Prevalence of neuropathic pain in patients with symptomatic endometriosis: Assessment using the DN4 score.

The mechanisms underlying pain in cases of endometriosis or chronic pelvic pain are complex, often involving various types of pain; mainly nociceptive pain, central sensitization, and neuropathic pain. Our main objective was to examine the prevalence of neuropathic pain in women with symptomatic endometriosis, and secondary, to explore the factors associated with this type of pain and to assess the prevalence of a positive PPSC score and a history of sexual violence within this population. This study is a retrospective, comparative, single-center cohort study conducted from September 2019 to January 2023. The presence of neuropathic pain was confirmed by a positive DN4 score, defined as greater than or equal to 4. The association with the following variables was studied: age, BMI, marital status, smoking, alcohol and drugs consumption, age at menarche, gestity, parity, duration of exposure to endometriosis, MRI locations, laparoscopy for endometriosis and post-laparoscopy r-ASRM classification, hormone treatment, associated symptoms, VAS, associated pathologies, infertility consultation, Pain Center consultation, EPH-5 score, positive PPSC score (≥5), and history of sexual violence. The prevalence of neuropathic pain was 44.1%. Younger age, being in a relationship, having a high EPH-5 score and undergoing laparoscopy for endometriosis are associated with neuropathic pain independently of other variables. Our study underscores the persistent high prevalence of neuropathic pain in endometriosis cases, emphasizing the importance of actively screening for it. Identifying neuropathic pain could prompt referrals to pain specialists, integrating it into a comprehensive multidisciplinary approach.

Estimation of the prevalence of uterine infertility and its different causes in France according to data from a literature review.

INTRODUCTION: Uterine infertility (UI) is defined as the complete absence of a uterus (absolute uterine infertility or AUI) or the presence of a non functional uterus (non-absolute uterine infertility or NAUI). The exact prevalence of uterine infertility is currently unknown. Our aim was to assess the number of French women concerned by Uterine Infertility according to a recent literature review. MATERIALS AND METHODS: We have previously conducted a systematic review of the literature on UI and its various causes in the world. Based on these study and demographic data of 2022 from INSEE (Institut National de la Statistique et des Études Économiques), we attempted to estimate the number of women under 40 years of age in France affected by potential UI using direct standardization. RESULTS AND DISCUSSION: Based on the estimation from INSEE data, approximately 2066 women of childbearing age would have MRKH syndrome in France, 380 the Androgen Insensitivity Syndrome and 3700 had an haemostasis hysterectomy in France. We did not find data on the prevalence of hysterectomies before the age of 40 in France. For the following pathologies: uterine malformations, radiation uterus, synechiae, myomas and adenomyosis there was a huge amount of missing data, which does not allow us to estimate the number of potentially infertile patients. CONCLUSION: Prevalence of UI is poorly known. UI probably concerns several thousand patients in France. The creation of a UI registry would make enable to assess the number of patients potentially eligible for adoption, uterus transplantation or even surrogacy.

Inferior turbinate reduction: comparing post-operative bleeding between different surgical techniques.

OBJECTIVE: Post-operative bleeding is one of the most common and severe complications of turbinate surgery. This study compared post-operative bleeding following partial turbinectomy, submucosal turbinate reduction and endoscopic turbinoplasty. METHODS: Post-operative bleeding was assessed in patients who underwent inferior turbinate intervention by partial turbinectomy, submucosal turbinate reduction or endoscopic turbinoplasty between January 2016 and November 2017 and had completed at least one month of follow up. RESULTS: Of 1035 patients who underwent inferior turbinate surgery during the study period, 751 were included. Of these, 56 (7.5 per cent) presented to the emergency room with post-operative bleeding; 31 (8.4 per cent) had undergone partial turbinectomy, 19 (10.7 per cent) had undergone submucosal turbinate reduction and 6 (3.0 per cent) had undergone endoscopic turbinoplasty. The odds ratio of requiring an intervention to control bleeding was significantly lower in the endoscopic turbinoplasty group than in the submucosal turbinate reduction group (odds ratio = 3.26, 95 per cent confidence interval = 1.02-10.43). CONCLUSION: Endoscopic turbinoplasty had the lowest rate of post-operative bleeding and the lowest rate of patients requiring intervention.

Profilicollis chasmagnathi (Acanthocephala) parasitizing freshwater fishes: paratenicity and an exception to the phylogenetic conservatism of the genus?

