Showing papers by "Hebron University published in 2008"

NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations

Abstract: Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab The PI3K pathway is, therefore, an attractive target for cancer therapy We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR) NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235 NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

Abstract: The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.

The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2

Abstract: Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR+/HER2+ breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR+/HER2+ breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-HER2 therapy in postmenopausal women with HR+/HER2+ advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR+/HER2+ breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR+/HER2+ advanced breast cancer.

Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum‐based therapies

Abstract: BACKGROUND. The epidermal growth factor receptor (EGFR) inhibitor cetuximab is active in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The activity of cetuximab was compared with that of commonly used treatments in this setting. METHODS. All patients had recurrent and/or metastatic SCCHN and had progressed on cisplatin- or carboplatin-based chemotherapy. Efficacy data from 3 prospective studies (n = 278 patients) that administered cetuximab as a single agent (n = 103 patients) or combined with either cisplatin/carboplatin (n = 96 patients) or cisplatin (n = 79 patients) were compared with the results from a retrospective study of patients who received various second-line treatments (all treatments including best supportive care only, n = 151 patients; chemotherapy, n = 43 patients). Safety data considered were only those from the cetuximab studies. RESULTS. Over the 3 cetuximab trials, overall response rates from 10% to 13% and disease control rates from 46% to 56% were observed. The median time to disease progression ranged between 2.2 months and 2.8 months, and the median overall survival ranged between 5.2 months and 6.1 months. No patients who progressed on cetuximab alone responded to additional platinum. These survival data compared favorably with those from the retrospective study (median survival, 3.4 months [n = 151 patients] and 3.6 months [n = 43 patients]). Cetuximab-based treatments generally were tolerated well, and cetuximab did not increase the side effects associated with platinum therapy. CONCLUSIONS. Cetuximab has the potential to prolong survival in patients with recurrent and/or metastatic SCCHN who fail on platinum therapy compared with various second-line therapies. Cetuximab did not increase the toxicities associated with chemotherapy. The results obtained by treatment with cetuximab alone after platinum failure did not appear to differ from the results obtained by reintroducing platinum in combination with cetuximab. Cancer 2008. © 2008 American Cancer Society.

Effects of probiotic Lactobacillus casei DN-114 001 in prevention of radiation-induced diarrhea: results from multicenter, randomized, placebo-controlled nutritional trial.

Abstract: Purpose To determine whether a probiotic drink containing Lactobacillus casei DN-114 001 reduces the incidence of radiation-induced diarrhea in patients with gynecologic cancer. Methods and Materials Patients who were undergoing pelvic radiotherapy (45–50 Gy, conventional fractionation) for either cervical carcinoma (radiotherapy and weekly cisplatin) or endometrial adenocarcinoma (postoperative radiotherapy) were randomly assigned to a probiotic drink or placebo, in a double-blind fashion. The probiotic drink consisted of liquid yogurt containing L. casei DN-114 001 at 10 8 CFU/g. The patients recorded the daily the number of bowel movements and scored the stool consistency using the Bristol scale. Diarrhea was graded weekly according the Common Toxicity Criteria system. The primary endpoint was to reduce the incidence of diarrhea, defined by a Common Toxicity Criteria Grade of 2 or greater or the need for loperamide. Results A total of 85 patients were enrolled. Grade 2 or greater diarrhea and/or the use of loperamide was observed in 24 of 41 patients in the placebo group and 30 of 44 in the probiotic group ( p = 0.568). No differences were found in the median time to the presentation of the primary endpoint. Probiotic intervention had a significant effect on stool consistency ( p = 0.04). The median time for patients to present with Bristol scale stools of Type 6 or greater was 14 days for patients receiving the probiotic drink vs. 10 days for those receiving placebo. Conclusion Nutritional intervention with the probiotic drink containing L. casei DN-114 001 does not reduce the incidence of radiation-induced diarrhea as defined by a Common Toxicity Criteria Grade 2 or greater. However, it had a significant effect on stool consistency as measured by the Bristol scale.

