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Background Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study. Methods This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment. Results Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR). Conclusions HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. Trial registration: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

Background: High frequency spinal cord stimulation at 10 kHz (HF10 therapy) represents a prominent advance in spinal cord stimulation (SCS) therapy, having demonstrated enhanced efficacy in patients with back and leg pain and pain relief without paresthesia that is sustained at 24 months post implant. Objective: To report on the effectiveness HF10 SCS therapy for a wide range of intractable pain conditions in clinical practice. Study Design: Retrospective investigation of 256 patients who trialed HF10 SCS for chronic intractable pain of various etiologies. Setting: Three Australian pain clinics. Methods: Two hundred fifty-six patients trialed HF10 SCS with view of a permanent implant if successful. Pain distributions included back + leg, back only, head ± neck, and neck ± arm/ shoulder. About 30% of patients had previously failed traditional low-frequency paresthesiabased stimulation, while the remaining cohort were either highly refractory to treatment or not recommended by the pain physician for traditional SCS. Pain scores (numerical pain rating scale – NPRS) and functional outcome measures (Oswestry Disability Index – ODI; and activity tolerance times) were assessed at baseline, post-trial, and at 3 and 6 months post-implant as available in the medical records. Results: Of the 256 patients, 189 (73%) reported a positive trial and were implanted. Patients with back + leg pain demonstrated the highest trial success rate (81%). A mean reduction in pain, among those for whom data were available, of 50% was sustained up to 6 months postimplant across the entire patient population. Sixty-eight percent of patients who failed traditional SCS reported a positive trial and mean pain relief at 6 months was 49% (P < 0.001). An 8.6 point reduction in ODI (21%) at 6 months and improved sitting, standing, and walking tolerances were also reported. Limitations: As data was collected retrospectively, missing data points were unavoidable; this was primarily due to inconsistent data collection and patients being lost to follow-up. Patient populations were diverse and a control group was not appropriate in this setting. Conclusions: These retrospective results demonstrate a significant advancement for patients suffering with chronic intractable pain and are consistent with recently published clinical results for HF10 SCS. HF10 SCS appears to be a viable, paresthesia-free alternative to traditional SCS, with high trial success rates, demonstrated effectiveness in a range of pain distributions including those typically difficult to treat with traditional SCS, and the possibility to restore pain control in patients who have previously failed traditional SCS. Key words: Spinal cord stimulation, high frequency stimulation, HF10, paresthesia-free stimulation, back pain, leg pain, cervical pain, neuromodulation

Complex regional pain syndrome (CRPS) is a chronic, debilitating, neuropathic pain condition which is often misdiagnosed, difficult to manage, and lacks proven methods for remission. Most available methods provide some relief to a small percentage of patients. Recent FDA approval and superiority of the Nevro Senza 10-kHz high frequency (HF10) spinal cord stimulation (SCS) therapy over traditional low-frequency spinal cord stimulation for treatment of chronic back and leg pain may provide a new interventional therapeutic option for patients suffering from CRPS. We provide a case report of a 53-year-old Caucasian woman who suffered with CRPS in the right knee and thigh for over 7 years. Implantation of the HF10 device provided over 75% relief of pain, erythema, heat, swelling, and tissue necrosis to the entire region within 1 month of treatment. Because the HP10 therapy provides pain relief without paresthesia typical of traditional low-frequency, this system may provide relief for patients suffering from chronic pain.Key words: Complex regional pain syndrome, spinal cord stimulation, Nevro Senza HF10, erythema, knee, thigh.

In 2005, we initiated a clinical trial that examined the efficacy of the oncolytic virus HF10 to treat pancreatic cancer. Pancreatic cancer continues to have a high mortality rate, despite multimodal treatments for patients, and new therapeutic methods are greatly needed. The current mainstream methods for cancer treatment include biological therapeutics such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer. Oncolytic virus therapy is a new and promising treatment strategy for cancer. Oncolytic viruses are novel biological therapeutics for advanced cancer that appear to have a wide spectrum of anticancer activity with minimal human toxicity. To examine the efficacy of oncolytic virus therapy for pancreatic cancer, we initiated pilot studies by injecting six patients with non-resectable pancreatic cancer with three doses of HF10. All patients were monitored for 30 days for local and systemic adverse effects and were not administered any other therapeutics during this period. There were no adverse side-effects, and we observed some therapeutic potential based on tumor marker levels, survival, pathological findings and diagnostic radiography. The tumors were classified as stable disease in three patients, partial response in one patient and progressive disease in two patients.

