SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol.

INTRODUCTION: The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation. METHODS AND ANALYSIS: Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. ETHICS AND DISSEMINATION: The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02096913; Pre-results.

Neoadjuvant TACE before laser induced thermotherapy (LITT) in the treatment of non-colorectal non-breast cancer liver metastases: feasibility and survival rates.

PURPOSE: To evaluate safety, feasibility and overall survival rates for transarterial chemoembolization (TACE) alone or combined with MR-guided laser-induced-thermotherapy (LITT) in liver metastases of non-colorectal and non-breast cancer origin. METHODS AND MATERIALS: Included were patients with unresectable non-colorectal non-breast cancer liver metastases with progression under systemic chemotherapy. Excluded were patients with Karnofsky score ≤ 70, respiratory, renal and cardiovascular failure, and general TACE contraindications. TACE using Mitomycin alone, Mitomycin-Gemcitabine or Mitomycin-Gemcitabine-Cisplatin was performed to all patients. After TACE 146 metastases were ablated with MR-guided LITT. To be eligible for LITT metastases should be < 5 cm in size and ≤ 5 in number. Tumor response was evaluated using MRI according to RECIST. Survival was evaluated using Kaplan-Meier analysis. RESULTS: A total of 110 patients (mean age 59.2 years) with 371 metastases received TACE (mean 5.4 sessions/patient, n=110) with 76 (69%) receiving LITT (mean 1.6 session/patient) afterwards. TACE resulted in a mean decrease of mean maximum diameter of 52% ± 26.6 and volume change of -68.5% ± 22.9 in the 25 patients (23%) with partial response. Stable disease (n=59, 54%). Progressive disease (n=26, 23%). The RECIST outcome after LITT showed complete response (n=13, 17%), partial response (n=1, 1%), stable situation (n=41, 54%) and progressive disease (n=21, 28%). The mean time to progression (TTP) was 8.6 months. Median survival of all patients was 21.1 months. CONCLUSION: TACE with different protocols alone and in combination with LITT is a feasible palliative treatment option resulting in a median survival of 21.1 months for unresectable liver metastases of non-colorectal and non-breast cancer origin.