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Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T‐Vec (talimogene laherparepvec), a second‐generation oncolytic herpes simplex virus type 1 (HSV‐1) armed with GM‐CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T‐Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX‐594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM‐CSF‐expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild‐type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47∆, a third‐generation oncolytic HSV‐1, is ongoing in glioblastoma patients. G47∆ was recently designated as a “Sakigake” breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47∆ with priority reviews and a fast‐track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor‐specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients. Oncolytic virus therapy is rapidly emerging as a new approach of cancer treatment. This review depicts this new trend of cancer therapy, in which the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor specific viral replication. It is likely that cancer patients will be able to choose oncolytic virus therapy freely as a treatment option in the very near future.

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 10 8  pfu (low dose) or 1 × 10 9  pfu (set dose), twice to identical coordinates within 5–14 days. Thirteen patients completed treatment (low dose, n  = 3; set dose, n  = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7–34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for “immunoprogression” characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development. G47Δ is a third-generation, triple-mutated oncolytic HSV-1 that has demonstrated anti-tumor efficacy in preclinical studies. Here the authors report the results of a phase I/II study of G47Δ in patients with recurrent or progressive glioblastoma.

This investigator-initiated, phase 2, single-arm trial primarily assessed the efficacy of G47∆, a triple-mutated, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial glioblastoma after radiation therapy and temozolomide (UMIN-CTR Clinical Trial Registry UMIN000015995). G47Δ was administered intratumorally and repeatedly for up to six doses. The primary endpoint of 1-yr survival rate after G47∆ initiation was 84.2% (95% confidence interval, 60.4–96.6; 16 of 19). The prespecified endpoint was met and the trial was terminated early. Regarding secondary endpoints, the median overall survival was 20.2 (16.8–23.6) months after G47∆ initiation and 28.8 (20.1–37.5) months from the initial surgery. The most common G47∆-related adverse event was fever (17 of 19) followed by vomiting, nausea, lymphocytopenia and leukopenia. On magnetic resonance imaging, enlargement of and contrast-enhancement clearing within the target lesion repeatedly occurred after each G47∆ administration, which was characteristic to this therapy. Thus, the best overall response in 2 yr was partial response in one patient and stable disease in 18 patients. Biopsies revealed increasing numbers of tumor-infiltrating CD4 + /CD8 + lymphocytes and persistent low numbers of Foxp3 + cells. This study showed a survival benefit and good safety profile, which led to the approval of G47∆ as the first oncolytic virus product in Japan. Results from a pivotal single-arm phase 2 trial show that the repeated intratumoral administration of the oncolytic herpes virus G47∆ in residual or recurrent glioblastoma exhibits survival benefit and a safe profile.

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third‐generation oncolytic herpes simplex virus type 1 (HSV‐1) T‐01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T‐01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T‐01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH‐7, KYN‐2, PLC/PRF/5 and HepG2 human cells and Hepa1‐6 murine cells were used to investigate the in vivo efficacy of T‐01. T‐01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T‐01 compared with that of mock‐inoculated tumors. In a bilateral Hepa1‐6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T‐01 was inhibited, as was the case for contralateral tumors. T‐01 also significantly reduced tumor growth. T‐01 infection significantly enhanced antitumor efficacy via T cell‐mediated immune responses. Results demonstrate that a third‐generation oncolytic HSV‐1 may serve as a novel treatment for patients with HCC. Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. The third‐generation oncolytic herpes simplex virus type 1 (HSV‐1) T‐01 kills tumor cells without damaging the surrounding normal tissues. We examined the antitumor activities of T‐01 in HCC cell lines and mouse tumor xenograft models, and evaluated the host's immune response to HCC cells. Results demonstrate that a third‐generation oncolytic HSV‐1 may serve as a novel treatment for patients with HCC.