Paraneoplastic Vasculitis in Patients with Solid Tumors : Report of 15 Cases

Abstract: OBJECTIVE: To review all cases of concurrent vasculitis and solid tumors diagnosed at our Department over a 15-year period and explore evidence that would support the notion of vasculitis being a true paraneoplastic syndrome. METHODS: We reviewed the records of all patients diagnosed with vasculitis and solid tumors within 12 months of each other and prospectively followed until death or our report. We analyzed the main features and outcome of vasculitis in this setting. We also reviewed all cases published in the French-English literature. RESULTS: Fifteen patients (9 men and 6 women) in whom both vasculitis and solid tumor occurred within the same 12 months were identified. Mean age was 72.5 years (range 58-84). In 7 cases the diagnosis of vasculitis antedated that of cancer, in 6 both processes were synchronously diagnosed, and in 2 vasculitis appeared after cancer diagnosis. The most common vasculitis was cutaneous leukocytoclastic vasculitis (n = 9). Other vasculitides included Henoch-Shonlein purpura (n = 2), polyarteritis nodosa (n = 1), and giant cell arteritis (n = 3). The commonest malignancies were carcinomas of urinary organs (40%), lung (26.7%), and gastrointestinal tract (26.7%). The median followup was 28.4 months (range 1-96). Thirteen of the 15 patients demonstrated concordance of disease activity and treatment response for both cancer and vasculitis. Vasculitis flared heralding tumor recurrence or progression in 7 (46.6%) cases. CONCLUSION: In our patients, resolution of vasculitis following effective treatment of the putatively linked malignancy, and recurrence of vasculitis heralding tumor recurrence or progression, provide strong evidence for vasculitis being a true paraneoplastic syndrome. Chronic or persistent vasculitis with poor response to usually effective therapy, especially in elderly patients, should raise questions about underlying malignancy.

Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis.

Abstract: The objective of the study was to evaluate the clinical features, response to treatment, and long-term outcome of subglottic stenosis (SGS) in a series of patients diagnosed as having Wegener's granulomatosis (WG) at a single institution. Subglottic stenosis developed in 6 out of 51 (11.7%) patients, in four of them in the absence of other features of active disease, and was the symptom that leads to WG diagnosis in three cases. In two cases, SGS began while the patients were receiving systemic immunosuppressive therapy for disease activity involving other sites. PR3-ANCAs were positive in four cases. An urgent tracheostomy was needed in two patients. Four patients achieved SGS clinical remission on standard treatment with glucocorticoids and cyclophosphamide, but three of them experienced repeated local relapses and required additional immunosuppressive therapy and mechanical dilations. In one case, a local relapse was successfully managed with endotracheal dilation of the stenotic segment and intralesional injection of a long-acting corticosteroid plus mechanical dilation of the stenotic segment (ILCD) without adding supplemental immunosuppressant drugs. Two patients with isolated SGS were also successfully managed with ILCD alone and did not require the institution of systemic immunosuppressive therapy. One patient underwent open surgical repair when the disease was under control. Our data suggest that Subglottic stenosis often occurs or progresses independently of other features of active WG, and that ILCD may be a safe alternative to conventional immunosuppressive therapy in patients who develop SGS in the absence of other features of active disease, allowing reducing the treatment-related toxicity.

Monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic flow (Type III): feasibility and perinatal outcome of fetoscopic placental laser coagulation