The naturally occurring oncolytic herpes simplex virus canerpaturev (C-REV), formerly HF10, proved its therapeutic efficacy and safety in multiple clinical trials against melanoma, pancreatic, breast, and head and neck cancers. Meanwhile, patients with colorectal cancer, which has increased in prevalence in recent decades, continue to have poor prognosis and morbidity. Combination therapy has better response rates than monotherapy. Hence, we investigated the antitumor efficacy of cetuximab, a widely used anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and C-REV, either alone or in combination, in vitro and in an in vivo human colorectal xenograft model. In human colorectal cancer cell lines with different levels of EGFR expression (HT-29, WiDr, and CW2), C-REV exhibited cytotoxic effects in a time- and dose-dependent manner, irrespective of EGFR expression. Moreover, cetuximab had no effect on viral replication in vitro. Combining cetuximab and C-REV induced a synergistic antitumor effect in HT-29 tumor xenograft models by promoting the distribution of C-REV throughout the tumor and suppressing angiogenesis. Application of cetuximab prior to C-REV yielded better tumor regression than administration of the drug after the virus. Thus, cetuximab represents an ideal virus-associated agent for antitumor therapy, and combination therapy represents a promising antitumor strategy for human colorectal cancer.

Brachial plexopathy can sometimes cause severe chronic pain. There are many possible treatments for such neuropathic pain, including neuromodulation. However, rigorous scientific evidence on the usefulness of spinal cord stimulation (SCS) is still scarce. Here, we report the use of high-frequency (10 kHz) SCS (HFSCS) in a patient with brachial plexus injury (root avulsion). To assess the efficacy of HFSCS in root avulsion and to investigate the putative neurophysiological mechanisms of HFSCS. A 32-year-old woman visited our center following an iatrogenic brachial plexus injury. She underwent traditional, paresthesia-inducing, tonic SCS with cervical lead placement. She reported that stimulation-induced paresthesia was uncomfortable, without any pain reduction. After the successful trial of HFSCS, the patient was assessed at 1 month (T1) and 6 months (T6) after HFSCS implantation with pain and quality of life (QoL) scales. Moreover, she underwent a neurophysiological assessment (somatosensory evoked potentials [SEPs], reciprocal inhibition [RI], pain-motor integration [PMI], and the habituation of intraepidermal electrical stimulation-induced evoked potentials [IEPs]) with the stimulator switched on and switched off at T6. The patient reported 100% paresthesia-free pain relief, a consistent improvement of QoL, and a complete discontinuation of her previous pain treatment at T1 and T6. Moreover, we found suppression of SEPs, restored habituation of IEPs, and strengthening of RI and PMI. This is the first report to illustrate the usefulness and safety of HFSCS for treating root avulsion in a patient with failed tonic SCS. Our data indicate that HFSCS may either block large-diameter fibers or stimulate medium-/small-diameter fibers, thus inducing analgesia without paresthesia, probably by reducing the activation of the wide-dynamic-range neurons. Moreover, HFSCS seems to modulate spinal inhibitory mechanisms and the descending corticospinal inhibitory output. Thus, HFSCS can be an effective option for treating refractory pain following root avulsion.

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group ( P =0.016). Angiogenesis was significantly higher in treatment group ( P =0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group ( P =0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Abstract BACKGROUND Current treatment options for bladder disorders of neurogenic etiology often leave unsatisfactory results. Therefore, new and effective treatments must be investigated. High-frequency spinal cord stimulation (HF-SCS) at 10 kHz has proven to be effective in the treatment of refractory chronic back and leg pain. OBJECTIVE To evaluate the efficacy of HF-SCS at 10 kHz in alleviating lower urinary tract dysfunction and bladder incontinence in 5 patients with underlying neurological disease or spinal cord injury, through retrospective study. METHODS Urodynamic parameters such as voiding frequency, residual volume, episodes of incontinence, and the patients’ subjective impression impairment of life were assessed and compared pre- and postoperatively. Reduction in pain intensity was assessed as change on the Numeric Rating Scale (NRS). RESULTS All 5 patients had significantly positive outcomes. Episodes of leakage per day improved by 83% on average. Quality of life questionnaires and subjective bother scale revealed an improvement of 36% and 57%, respectively. Individual symptoms among the patient group such as residual volume also responded to the treatment as well. Mean pain NRS of 8.6 cm was reduced to 3.9 cm (55%) at 6 mo follow-up. CONCLUSION HF-SCS at 10 kHz significantly alleviated symptoms of neurogenic bladder incontinence in patients suffering from neurological disease or spinal cord injury. However, larger and prospective, randomized studies are necessary to make a clear statement regarding the efficacy of this therapy in lower urinary tract dysfunction and bladder incontinence.

Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte–macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro . However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM-CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10-packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors.