Pulmonary Recruitment Maneuver Reduces Shoulder Pain and Nausea After Laparoscopic Cholecystectomy: A Randomized Controlled Trial.

BACKGROUND: Pain and nausea are common after laparoscopic surgery. This prospective, randomized, controlled trial aimed to investigate postoperative pain and as a secondary endpoint nausea, when performing a ventilator-piloted Pulmonary Recruitment Maneuvre (PRM) at the end of laparoscopic cholecystectomy. METHOD: Patients having elective laparoscopic cholecystectomy were randomized to either ordinary exsufflation or ventilator-piloted PRM, to evacuate intra-abdominal carbon dioxide (CO2) before abdominal closure. A questionnaire with numeric rating scales (NRS) was utilized to evaluate pain and nausea at five occasions during 48 h following surgery. Analgesic and antiemetic treatment was also analyzed. RESULTS: 147 patients were analyzed, 76 receiving PRM and 71 controls. Overall pain was well controlled, with no significant difference between the groups regarding incidence (P=0.149) nor intensity (P=0.739). Incidence of shoulder pain was lower in the PRM group during the 48 postoperative hours, 44.7% versus 63.4% (P=0.023). The number needed to treat (NNT) to reduce shoulder pain was 6 (95% Confidence Interval, CI, 2.9-35.5) for the 48-h period. Incidence of nausea was lower in the PRM group during the 48-h period, 51.3% versus 70.4% (P=0.018). NNT was 6 (95% CI 2.9-27.4) for the 48-h period. Nausea intensity was lower in the PRM group during the 48 h (P=0.025). Fewer in the PRM population required antiemetics, 25.0% versus 42.3% (P=0.027). CONCLUSION: A ventilator-piloted PRM at the end of laparoscopic cholecystectomy reduced incidence of shoulder pain, and incidence and intensity of nausea. Clinical trial registration www.clinicaltrials.gov . Identifier: NCT03026543.

Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income country: Metro-Mali-02.

BACKGROUND: Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, metronomics appears to be an invaluable alternative to bring affordable targeted therapies in low-income countries. OBJECTIVE: The aim of this study was to report on the preliminary efficacy and safety of a metronomic vincristine/cyclophosphamide/methotrexate/valproic acid regimen given to children with refractory cancer of various tumor types or with a very advanced disease. MATERIALS AND METHODS: This prospective, single-center study evaluated the use of a metronomics protocol, consisting of a first cycle of weekly vincristine 1.5 mg/m2 (days: 1, 8, 15 and 22), daily cyclophosphamide 25 mg/m2 (days: 1-21), twice weekly methotrexate 15 mg/m² (days: 21-42) and daily valproic acid (30 mg/kg/d) followed by a 1-week break. For the following cycles, vincristine was administrated only at week 1 and 5 of the cycle. This treatment was proposed to children with refractory disease and patients who were not eligible for the protocols available in the hospital. Adverse events were determined through laboratory analyses and investigator observations. RESULTS: From January 2010 to January 2011, 7 children (mean age: 5.4 ± 3 years old) were treated. Most frequent diagnosis was retinoblastoma. Two partial responses were observed in patients with neuroblastoma and retinoblastoma. These two patients are alive with stable disease at last follow-up (6 and 26 months, respectively) after stopping treatment. CONCLUSION: Metronomics allows treating patients with advanced or refractory or relapsing disease and the introduction of targeted treatments in low-income countries. The potential of metronomics in children and young adults living in middle- and low-income countries warrants further larger studies.

ß-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma.

BACKGROUND: The use of ß-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether ß-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. METHODS: Seven ß-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. RESULTS: Three ß-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. ß-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, ß-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, ß-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). CONCLUSION: ß-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

A mathematical model for the administration of temozolomide: comparative analysis of conventional and metronomic chemotherapy regimens.