Abstract: Objectives To assess the feasibility and impact on perinatal outcome of fetoscopic laser coagulation of placental anastomoses in monochorionic twins with selective intrauterine growth restriction (sIUGR) and intermittent absent or reversed end-diastolic flow (iAREDF) in the umbilical artery (Type III), in comparison with expectant management. Methods This is a descriptive study of the outcome of 18 cases of monochorionic twins with Type III sIUGR treated with laser, and 31 pregnancies managed expectantly over the same period. All newborns underwent neonatal brain ultrasound scans. Perinatal outcome and the incidence of neurological damage were compared between the two groups. Results Laser coagulation could be performed in only 88.9% (16/18) of cases owing to technical difficulties, and in 12.5% (2/16) a second procedure was required to achieve complete coagulation of the large artery-to-artery anastomosis. Mean gestational age at delivery was 31.0 (range, 26–33) weeks in the expectant management group and 32.6 (range, 23–38) weeks in the laser group (P = 0.32). Overall perinatal survival was 85.5% (53/62) and 63.9% (23/36), respectively (P = 0.02). Intrauterine demise of the smaller twin occurred in 19.4% (6/31) and 66.7% (12/18), respectively (P = 0.001), and was associated with death of the cotwin in 50% (3/6) and 0% (0/12) of these cases, respectively (P = 0.02). The prevalence of periventricular leukomalacia in the larger fetus was 4/28 (14.3%) in the expectant management group and 1/17 (5.9%) in the laser group (P = 0.63). Conclusions Laser coagulation in sIUGR-iAREDF pregnancies is technically difficult and not always feasible. Placental dichorionization significantly increases the proportion of fetuses with intrauterine death of the growth-restricted twin, but it protects the normal twin from its cotwin's death in the event of demise of the growth-restricted twin. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Will Rogers phenomenon in multiple sclerosis.

Abstract: Objective Using different criteria for classifying patients into various stages of a disease can modify the stage-specific prognosis, even though the overall disease course remains unchanged. This is known as the “Will Rogers phenomenon,” precluding the use of historical controls for treatment trials. We assessed whether the Will Rogers phenomenon may affect multiple sclerosis (MS) prognosis when applying different diagnostic criteria. Methods Patients with a clinically isolated syndrome (CIS) suggestive of MS were studied. After 1 year, each patient was classified as CIS or evolved to MS according to two diagnostic criteria (Poser and McDonald). The outcome for prognosis was the time to reach an Expanded Disability Status Scale score ≥ 3.0. Results 309 patients were studied for a median period of 84 months. After 1 year, 16% of patients had MS according to Poser and 44% according to McDonald criteria. The probability to reach Expanded Disability Status Scale score ≥ 3.0 at median follow-up was 11% in CIS patients according to Poser and 7% according to McDonald criteria; it was 46% in MS patients according to Poser and 27% acccording to McDonald criteria. The group with a discordant diagnosis had a worse prognosis than that of CIS patients according to both criteria (p = 0.01), but better than that of MS patients according to both criteria (p = 0.01). Interpretation The use of different diagnostic criteria may generate spurious improvements in the medium-term prognosis of MS. This calls for caution in using historical controls for MS trials. Ann Neurol 2008

Successful treatment of pulmonary metastatic salivary ductal carcinoma with trastuzumab‐based therapy

Abstract: Background. Salivary ductal carcinoma (SDC) is an uncommon malignant tumor of the salivary glands. Although there is no known standard of care for the treatment of ad- vanced disease, the vast majority of patients with SDC may be offered palliative systemic therapy. We report a case of epi- dermal growth factor receptor 2 (HER2)-positive metastatic submandibular SDC with a complete and durable clinical response to treatment with trastuzumab in combination with chemotherapy. Methods and Results. A 62-year-old man was diagnosed with SDC of the left submandibular gland with extensive cervical lymph node involvement. The lesion was completely resected, and the patient underwent postoperative radiotherapy. After 6 months, multiple pulmonary metastatic lesions were detected. A complete response was reached with trastuzumab-based com- bination therapy, and no evidence of disease progression has been observed after 14 months of initiation of systemic therapy. Conclusion. Trastuzumab-based combination therapies should be considered for advanced SDC. V C 2007 Wiley Periodicals, Inc. Head Neck 30: 680-683, 2008

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

Abstract: Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC50 and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted.

