Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003).

BACKGROUND: High-dose pharmaceutical-grade biotin (MD1003) has positive effects on disability in progressive multiple sclerosis (PMS), but its mechanism of action remains unclear. The objective of our study was to quantify the effect of MD1003 in patients with PMS, using clinical response, plasma neurofilament light chain (pNfL) levels, and brain (BV) or cervical spinal cord volume (CSCV). MATERIALS AND METHODS: Forty-eight patients with PMS newly treated with MD1003 were followed during one year. Patients were assessed clinically using the Expanded Disability Status Scale (EDSS), the nine-hole peg test (9HPT), and the 25-foot walk time (25FWT). CSCV was quantified using CORDIAL software and BV using SIENA or SIENAX. We measured pNfL level using SIMOA at several time points. Bayesian linear and logistic regressions were used to evaluate potential prognostic factors. RESULTS: Treatment response, defined as a significant decrease of EDSS, 25FWT, or 9HPT at 1 year, was observed in 13 patients (27%). A gain of volume was noted in 7/24 patients for brain and in 10/19 patients for cervical spinal cord. The strongest predictors of poor treatment response were a high pNfL level at MD1003 onset (OR 0.96; 95% CI [0.91; 1]), high age at MS onset (OR 0.95; 95% CI [0.89; 1.01]), and an increase in brain lesion load during MD1003 treatment (OR 0.81; 95% CI [0.55; 1.05]). CONCLUSIONS: MD1003 treatment was associated with clinical, BV, and CSCV improvement at 1 year. The correlation between the levels of pNfL at baseline, the age at multiple sclerosis onset, and a treatment response at M12 is consistent with a better effect in less disabled patients.

Management of adjuvant settings for Stage III melanoma patients in France prior to checkpoint inhibitors: epidemiological data from the RIC-Mel database.

BACKGROUND: Targeted therapies such as BRAF and MEK inhibitors and immunotherapies have been made available to treat melanoma. OBJECTIVES: To provide an overview of the management of the French Stage III melanoma population after complete lymph node resection prior to new adjuvant therapies. MATERIALS AND METHODS: A subgroup data analysis. RESULTS: Data from 1,835 patients were analysed (15.58% Stage IIIA, 39.24% Stage IIIB, 43.92% Stage IIIC and 1.25% Stage IIID). Superficial spreading melanoma was the most frequent (70.98% in Stage IIIA for whom mutation analysis was performed; BRAF mutation was identified in up to 62% Stage IIIA patients). Sentinel lymph node biopsy was performed in 88.46% of Stage IIIA patients, 42.36% of Stage IIIB, 53.97% of Stage IIIC and 34.78% of Stage IIID. Up to 80% of Stage IIIA patients had no adjuvant treatment follow-up. Ulceration (p = 0.004; RR: 2.98; 95% CI: 1.4-6.3) and age at diagnosis (p = 0.0002; RR: 1.04; 95% CI: 1.02-1.06) were significant predictive factors for survival. Adjuvant interferon-α was administered in up to 13.04% of Stage IIID patients. CONCLUSION: Only a small number of Stage III melanoma patients were treated with interferon-α in adjuvant settings. New adjuvant therapies are currently having an effect on clinical practice in France, increasing survival and decreasing cost.

Evolution of Complex Asexual Reproductive Strategies in Jellyfish.

Many living organisms in terrestrial and aquatic ecosystems rely on multiple reproductive strategies to reduce the risk of extinction in variable environments. Examples are provided by the polyp stage of several bloom-forming jellyfish species, which can reproduce asexually using different budding strategies. These strategies broadly fall into three categories: (1) fast localized reproduction, (2) dormant cysts, or (3) motile and dispersing buds. Similar functional strategies are also present in other groups of species. However, mechanisms leading to the evolution of this rich reproductive diversity are yet to be clarified. Here we model how risk of local population extinction and differential fitness of alternative modes of asexual reproduction could drive the evolution of multiple reproductive modes as seen in jellyfish polyps. Depending on environmental parameters, we find that evolution leads to a unique evolutionarily stable strategy, wherein multiple reproductive strategies generally coexist. As the extinction risk increases, this strategy shifts from a pure budding mode to a dual strategy and finally to one characterized by allocation into all three modes. We identify relative fitness-dependent thresholds in extinction risk where these transitions can occur and discuss our predictions in light of observations on polyp reproduction in laboratory and natural systems.

