ObjectiveRandomised controlled trials (RCTs) have given contradictory results about the efficacy and safety of ibandronate in treating metastatic bone disease (MBD) or multiple myeloma. This review meta-analysed the literature to gain a more comprehensive picture.DesignSystematic review and meta-analysis of ibandronate compared with placebo or zoledronate.Data sourcesPubMed, EMBASE and the Cochrane Library databases were systematically searched to identify RCTs published up to March 2015 evaluating ibandronate to treat MBD or multiple myeloma.Review method10 RCTs involving 3474 patients were included. Six RCTs were placebo-controlled and four compared ibandronate with zoledronate. The studies included in this review were mainly from European countries.ResultsIntravenous ibandronate (6 mg) or oral drug (50 mg) decreased the risk of skeletal-related events compared to placebo (risk ratio (RR) 0.80, 95% CI 0.71 to 0.90, p=0.002). It also reduced the bone pain score below baseline significantly more than did placebo at 96 weeks (weighted mean difference −0.41, 95% CI −0.56 to −0.27, p<0.001). The incidence of diarrhoea, nausea and adverse renal events was similar between the ibandronate and placebo groups, but ibandronate was associated with greater risk of abdominal pain. Ibandronate was associated with similar risk of skeletal-related events as another bisphosphonate drug, zoledronate (RR 1.02, 95% CI 0.82 to 1.26, p=0.87). The incidence of nausea, jaw osteonecrosis and fatigue was similar for the two drugs, but the incidence of adverse renal events was significantly lower in the ibandronate group.ConclusionsIbandronate significantly reduces the incidence of skeletal-related events and bone pain in patients with MBD or multiple myeloma relative to placebo. It is associated with a similar incidence of skeletal-related events as zoledronate.

Purpose: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP1 substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking. Experimental Design: Using in silico genomic and transcriptomic tumor data, proteomics analysis and genetically modified cell line models we demonstrate mechanistic links between SPOP mutations, STING signaling alterations and PARP inhibitor vulnerabilities. Results: We demonstrate that SPOP mutations are associated with upregulation of a 29-gene non-canonical (NC) STING1 (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING protein, and prostate cancer ̶ associated SPOP mutations result in upregulated NC-STING-NF-κB signaling and macrophage- and tumor microenvironment (TME)-facilitated reprogramming, leading to tumor cell growth. Importantly, we provide in vitro and in vivo mechanism-based evidence that PARP inhibitor (PARPi) treatment results in a shift from immunosuppressive NC-STING-NF-κB signaling to anti-tumor, canonical cGAS-STING-IFN-β signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition. Conclusions: We provide evidence that SPOP is critical in regulating immunosuppressive versus anti-tumor activity downstream of DNA damage-induced STING activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, anti-tumor cGAS-STING-IFN-β signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.

To investigate the usefulness of diffusion-weighted imaging (DWI) for differentiating bland portal vein thrombus from tumour thrombus. Fifteen patients with clinical comprehensive diagnoses of portal vein thrombus were analysed retrospectively. The thrombus signal intensity on 21 DWI slices and apparent diffusion coefficient (ADC) values were analysed quantitatively. The portal vein thrombus was divided into four types (low/low, high/low, low/high, and high/high) based on the DWI/ADC ratios between the thrombus and liver parenchyma (rDWI and rADC, respectively). Twenty patients with portal vein tumour thrombi were used for comparison as controls. The average ADC value for the bland thrombus was 1.84 ± 0.70 × 10 −3 mm 2 s −1 (range: 0.46-2.77 × 10 −3 mm 2 s −1 ), and was 2.18 ± 0.51 × 10 −3 mm 2 s −1 (range: 1.39-2.82 × 10 −3 mm 2 s −1 ) for the liver parenchyma; the rADC was therefore 0.90 ± 0.45 (range: 0.26-1.86). The tumour thrombi were high/low and high/high type. The average ADC for the tumour thrombus was 1.25 ± 0.26 × 10 −3 mm 2 s −1 (range: 0.68-1.67 × 10 −3 mm 2 s −1 ), and 1.56 ± 0.33 × 10 −3 mm 2 s −1 (range: 1.11-2.34 × 10 −3 mm 2 s −1 ) for the liver parenchyma; the rADC was therefore 0.82 ± 0.16 (range: 0.39-1.08). There was no statistical difference in rADC values and rDWI/rADC classification performance between the bland and tumour thrombi. The ADC difference between portal vein bland and tumour thrombi was statistically significant, but the ADC values of bland thrombi have a wider range, which contains the ADC values of tumour thrombi with a narrower range. The elevated ADC values of the liver parenchyma adjacent to portal vein emboli may be helpful for the diagnosis of bland thrombi.

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