Outcome in patients with critical limb ischemia in the ESES-trial : spinal cord stimulation versus optimal medical treatment

There has been a long history of interest in the effects of spinal cord stimulation (SCS) for critical limb ischemia (CLI), especially if meaningful revascularisation is not possible. In a randomized trial (ESES-trial), we compared two treatment regimens (best medical treatment and best medical treatment plus SCS). We did not find that spinal-cord stimulation was of benefit above that of best medical treatment. Amputation-free survival was not improved (p=0.86). The rates of amputation were similar in both groups (p=0.47) and were particularly high during the first 3 months.Quality of life showed poor scores compared with matched reference values of the general population, but there were no significant differences between the randomized treatment group during treatment. Although patients with a spinal-cord stimulator used significantly less pain medication (suggesting substantial pain relief from this treatment), similar pain reduction was seen in the medical and SCS-treatment groups. Over two years, the costs of SCS-treatment were higher as compared to best medical treatment alone (€36,600 vs. €28,700, p=0.009)

A prognostic model for amputation in critical lower limb ischemia

In a (negative) multicenter randomized trial on management for inoperable critical lower limb ischemia, comparing spinal cord stimulation and best medical treatment, a number of pre-defined factors were analyzed for prognostic value. We included a radiological arterial disease score, modified from the SVS/ISCVS runoff score. The purpose of this analysis was to evaluate clinical factors and commonly used circulatory measurements for prognostic modeling in patients with critical lower limb ischemia. We determined the incidence of amputation and its relation to various pre-defined risk factors. A total of 120 patients with critical limb ischemia were included in the study. The integrity of circulation in the affected limb was evaluated on five levels: suprainguinal, infrainguinal, popliteal, infrapopliteal and pedal. A total radiological arterial disease score was calculated from 1 (full integrity of circulation) to 20 (maximally compromised state). We used Cox regression analysis to quantify prognostic effects and differential treatment (predictive) effects. Major amputation occurred in 33% of the patients at 6 months and in 51% at 2 years. The presence of ischemic skin lesions and the radiological arterial disease score were independent prognostic factors for amputation. Patients with ulcerations or gangrene had a higher amputation risk (hazard ratio 2.38, p = 0.018 and 2.30, p = 0.036 respectively) as well as patients with a higher radiological arterial disease score (hazard ratio 1.17 per increment, p = 0.003). We did not observe significant interactions between prognostic factors and the effect of spinal cord stimulation. In conclusion, in patients with critical lower limb ischemia, the presence of ischemic skin lesions and the described radiological arterial disease score can be used to estimate amputation risk

Trimodality therapy for malignant pleural mesothelioma: Results from an EORTC phase II multicentre trial

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m -2 and pemetrexed 500 mg·m -2. Nonprogressing patients underwent extrapleural pneumonectomy followed by postoperative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary. Copyrigh

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.</p