We propose a mathematical model that takes into account a classical maximum tolerated dose (MTD) chemotherapy regimen (whose primary targets are the tumor cells) as well as a metronomic chemotherapy regimen (whose primary targets are the tumor endothelial cells) for the administration of temozolomide (Temodal(®)) in order to compare the effectiveness of these two types of protocols. The model is built from 4 natural hypotheses: (H1) without treatment the tumor growth follows a Gompertz model, (H2) endothelial cells are more sensitive to temozolomide than cancer cells, (H3) the anti-angiogenic effect blocks tumor growth, and (H4) endothelial cells are more genetically stable than cancer cells and thus less likely to develop resistance to temozolomide. Then, we compared a conventional MTD regimen of 200 mg/m(2) temozolomide J1-J5 every 28 days with a daily metronomic regimen of 85 mg/m(2)/day for cycles of 42 days. Our mathematical model shows that the metronomic regimen induces tumor regression through anti-angiogenic effects while the MTD regimen fails to do so, due to the emergence of temozolomide resistance in cancer cells. Overall, our model is consistent with clinical observations and provides an interesting tool toward the personalization of anticancer treatments, through optimization of dose and schedule of chemotherapy based on individual patient characteristics.

Endothelial cell dysfunction and cytoskeletal changes associated with repression of p16(INK4a) during immortalization.

The immortalization process is a fundamental step in the development of most (if not all) human cancers, including the aggressive endothelial cell (EC)-derived malignancy angiosarcoma. Inactivation of the tumor suppressor p16(INK4a) and the development of multiple chromosomal abnormalities are features of angiosarcoma that are recapitulated during telomerase-mediated immortalization of human ECs in vitro. The present study used a panel of telomerase-immortalized bone marrow EC (BMEC) lines to define the consequences of inactivation of p16(INK4a) on EC function and to identify molecular changes associated with repression of p16(INK4a). In a comparison of two immortalized BMEC mass cultures and six clones, the cell lines that repressed p16(INK4a) showed a higher rate of proliferation and an impaired ability to undergo morphogenic differentiation and form vessel-like structures in vitro. Proteomic comparison of a p16(INK4a)-negative and a p16(INK4a)-positive BMEC mass culture at early- and late-passage time points following transduction with telomerase reverse transcriptase (hTERT) revealed altered expression of cytoskeletal proteins, including vimentin and α-tropomyosin (αTm), in the immortal cells. Immunoblot analyses of a panel of 11 immortal clones showed that cells that lacked p16(INK4a) expression tended to accumulate more dramatic changes in these cytoskeletal proteins than cells that retained p16(INK4a) expression. This corresponded with aberrant cytoskeletal architectures among p16(INK4a)-negative clones, which featured thicker actin stress fibers and less fluid membrane ruffles than p16(INK4a)-positive cells. A direct link between p16(INK4a) repression and defective EC function was confirmed by analysis of normal cells transfected with small interfering RNA (siRNA) targeting p16(INK4a). siRNA-mediated repression of p16(INK4a) significantly impaired random motility and vessel formation in vitro. This report is the first to demonstrate that ECs that repress the expression of p16(INK4a) are prone to defects in motility, morphogenesis and cytoskeletal organization. These defects are likely to reflect alterations that occur during the development of EC-derived malignancies.

[Metronomic chemotherapy in pediatric oncology: hype or hope?]. / Chimiothérapie métronomique en oncologie pédiatrique : effet de mode ou espoir réel ?

Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.

Understanding microtubule dynamics for improved cancer therapy.

Microtubules (MTs), key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments. MT dynamics are highly regulated both spacially and temporally by several MT-related proteins, themselves regulated by several kinases and phosphatases via signaling cascades, and also by coordinated interactions with actin cytoskeleton and adhesion sites. Regulation of MT dynamics is crucial for mitosis, cell migration, cell signaling and trafficking. MT-targeted drugs (MTDs), which constitute a major anticancer drug family with antimitotic and antiangiogenic properties, inhibit tumor progression mainly by altering MT dynamics in both cancer and endothelial cells. Identification of proteins regulating the MT network will lead to a better understanding of tumor progression regulators and will be helpful in improving cancer therapy.