The characteristics of coronary artery calcium responsible for vulnerable plaque remain incompletely elucidated. We used optical coherence tomography to investigate the characteristics of coronary calcium in acute myocardial infarction (AMI), unstable angina pectoris (UAP), and stable angina pectoris (SAP). We evaluated calcium deposits in the culprit lesions (30-mm segment) using optical coherence tomography in 187 patients with AMI (n = 44), UAP (n = 73), or SAP (n = 70). The arc, area, and length of calcium were significantly smaller in those with AMI and UAP than in those with SAP (p <0.001). The number of spotty calcium deposits (with an arc of <90°) per patient was significantly larger in the AMI and UAP groups than in the SAP group (p <0.001). The number of large calcium deposits (with an arc of >90°) per patient was significantly lower in the AMI and UAP groups than in the SAP group (p <0.001). The minimum distance between the inner edge of the calcium and the luminal surface was significantly shorter in the AMI and UAP groups than in the SAP group (p <0.001). Plaque rupture frequency correlated positively with the number of spotty calcium deposits (r = 0.479, p <0.001) and inversely with the number of large calcium deposits (r = −0.219, p = 0.003). In conclusion, calcium was very spotty and more superficial in the culprit lesions of AMI and UAP. These characteristics of calcium might play an important role in the pathogenesis of plaque vulnerability.

The prediction of a perioperative adverse cardiovascular event (PACE) is an important clinical issue in the medical management of patients undergoing noncardiac surgery. Although several predictors have been reported, simpler and more practical predictors of PACE have been needed. The aim of this study was to investigate the predictors of PACE in noncardiac surgery. We retrospectively analyzed 723 patients who were scheduled for elective noncardiac surgery and underwent preoperative examinations including 12-lead electrocardiography, transthoracic echocardiography, and blood test. PACE was defined as cardiac death, non-fatal myocardial infarction, unstable angina, congestive heart failure, arrhythmia attack that needs emergency treatment (rapid atrial fibrillation, ventricular tachycardia, and bradycardia), acute pulmonary embolism, asystole, pulseless electrical activity, or stroke during 30 days after surgery. PACE occurred in 54 (7.5%) of 723 patients. High-risk operation (11% vs. 3%, p  = 0.003) was more often seen, left ventricular ejection fraction (LVEF) (55 ± 8% vs. 60 ± 7%, p  = 0.001) and preoperative hemoglobin level (11.8 ± 2.2 g/dl vs. 12.7 ± 2.0 g/dl, p  = 0.001) were lower in patients with PACE compared to those without PACE. By multivariate logistic regression analysis, high-risk operation (odds ratio (OR): 7.05, 95% confidence interval (CI) 2.16–23.00, p  = 0.001), LVEF (OR 1.06, every 1% decrement, 95% CI 1.03–1.09, p  = 0.001), and preoperative hemoglobin level (OR 1.22, every 1 g/dl decrement, 95% CI 1.07–1.39, p  = 0.003) were identified as independent predictors of PACE. Receiver operating characteristic analysis demonstrated that LVEF of 58% (sensitivity = 80%, specificity = 61%, area under the curve (AUC) = 0.723) and preoperative hemoglobin level of 12.2 g/dl (sensitivity = 63%, specificity = 64%, AUC = 0.644) were optimal cut-off values for predicting PACE. High-risk operation, reduced LVEF, and reduced preoperative hemoglobin level were independently associated with PACE in patients undergoing noncardiac surgery.

Optical coherence tomography (OCT)-angiography coregistration during stent implantation may be useful to avoid geographical mismatch and incomplete lesion coverage. Untreated lipid-rich plaque at stent edge is associated with subsequent stent edge restenosis. The present study sought to compare the frequency of untreated lipid-rich plaque at the stent edge between OCT-guided percutaneous coronary intervention (PCI) with and without OCT-angiography coregistration. We investigated 398 patients who underwent OCT-guided stent implantation ( n  = 198 in the coregistration group, and n  = 200 in the no coregistration group). In OCT after PCI, untreated lipid-lich plaque was identified by the maximum lipid arc > 180˚ in the 5-mm stent edge segment. The PCI-targeted lesion characteristics and stent length were not different between the coregistration group and the no coregistration group. The frequency of untreated lipid-rich plaque in either proximal or distal stent edge segment was significantly lower in the coregistration group than in the no coregistration group (16% vs. 26%, P  = 0.015). The frequency of stent-edge dissection (5% vs. 6%, P  = 0.516) and untreated stenosis (2% vs. 3%, P  = 0.724) was low and without significant differences between the two groups. In OCT-guided PCI, the use of OCT-angiography coregistration was associated with a reduced frequency of untreated lipid-rich plaque at stent edges. OCT-angiography coregistration has a positive impact on PCI results.

