response against the tumor, adding tiragolumab might make the treatment more effective.The study is being done worldwide and includes patients who have not received any previous systemic treatment for their advanced liver cancer. Patients participating in the study will be randomly placed into two groups. One group will receive the new combination of three medications, while the other group will receive the standard treatment of two medications plus a placebo (a treatment with no active ingredient). The main goal is to see if the new combination helps patients live longer and slows the cancer's growth compared with the standard treatment. Safety and how patients feel during the treatment are also important parts of the study.

Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): final analysis of a phase III, randomized, double-blind, placebo-controlled study.

PURPOSE: PUFFIN (NCT02896855), a Chinese bridging study in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer, assessed consistency of efficacy and safety of pertuzumab plus trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel, with CLEOPATRA (NCT00567190). METHODS: Eligible patients, n = 243, were randomized 1:1, stratified by visceral disease and hormone receptor status, to pertuzumab, trastuzumab, and docetaxel or placebo, trastuzumab, and docetaxel. PRIMARY ENDPOINT: investigator-assessed progression-free survival (PFS). Secondary endpoints: safety and overall survival (OS). After primary analysis, patients could cross over to the pertuzumab arm. RESULTS: Updated median PFS: 16.5 months (pertuzumab arm) and 12.5 months (placebo arm), with a hazard ratio (HR) of 0.60 [95% confidence interval (CI) 0.45, 0.81; p = 0.0008]. Median OS was not reached in either arm; the OS HR was 0.68 (95% CI 0.45, 1.03; p = 0.0658). Safety was similar in both arms with no new safety signals: 73.8% (pertuzumab arm) and 69.2% (placebo arm) experienced grade ≥ 3 adverse events. No heart failure, symptomatic left ventricular systolic dysfunction, or left ventricular ejection fraction decline of < 40% were reported. CONCLUSIONS: The PUFFIN final analysis showed, per the primary analysis, that overall efficacy of pertuzumab plus trastuzumab and docetaxel was consistent with CLEOPATRA. Safety remained consistent with the known pertuzumab profile. Overall, PUFFIN contributes to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit-risk profile of pertuzumab in Chinese patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02896855, registered 7 September 2016.

Tacrolimus promotes hepatocellular carcinoma and enhances CXCR4/SDF­1α expression in vivo.

The aim of our study was to elucidate the effect of tacrolimus (FK506) and of C-X-C chemokine receptor type 4 (CXCR4), which is a receptor specific to the stromal cell-derived factor-1α (SDF­1α), on growth and metastasis of hepatocellular carcinoma (HCC). Following treatment with different concentrations of FK506, AMD3100 or normal saline (NS), the proliferation of Morris rat hepatoma 3924A (MH3924A) cells was measured by the MTT assay, the expression of CXCR4 was analyzed with immunohistochemistry, and the morphological changes and the invasiveness of cells were studied with a transwell assay and under a scanning electron microscope, respectively. In addition, August Copenhagen Irish rat models implanted with tumor were used to examine the pathological changes and invasiveness of tumor in vivo, the expression of CXCR4 in tumor tissues and the expression of SDF­1α in the adjacent tissues to the HCC ones, using immunohistochemistry. In vitro, FK506 (100­1,000 µg/l) significantly promoted the proliferation of MH3924A cells (P<0.01), and increased the expression of CXCR4 in MH3924A cells, albeit with no significance (P>0.05). By contrast, AMD3100 had no effect on the proliferation of MH3924A cells, but significantly reduced the expression of CXCR4 (P<0.05). The invasiveness of MH3924A cells was significantly (P<0.01) enhanced following treatment with FK506, SDF­1α, FK506 + AMD3100, FK506 + SDF­1α or FK506 + AMD3100 + SDF­1α. In vivo, tumor weight (P=0.041), lymph node metastasis (P=0.002), the number of pulmonary nodules (P=0.012), the expression of CXCR4 in tumor tissues (P=0.048) and that of SDF­1α in adjacent tissues (P=0.026) were significantly different between the FK506-treated and the NS group. Our results suggest that FK506 promotes the proliferation of MH3924A cells and the expression of CXCR4 and SDF­1α in vivo. Therefore, inhibiting the formation of the CXCR4/SDF­1α complex may partly reduce the promoting effect of FK506 on HCC.