Acupuncture version of breech presentation: a randomized sham-controlled single-blinded trial.

BACKGROUND: Several studies have investigated the efficacy of moxibustion with or without acupuncture for fetal version, but the results are discordant. Meta-analyses pointed out the need for robust, methodologically sound, randomized controlled trials. OBJECTIVE: The objective of this study was to assess the effectiveness of acupuncture with fire needling on acupoint BL67 for version of breech presentation. STUDY DESIGN: This was a randomized, sham-controlled, single-blinded trial, which took place in Strasbourg teaching maternity hospital, France. A total of 259 patients between 32 and 34 weeks of gestation have been randomized and analyzed. Patients were randomized to either acupuncture with fire needling or sham group, and were analyzed in their initial allocation group. Statistical analysis was conducted using Bayesian methods, in univariate analysis and in multivariate analysis after adjustment on parity. RESULTS: The primary outcome was the rate of cephalic presentations at ultrasound examination performed between 35 and 36 weeks of gestation. A total of 49 (37.7%) fetuses were in cephalic presentation in the acupuncture group, versus 37 (28.7%) in the sham group: RR 1.34 [0.93-1.89], Pr RR>1=94.3%. After adjustment on parity, the acupuncture did not increase the rate of fetal cephalic version: OR 1.47 [0.84-2.42], Pr OR>1=90.3%. CONCLUSIONS: Our study suggests that acupuncture with fire needling on acupoint BL67 does not promote fetal cephalic version. Further studies might investigate effectiveness of other protocols of acupuncture. Randomization should be stratified for nulliparous and parous patients.

The global susceptibility of coastal forage fish to competition by large jellyfish.

Competition between large jellyfish and forage fish for zooplankton prey is both a possible cause of jellyfish increases and a concern for the management of marine ecosystems and fisheries. Identifying principal factors affecting this competition is therefore important for marine management, but the lack of both good quality data and a robust theoretical framework have prevented general global analyses. Here, we present a general mechanistic food web model that considers fundamental differences in feeding modes and predation pressure between fish and jellyfish. The model predicts forage fish dominance at low primary production, and a shift towards jellyfish with increasing productivity, turbidity and fishing. We present an index of global ecosystem susceptibility to shifts in fish-jellyfish dominance that compares well with data on jellyfish distributions and trends. The results are a step towards better understanding the processes that govern jellyfish occurrences globally and highlight the advantage of considering feeding traits in ecosystem models.

Peritoneal carcinomatosis with synchronous liver metastases from colorectal cancer: Who will benefit from complete cytoreductive surgery?

PURPOSE: Selection of patients for resection of synchronous liver metastases (LM) and peritoneal carcinomatosis (PC) of colorectal cancer (CRC) remains a debated issue since morbidity of this surgery is not negligible. We aimed to define overall survival (OS) prognostic criteria in patients undergoing PC surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and LM resection. METHODS: This monocentric and comparative study included all consecutive patients operated for LM (LM group, n = 77), PC (HIPEC group, n = 18) and PC + LM (LM + HIPEC group, n = 9) from January 2007 to May 2011. Characteristics of the 3 groups were prospectively collected and retrospectively compared. RESULTS: Median follow-up was 56,5 months. Major morbidity and mortality were respectively 14% and 3%. Two-year disease free and overall survival rates were respectively 23% and 76%. There were significantly more Dindo grade III-IV complications in LM + HIPEC group. In multivariate analysis, grade II and III preoperative chemotherapy-induced toxicity and size of LM were identified as poor OS prognostic factors whereas response to preoperative chemotherapy significantly increases OS. OS was not different (p = 0.235) between the 3 groups. CONCLUSION: Toxicity to preoperative chemotherapy and size of LM were identified as poor prognostic factors in patients undergoing simultaneous PC and LM surgery. These criteria could help in better selecting patients for such extensive surgery.