Effects of delta5 polyunsaturated fatty acids of maritime pine (Pinus pinaster) seed oil on the fatty acid profile of the developing brain of rats.

Conifer (pine) seeds are a potential source of dietary oils, but their safety and nutritional properties are not well established. Conifer seed oils differ from common edible vegetable oils in having a series of unusual polyunsaturated fatty acids (PUFA) with a polymethylene-interrupted (PMI) double bond system and a double bond at the delta5 position. A rat study was conducted to assess whether delta5 PMI-PUFA of conifer seeds could alter the levels of n-6 and n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in mothers' milk and the developing brain of fetuses and pups. Feeding maritime pine (Pinus pinaster) seed oil (MPO) diet with a delta5 PMI-PUFA content of 1.4 g/100 g throughout pregnancy and lactation resulted in a large incorporation of delta5 PMI-PUFA in mothers' milk (5.1 +/- 0.5% of total fatty acids). The fetus (17 d old) and pup (22 d) brains, however, accumulated very little (0.6 and 0.4% of total fatty acids, respectively) delta5 PMI-PUFA. Mother's milk and pup's brain of the MPO group contained normal levels of 20:4n-6, 22:4n-6, and 20:5n-3 compared to a reference group of rats fed a fat blend of sunflower, high-oleic sunflower, and canola oils. The level of 22:6n-3, however, was slightly but significantly (P < 0.05) higher in milk and pup brain of the MPO group. These results show that delta5 PMI-PUFA of MPO exert no negative effect on the levels of n-6 and n-3 LC-PUFA in rat brain during its early development.

A cross sectional study of antiphospholipid-protein antibodies in patients with venous thromboembolism.

OBJECTIVE: To look for an association between venous thromboembolism (VTE) and antiphospholipid antibodies (aPL) in patients without Systemic Lupus Erythematosus (SLE) when implementing, beside conventional assays, new tests for aPL screening directed towards purified proteic targets. METHODS: We conducted a cross-sectional, hospital-based study of consecutive unselected outpatients. We compared VTE+ patients to VTE- among 398 consecutive unselected outpatients referred for clinical suspicion of VTE. To detect aPL, the following ELISAs were performed: 1) a conventional standardized ELISA 2) an improved APA assay, 3) an anti-Beta2GPI ELISA, 4) an anti-Annexin V ELISA, 5) an anti-Prothrombin ELISA. We sought an association between VTE and aPL through a quantitative (t-test) and a qualitative comparison (chi-square test, according to the cut-off values set as the 95th percentile of aPL distribution). First we conducted an analysis of all patients. Then we stratified them into 2 subgroups, with or without a wellknown risk factor for VTE (prolonged immobilization >72h, surgery or trauma within the past three months, current malignancy). RESULTS: 61% of patients were classified as VTE-positive. Before stratification, we did not find any significant association between the VTE status and aPL. However, after stratification, in the subgroup without risk factors for VTE, the frequency of positive values as regards the anti Prothrombin antibodies detection was significantly higher in VTE+ patients (p = 0,04). CONCLUSION: The presence of anti Prothrombin antibodies might be an independent risk factor of VTE. However systematic screening for aPL in non SLE patients referred for VTE suspicion at the time of the thrombo-embolic event has little clinical relevance.

First case of pneumatosis cystoides intestinalis in adult dermatomyositis.

We describe the first case of pneumatosis cystoides intestinalis in dermatomyositis (DM) of an adult. Our patient had been in remission of her DM for years when pneumatosis cystoides intestinalis occurred. Discovery of it was concomitant with that of interstitial lung disease. The overall course of pneumatosis cystoides intestinalis was benign. We discuss the mechanism of bowel and lung involvement and hypothesize that vasculitis could be the underlying process.