Recent clinical trials have raised concerns about the safety and efficacy of ABSORB™ bioresorbable vascular scaffolds (BVS). The difference in the vascular healing process between SYNERGY™ bioabsorbable polymer-coated everolimus-eluting stents (BP-EES) and BVS remains unclear. The aim of the ENHANCE study was to compare vascular healing on BP-EES versus BVS by optical coherence tomography (OCT) and coronary angioscopy (CAS) at 4- and 12-month follow-ups. This is a prospective, non-randomized, single center clinical trial. Thirteen eligible patients with multivessel disease were enrolled. BP-EES and BVS were simultaneously implanted in the same patients, but in different coronary vessels. Imaging follow-up with both OCT and CAS was completed in 11 patients at 12 months. Neointimal coverage rates were similar between the two groups based on OCT measurements. The neointimal thickness of BP-EES was significantly thicker at the 12th month than at the 4th month, whereas the neointimal thickness of BVS did not change between the measurements taken at the 4th and 12th month. Existence of intra-stent thrombus was significantly higher in the BVS group, compared to the BP-EES group. On the other hand, CAS revealed that red-thrombi and yellow-plaque were more frequently observed in BVS at 4 months and up to 12-month follow-ups than in BP-EES. These findings suggested that the evidence of instability remained up to 12 months in the vascular healing with BVS, compared to that with BP-EES. Vascular healing of the stented wall was recognized at the very early phase after BP-EES implantation. However, vascular healing with BVS was still incomplete after 12 months.

Long-term safety of second generation drug-eluting stents (DES) has not yet been evaluated. We sought to evaluate the very late phase (> 3 years) vascular response after second generation everolimus-eluting stent (EES) as compared with first generation sirolimus-eluting stent (SES) by using optical coherence tomography (OCT). We examined the vascular response in 39 patients with a total of 55 DESs [31 EESs (mean 54 months after stenting) and 24 first generation SES (mean 66 months after stenting)] by OCT. The frequency of lesions with any malapposed stent struts (19% vs. 46%, p = 0.035) and evagination (6% vs. 42%, p = 0.002) was significantly lower. Segments with malapposed stent struts were significantly shorter (0.4 ± 0.9 mm vs. 1.9 ± 3.5 mm, p = 0.024), maximal malapposition area and malapposition volume were significantly smaller (0.26 ± 0.38 mm2 vs. 0.95 ± 1.54 mm2, p = 0.019, and 0.78 ± 1.35 mm3 vs. 6.22 ± 15.76 mm3, p = 0.016, respectively) in EES. Compared with first generation SES, second generation EES showed more favourable vascular responses at the very late phase.

The optimal timing of pretreatment with prasugrel in percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) is unclear. We used optical coherence tomography (OCT) to compare in-stent thrombus volume immediately after PCI between the administration of low-dose prasugrel (20 mg loading dose) at the time of diagnosis of ACS (early prasugrel: n  = 34) and the administration of low-dose prasugrel immediately after diagnostic angiography prior to PCI for ACS (late prasugrel: n  = 56). The durations between the administration of prasugrel and OCT in the early prasugrel group and late prasugrel group were 5.1 ± 6.5 and 0.9 ± 0.7 h, respectively ( p  < 0.001). OCT detected thrombus/plaque protrusion in all stented segments. In-stent thrombus/plaque protrusion volume (2.92 ± 1.96 vs. 6.48 ± 4.97 mm 3 , p  < 0.001), mean in-stent thrombus/plaque protrusion area (0.13 ± 0.07 vs. 0.29 ± 0.23 mm 2 , p  < 0.001) and maximum in-stent thrombus/plaque protrusion area (0.70 ± 0.36 vs. 1.06 ± 0.56 mm 2 , p  < 0.001) were significantly smaller in the early prasugrel group as compared with the late prasugrel group. The administration of prasugrel at the time of diagnosis of ACS was associated with significantly reduced in-stent thrombus/plaque protrusion immediately after PCI as compared with the administration of prasugrel after the coronary angiography prior to PCI.