Determinants of RAsistance to Anti-Epidermal Growth Factor Receptor Agents

Abstract: There is a general agreement that oncologists are not doing well in selecting patients most likely to benefit from molecularly targeted therapies. The consequences of administering these agents to inappropriately selected patients include unnecessary toxicities for patients who are unlikely to derive benefit, a waste of time, and an inefficient use of increasingly constrained financial resources. Agents directed at epidermal growth factor receptor (EGFR) provide a good example of our need to improve this selection process. On one hand, anti-EGFR agents are approved in the therapy of non–small-cell lung cancer (NSCLC), colon cancer, and head and neck cancer, in which they provide significant clinical benefit. Yet, there is an absence of validated predictive markers of response to anti-EGFR agents with the exception of the rare EGFR mutations/amplifications that occur in NSCLC. It is therefore not surprising that these agents have limited activity; for example, in colon cancer, the anti-EGFR monoclonal antibodies cetuximab and panitumumab have single-agent response rates in the range of only 10%. The lack of validated predictive markers of benefit to antiEGFR agents may be the result of the complex biology of the EGFR system itself that defies the definition of EGFR dependency. This complexity is due to the existence of multiple EGFR ligands, a variety of receptor dimerization partners, and the frequent occurrence of receptor cross-talk with members of other receptor families, among other reasons. Furthermore, it is likely that the biologic consequences of EGFR activation varies as a consequence of other mutations present in the tumor. Taking all of these aspects into consideration, although it has been possible to identify some predictors of clinical benefit, it may be more fruitful to identify negative predictive factors of benefit to anti-EGFR agents. These would be markers that, when present, would render tumors EGFR independent and therefore not sensitive to EGFR inhibition. Emerging data suggest that a hyperactive mutant KRAS is likely to be a powerful negative predictive factor of EGFR response. The RAS proteins are members of a large superfamily of guanosine-5’-triphosphate (GTP)–binding proteins that play a complex role in the normal transduction of growth factor receptor–induced signals. Stimulation of growth factor receptors, such as EGFR, causes activation of multiple regulatory molecules, including the RAS protein. EGFR activates RAS by stimulating its binding to GTP. RAS, in its active, GTP-bound state, binds several key target proteins, which results in the subsequent activation of several downstream pathways, including those mediated by MAP kinase, PI3K, and RAL-GDS. Engagement of these pathways leads to stimulation of cell cycle progression, desensitization of the cell to proapoptotic stimuli, changes in cytoskeletal organization and invasion, and other processes required for cell proliferation. Activating mutations of the KRAS and NRAS genes occurs frequently in human cancer. KRAS mutations are prevalent in pancreatic (60%), colorectal ( 30%), endometrial (15%), biliary tract ( 30%), lung (20%), and cervical cancers (10%). In most cases, the somatic RAS missense mutations found in cancer introduce amino acid substitutions at positions 12, 13, and 61. These mutations disable the endogenous GTPase activity of the RAS protein, and cause cancer-associated RAS to accumulate in the active, GTP-bound conformation. This, in turn, results in activation of PI3K, MAP kinase, and RAL-GDS, which results in malignant transformation. Because RAS is downstream from EGFR, aberrant RAS signaling like the one occurring in cells with mutant KRAS, may lead to dysregulation of RAS-dependent pathways and downstream signaling even if the upstream receptor is silenced by anti-EGFR monoclonal antibodies. Since the introduction of anti-EGFR therapies, there is increasing evidence that this may be the case. Several retrospective analyses have reported lack of benefit from the anti-EGFR monoclonal antibody cetuximab in patients with colorectal cancer (CRC) harboring KRAS mutations. In a recent prospective biomarker driven clinical trial with single-agent cetuximab in patients with CRC with mandatory tumor sampling for the identification of candidate predictive marker, the correlation between KRAS and clinical benefit was also analyzed. In this study, KRAS mutations strongly correlated with lack of clinical benefit; mutations were present in only three (11%) of 27 patients that achieved clinical benefit but were detected in 27 (51%) of 53 nonresponders. In this issue of the Journal of Clinical Oncology, Amado et al assessed the predictive role of KRAS in the recently reported, large, phase III randomized trial comparing the anti-EGFR monoclonal antibody panitumumab, given as monotherapy, to best supportive care (BSC) in patients with chemotherapy-refractory metastatic CRC. KRAS status was assessed in 427 (92%) of 463 patients and KRAS mutations were found in 43%. The treatment effect on progression-free survival in the wild-type (WT) KRAS group (hazard ratio, 0.45) was significantly greater (P .0001) than in the KRAS mutant group, in which panitumumab had no benefit at all. Median progression-free survival in the WT KRAS group was 12.3 weeks for JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 10 APRIL 1 2008