Acute thoracic aortic dissection (stanford type B) complicated with acute renal failure.

We report a recent case and review some literatures of acute aortic dissection (AAD) Stanford type B complicated with late onset of acute renal failure. The patient underwent preoperational peritoneal dialysis followed by thoracic endovascular aortic repair (TEVAR) and was fully recovered and discharged soon after surgery. We conclude that an AAD case is difficult to achieve a timely diagnosis, but with attention to systemic symptoms and dedication thorough treatment plan, a full recovery and positive prognosis are expected.

The dynamic changes of T-bet(+)/GATA-3(+) and RORgammat(+)/FOXP3(+) cells in recipient spleens and grafts after rat orthotopic liver transplantation.

BACKGROUND: Rejection of transplanted liver occurs when the host generates alloantigen-reactive T cells, and CD4(+) T-cell subsets, including Th1, Th2, T17 and iTreg, could be involved in changing the dynamics of graft rejection onset. In the current immunosuppressive strategies, rejection is treated as an undifferentiated process that is uniform, which results in the failure of tolerance induction. Here, we established a rejection model to observe the reciprocal interaction of CD4(+) T-cell subsets in the complex networks of the immune system. METHODS: Orthotopic liver transplantation (OLT) from male inbred Lewis rats (n=15) to male inbred Brown Norway (BN) rats was performed by Kamada's two-cuff technique without reconstruction of the hepatic artery. OLT from BN to BN rats (n=5) was performed as a control. Recipients were sacrificed on postoperative days 3, 5, 7, 9, 11, 13 and 15. Recipient spleens and grafts were harvested, fixed in 10% neutral formalin, and embedded in paraffin. Meanwhile, hematoxylin and eosin and immunohistochemical staining was done, acute rejection was graded by the Banff scheme, and the number of T-bet(+), GATA-3(+), RORgammat(+) and FOXP3(+) cells in the spleen and grafts were counted. RESULTS: In recipient spleens, the T-bet(+) and RORgammat(+) cells were increased more significantly in the mild acute rejection (AR) group than in the control group (P=0.016, P=0.009, respectively), while both cell types were decreased in the moderate AR group. Compared with the control group, the RORgammat(+) cells did not differ significantly in the severe AR group, while the T-bet(+) cells were significantly decreased (P=0.465, P=0.009, respectively). The GATA-3(+) cells were significantly decreased in the mild AR group compared with the control group (P=0.009). With regard to the FOXP3(+) cells, there was no significant difference between the control and mild AR groups (P=0.754), while they were significantly decreased in the moderate and severe AR groups (P=0.028, P=0.009, respectively). The ratio of T-bet(+)/GATA-3(+) cells was more associated with AR than was the RORgammat(+)/FOXP3(+) cell ratio in the early stage. In the graft, the T-bet(+) and RORgammat(+) cells were significantly increased in mild, moderate and severe AR groups compared with the control group (P<0.009). The expression of GATA-3(+) cell was not significantly increased in the mild AR group compared with the control group, while it was significantly increased in the moderate and severe AR groups (P=0.028, P=0.009, respectively). Concerning the FOXP3(+) cells, no significant difference was found between the control and mild AR groups (P=0.347), while they were significantly increased in the moderate and severe AR groups (P<0.009). CONCLUSIONS: Our study revealed the dynamic changes of T-bet(+), GATA-3(+), RORgammat(+) and FOXP3(+) cells in the spleen and grafts of recipient rats. It seems that the ratio of T-bet(+)/GATA-3(+) cells was more associated with AR than was RORgammat(+)/FOXP3(+) cells in the early stage of rejection, while the ratio of RORgammat(+)/FOXP3(+) cells was associated more with the later but more persistent stage of rejection. This study could make a contribution to the optimal selection of immunosuppressive regimens according to the dynamic changes in CD4(+) T-cell subsets at different stages of rejection.