Mitomycin C Pharmacokinetics as Predictor of Severe Neutropenia in Hyperthermic Intraperitoneal Therapy.

BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an approach to overcome peritoneal carcinomatosis from colorectal adenocarcinoma. Mitomycin C (MMC) is frequently used but not devoid of toxicity, of which the most common and feared is neutropenia. Our study explores the clinical and surgical risk factors of neutropenia and a possible link between MMC pharmacokinetics and neutropenia as HIPEC's supervention. METHODS: A total of 45 patients undergoing CRS-HIPEC for peritoneal carcinomatosis of colorectal origin between 2004 and 2010 were followed. For each patient, MMC was measured in plasma at different times during HIPEC and the area under the MMC concentration-time curve (MMC-AUC) was calculated. RESULTS: The incidence of neutropenia was 40 %. No demographic, clinical, or surgical factors increased the risk of neutropenia. However, we found that the occurrence of neutropenia and its gravity increased in direct correlation with an increase in MMC plasma concentration 30 min (T30) and 45 min (T45) after the start of HIPEC. The same correlation was observed between the MMC-AUC and the risk of neutropenia. CONCLUSIONS: Neutropenia is a frequent complication associated with MMC-HIPEC. The results of our study indicate the feasibility and the potential benefit of a protocol including the MMC dosage at T30 after the start of HIPEC. A threshold of 572 µg/L gives a predictive sensitivity of 86 % and a specificity of 80 %. These results must be considered in the management of patients undergoing MMC-HIPEC in order to place high-risk patients under neutropenic monitoring while the other patients can undergo simple hematological monitoring.

Pruritus in cutaneous T-cell lymphomas: frequent, often severe and difficult to treat.

Pruritus has a well-known association with Hodgkin's disease and other nodal lymphomas; indeed it often reveals the disease. Pruritus is also an important symptom of cutaneous T-cell lymphomas. Lymphoma-associated itch is thus both frequent and severe, but its pathophysiology remains unclear. Few studies have evaluated the efficacy of therapeutic agents in the management of cutaneous T-cell lymphoma-related pruritus. The main objective of treatment remains disease control. Pruritus management is generally based on the physician's experience. Treatment is very difficult, especially in Sézary syndrome. We present here management strategies for cutaneous lymphoma-associated pruritus.

Targeting the nuclear factor-kappaB rescue pathway has promising future in human renal cell carcinoma therapy.

Metastatic renal cell carcinoma (RCC) remains refractory to therapies. The nuclear factor-kappaB (NF-kappaB) transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting NF-kappaB could be of therapeutic and prognostic values in human RCC. The activation of the NF-kappaB pathway in human RCC cells and tumors was investigated by Western blot. In vitro, the effects of BAY 11-7085 and sulfasalazine, two NF-kappaB inhibitors, on tumor cell growth were investigated by cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and fluorescence-activated cell sorting. Their specificity toward NF-kappaB was analyzed by Western blot, confocal microscopy, NF-kappaB small interfering RNA, and NF-kappaB transcription assay. In vivo, the effects of BAY 11-7085 on the growth of human RCC tumors were investigated in nude mice. A tissue microarray (TMA) containing 241 cases of human RCC with 12 to 22 years of clinical follow-up and corresponding normal tissues was built up to assess prognostic significance of activated NF-kappaB. NF-kappaB is constitutively activated in cultured cells expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as a consequence of Akt kinase activation and in tumors. In vitro and in vivo NF-kappaB inhibition blocked tumor cell growth by inducing cell apoptosis. On the TMA, NF-kappaB activation was correlated with tumor dimension but was not found to be an independent prognostic factor for patient survival. This report provides strong evidence that the mechanisms responsible for the intrinsic resistance of RCC cells to apoptosis converge on NF-kappaB independently of VHL expression and that targeting this pathway has great anticancer potential.