A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy

Abstract: Purpose: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non–small cell lung cancer patients refractory to platinum-based chemotherapy. Experimental Design: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks9 treatment. Results: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease ≥12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR ( P = 0.002), p-MAPK ( P = 0.001), and Ki-67 ( P = 0.025) levels were significantly reduced after 6 weeks9 treatment. Apoptosis was significantly increased in patients with clinical benefit ( P = 0.029), and may be a marker of clinical benefit. Conclusion: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.

Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis.

Abstract: BACKGROUND Immunomodulatory drugs have been shown to be only modestly effective in clinically definite relapsing remitting multiple sclerosis (RRMS). It has been hypothesized that their efficacy could be higher if used at the first appearance of symptoms, that is in the clinically isolated syndromes (CIS) suggestive of demyelinating events, a pathology which carries a high risk to convert to clinically definite MS (CDMS). OBJECTIVES The objective of this review was to assess the effects of immunomodulatory drugs compared to placebo in adults in preventing conversion from CIS to CDMS which means the prevention of a second attack. SEARCH STRATEGY We searched the Cochrane MS Group Trials Register (June 2007), Cochrane Central Register of Controlled Trials (CENTRAL)The Cochrane Library Issue 3, 2007, MEDLINE (January 1966 to June 2007), EMBASE (January 1974 to June 2007) and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA The trials selected were double-blind, placebo-controlled, randomised trials of CIS patients treated with immunomodulatory drugs. DATA COLLECTION AND ANALYSIS Study selection have been independently done by two reviewers. Two further reviewers independently assessed trial quality and extracted and analysed data. Study authors were contacted for additional informations. Adverse effects information was collected from the trials. MAIN RESULTS Only three trials tested the efficacy of interferon (IFN) beta including a total of 1160 participants (639 treatment, 521 placebo); no trial tested the efficacy of glatiramer acetate (GA). The metanalyses showed that the proportion of patients converting to CDMS was significantly lower in IFN beta-treated than in placebo-treated patients both after one year (pooled OR 0.53; 95% CI, 0.40 to 0.71; p <0.0001) as well as after two years of follow-up (pooled OR 0.52; 95% CI, 0.38 to 0.70; p <0.0001). Early treatment with IFN beta was associated with the side effect profile reported by the randomised controlled trials with this drug. Since side effects were reported with some heterogeneity in the three studies the metanalysis was possible only for the frequency of serious adverse events, not significantly different in IFN beta-treated or placebo-treated patients. AUTHORS' CONCLUSIONS The efficacy of IFN beta treatment on preventing the conversion from CIS to CDMS was confirmed over two years of follow-up. Since patients had some clinical heterogeneity (length of follow-up, clinical findings of initial attack), it could be useful for the clinical practice to further analyse the efficacy of IFN beta treatment in different patient subgroups.

Administration of Cetuximab Every 2 Weeks in the Treatment of Metastatic Colorectal Cancer: An Effective, More Convenient Alternative to Weekly Administration?

Abstract: The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor-targeted IgG(1) monoclonal antibody that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m(2) initial dose followed by 250 mg/m(2) weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5-fluorouracil [5-FU]/folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m(2) every 2 weeks exhibited predictable pharmacokinetics, which were similar to those of the approved weekly dosing regimen. Active serum concentrations of cetuximab were maintained throughout the 2-week dosing period with this regimen. There was no difference between the dosing regimens on pharmacodynamic parameters in skin. The efficacy and safety of the every-2-weeks dosing regimen were similar to those reported for the approved weekly dosing regimen. The indication from these preliminary findings is that every-2-weeks administration of cetuximab (500 mg/m(2)) may be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m(2) (following an initial dose of 400 mg/m(2)) in the treatment of mCRC.