Polymorphid acanthocephalans are parasites of marine mammals, waterfowl and ichthyophagous birds. Among these, the genus Profilicollis is known to use exclusively decapods as intermediate hosts. Here, we report the first record of living cystacanths of Profilicollis parasitizing the body cavity of a fish host, Oligosarcus jenynsii, inhabiting the freshwater section of an estuarial system, Mar Chiquita coastal lagoon, in south-east Buenos Aires Province, Argentina. In this environment, cystacanths of Profilicollis chasmagnathi have been previously recorded infecting decapod crabs and as transient accidental infections in the gut of some carcinophagous fishes. In the present study, larvae from the crab Neohelice granulata, from the intestine of the estuarine fish Odontesthes argentinensis and from the body cavity of O. jenynsii were morphologically and genetically compared, confirming their identity as P. chasmagnathi, a species characteristic of estuaries and marine coasts along Argentina, Uruguay and Chile. These findings can be interpreted as a possible case of incipient paratenicity for Profilicollis, and a colonization event of freshwater habitats, probably promoted by the highly variable conditions, typical of ecotonal environments. In addition, cystacanths of the genus Polymorphus were also found in O. jenynsii, representing the first record of this genus in Oligosarcus from Argentina.

Is there a relationship between vitamin D nutritional status and metabolic syndrome in childhood acute lymphoblastic leukemia survivors? A PETALE study.

BACKGROUND: Treatment of childhood acute lymphoblastic leukemia (cALL) has reached unprecedented success leading to survival rates reaching 90%. This is regrettably linked to increased risk of developing long-term health-related sequels into early adulthood. OBJECTIVE: This study aims at assessing the relationship between the vitamin D status and metabolic biomarkers in PETALE, a well-characterized cohort of cALL survivors. RESULTS: We demonstrate that 15.9% of the study participants exhibited 3 or more metabolic syndrome (MetS) risk factors. We also show a direct relationship between s25OHD3 and plasma HDL-Cholesterol concentrations in female but not male participants. CONCLUSION: Our data, from a metabolically well-described cohort, support a modest role for vitamin D in lipid metabolism in childhood leukemia survivors. The major outcome of this study is the strong association between HDL-Cholesterol concentration and s25OHD3 only in female subjects, thereby conveying vitamin D a gender-specific cardio-protective effect. cALL survivors represent a population at higher risk for secondary diseases. For this reason thorough nutritional evaluation, including vitamin D should be part of the regular follow-up.

Vitamin D nutritional status and bone turnover markers in childhood acute lymphoblastic leukemia survivors: A PETALE study.

BACKGROUND: The remarkable progress in the treatment of childhood acute lymphoblastic leukemia (cALL) has led to a survival rate reaching 90%. This success story is unfortunately linked to increased risk of impaired skeletal mass accumulation during childhood and adolescence, predisposing the patients to osteoporosis and pathological fractures at adulthood. OBJECTIVE: This study aims at characterizing the vitamin D status and bone health biomarkers in a well-characterized cohort of cALL survivors. RESULTS: Food frequency questionnaires reveal that (i) the total vitamin D intake varies greatly (44-2132 IU/d), (ii) only 16.8% of the participants consume vitamin D supplements, and (iii) 74% of survivors' intakes are below the Recommended Daily Intakes (400 IU/d). For the 42 participants taking vitamin D supplements, the median (2.5-97.5%iles) intake is 600 IU/d (21.2-1972 IU/d). Sixteen participants are vitamin D deficient (<30 nM) and 66 insufficient (≥30 - <50 nM). Serum 24,25(OH)2D3 concentrations are directly related to those of 25OHD3, and those of 3-epi-25OHD3 below the Lower Limit of Quantification in most samples. The participants' serum concentrations of cross-linked C-telopeptide of type-I collagen and intact amino-terminal pro-peptide of type-I collagen decrease steadily with age, leveling at adulthood, and are at all times higher in males. CONCLUSION: The present study shows that the prevalence of vitamin D insufficiency or deficiency is not greater in cALL survivors compared to the general Canadian population despite low vitamin D food and supplement intakes. Furthermore, there seem to be no overt imbalance in the gender- and age-adjusted serum bone turnover marker concentrations.

Data for the measurement of serum vitamin D metabolites in childhood acute lymphoblastic leukemia survivors.

This article describes data related to a companion research paper entitled "Vitamin D nutritional status and bone turnover biomarkers in childhood acute lymphoblastic leukemia (cALL) survivors." (Delvin et al., submitted for publication) [1]. Various methods for the measurement of serum 25OHD3, the accepted biomarker for assessing vitamin D nutritional status, have been described (Le Goff et al., 2015; Jensen et al., 2016) [2], [3]. This article describes a novel mass spectrometry-QTOF method for the quantification of circulating 25OHD3, 3-epi-25OHD3 and 24,25(OH)2D3. It provides the description of the extraction, chromatography and mass spectrometry protocols, a sample of mass spectra obtained from standards and extracted serum, and a comparison with another HPLC-MS/MS (Jensen et al., 2016) [3] method for the measurement of serum concentrations of 25OHD3.

Predictors of Incomplete Occlusion following Pipeline Embolization of Intracranial Aneurysms: Is It Less Effective in Older Patients?