TGF-β signalling-related markers in cancer patients with bone metastasis

Abstract: We measured transforming growth factor (TGF)-β-dependent biomarkers in plasma and in peripheral blood mononuclear cells (PBMCs) to identify suitable pharmacodynamic markers for future clinical tria...

Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer

Abstract: Background Few data are available from clinical trials for elderly patients receiving cetuximab. Patients and methods The clinical data of consecutive patients aged ≥70 years given cetuximab for metastatic CRC were retrospectively captured from hospital pharmacy registries in seven centers. Results Fifty-six patients received cetuximab ± with irinotecan. Median age was 76 years (70–84), 86% of patients were pretreated with fluoropyrimidines, irinotecan and oxaliplatin and 69.6% had documented resistance to irinotecan. Objective response rate was 21% (95% CI: 11–32%). The median progression-free survival was 4.4 months (95% CI: 3.0–5.7 months) and the median overall survival was 16.0 months (95% CI: 13.5–18.5 months). Skin rash occurred in 75% of the patients (11% grade 3) and diarrhea in 80% (20% grades 3–4). Conclusion Tolerability of cetuximab was acceptable in elderly patients with pretreated metastatic CRC. Efficacy appeared similar to that observed in younger patients.

The use of hyperventilation therapy after traumatic brain injury in Europe: an analysis of the BrainIT database

Abstract: To assess the use of hyperventilation and the adherence to Brain Trauma Foundation-Guidelines (BTF-G) after traumatic brain injury (TBI). Twenty-two European centers are participating in the BrainIT initiative. Retrospective analysis of monitoring data. One hundred and fifty-one patients with a known time of trauma and at least one recorded arterial blood–gas (ABG) analysis. A total number of 7,703 ABGs, representing 2,269 ventilation episodes (VE) were included in the analysis. Related minute-by-minute ICP data were taken from a 30 min time window around each ABG collection. Data are given as mean with standard deviation. (1) Patients without elevated intracranial pressure (ICP) (<20 mmHg) manifested a statistically significant higher PaCO2 (36 ± 5.7 mmHg) in comparison to patients with elevated ICP (≥20 mmHg; PaCO2: 34 ± 5.4 mmHg, P < 0.001). (2) Intensified forced hyperventilation (PaCO2 ≤ 25 mmHg) in the absence of elevated ICP was found in only 49 VE (2%). (3) Early prophylactic hyperventilation (<24 h after TBI; PaCO2 ≤ 35 mmHg, ICP < 20 mmHg) was used in 1,224 VE (54%). (4) During forced hyperventilation (PaCO2 ≤ 30 mmHg), simultaneous monitoring of brain tissue pO2 or SjvO2 was used in only 204 VE (9%). While overall adherence to current BTF-G seems to be the rule, its recommendations on early prophylactic hyperventilation as well as the use of additional cerebral oxygenation monitoring during forced hyperventilation are not followed in this sample of European TBI centers. Neurotrauma

A rare case of malignant solitary fibrous tumor of the spinal cord.

Abstract: Study design Case report. Objective We present a case of an ambulatory patient with a solitary fibrous tumor of the spinal cord. Summary of background data Solitary fibrous tumor (SFT) is an uncommon mesenchymal tumor of the pleural cavity, increasingly recognized at numerous extrathoracic sites, including, among others, prostate, kidney, and thyroid. The spinal cord is an extremely rare localization of SFTs with only 17 cases reported in the literature since 1996. Although SFTs are usually indolent neoplasms that are cured with complete surgical resection, malignant transformation has been described within histologically benign SFTs. However, no cases of malignant dissemination have been described in this localization. Methods Discussion of the patient's clinical and radiologic history with a review of the relevant background literature. Results We report the first case of spinal cord SFT with visceral dissemination years after the primary diagnosis, despite benign histologic features of the primary tumor. Conclusion This finding may indicate that long-term follow-up might be necessary in these patients. In addition, metastatic radical surgery of SFTs should be considered to achieve long-term survival since there are no currently available effective systemic therapies.