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device (PED) for the treatment of intracranial aneurysms is associated with a high rate of aneurysm occlusion. However, clinical and radiographic predictors of incomplete aneurysm occlusion are poorly defined. In this study, predictors of incomplete occlusion at last angiographic follow-up after PED treatment were assessed. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the PED between 2009 and 2016, at 3 academic institutions in the United States, was performed. Cases with angiographic follow-up were selected to evaluate factors predictive of incomplete aneurysm occlusion at last follow-up. RESULTS: We identified 465 aneurysms treated with the PED; 380 (81.7%) aneurysms (329 procedures; median age, 58 years; female/male ratio, 4.8:1) had angiographic follow-up, and were included. Complete occlusion (100%) was achieved in 78.2% of aneurysms. Near-complete (90%-99%) and partial (<90%) occlusion were collectively achieved in 21.8% of aneurysms and defined as incomplete occlusion. Of aneurysms followed for at least 12 months (211 of 380), complete occlusion was achieved in 83.9%. Older age (older than 70 years), nonsmoking status, aneurysm location within the posterior communicating artery or posterior circulation, greater aneurysm maximal diameter (≥21 mm), and shorter follow-up time (<12 months) were significantly associated with incomplete aneurysm occlusion at last angiographic follow-up on univariable analysis. However, on multivariable logistic regression, only age, smoking status, and duration of follow-up were independently associated with occlusion status. CONCLUSIONS: Complete occlusion following PED treatment of intracranial aneurysms can be influenced by several factors related to the patient, aneurysm, and treatment. Of these factors, older age (older than 70 years) and nonsmoking status were independent predictors of incomplete occlusion. While the physiologic explanation for these findings remains unknown, identification of factors predictive of incomplete aneurysm occlusion following PED placement can assist in patient selection and counseling and might provide insight into the biologic factors affecting endothelialization.

Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Pipeline Embolization Device with or without Adjunctive Coil Embolization: Analysis of Complications from the IntrePED Registry.

Flow diversion to treat cerebral aneurysms has revolutionized neurointerventional surgery. Because the addition of coils potentially increases the time and complexity of endovascular procedures, we sought to determine whether adjunctive coil use is associated with an increase in complications. Patients in the International Retrospective Study of Pipeline Embolization Device registry were divided into those treated with the Pipeline Embolization Device alone (n = 689 patients; n = 797 aneurysms; mean aneurysm size, 10.3 ± 7.6 mm) versus those treated with the Pipeline Embolization Device and concurrent coil embolization (n = 104 patients; n = 109 aneurysms; mean aneurysm size, 13.6 ± 7.8 mm). Patient demographics and aneurysm characteristics were examined. Rates of neurologic morbidity and mortality were compared between groups. The Pipeline Embolization Device with versus without coiling required a significantly longer procedure time (135.8 ± 63.9 versus 96.7 ± 46.2 min; P < .0001) and resulted in higher neurological morbidity (12.5% versus 7.8%; P = .13). These data suggest that either strategy represents an acceptable risk profile in the treatment of complex cerebral aneurysms and warrants further investigation.

Endovascular intracranial treatment of acute ischemic strokes.

Acute ischemic stroke (AIS) is the leading cause of long-term disability and the second cause of death worldwide. Intravenous (IV) tissue plasminogen activator (tPA) remains the only FDA-approved treatment for AIS. The use of IV tPA in AIS related to large-vessel occlusion (LVO) has shown low recanalization rates and poor clinical outcomes. Over the last decade, endovascular treatment has demonstrated safety and effectiveness in the management of LVO-associated AIS due to the evolution of endovascular techniques and technologies, beginning with intraarterial thrombolysis, aspiration, self- expanding intracranial stents, and now retrievable stents. With the recent publication of the results of 5 randomized controlled studies, mechanical thrombectomy in combination with IV tPA demonstrated significant radiographic and clinical benefit over traditional strategies with IV tPA alone. In light of these results, endovascular therapy has been placed at the forefront of stroke treatment, redefining the standard of care. This review presents the evolution of endovascular treatment of AIS resulting from LVO; provides an analysis of the initial and latest RCTs; and discusses the association between endovascular mechanical thrombectomy and clinical outcomes, functional outcomes, and rates of revascularization, intracranial hemorrhage, morbidity, and mortality. Finally, shortcomings of the recent technological advances, such as clot fragmentation, and potential solutions to overcome these drawbacks are presented.

[Stevens-Johnson syndrome and Hodgkin's disease: A fortuitous association or paraneoplastic syndrome?]. / Syndrome de Stevens-Johnson et maladie de Hodgkin : association fortuite ou syndrome paranéoplasique ?

BACKGROUND: Hodgkin's disease has been associated with a variety of cutaneous symptoms. We report two cases of Stevens-Johnson syndrome (SJS) associated with Hodgkin's disease. PATIENTS AND METHODS: Case 1: a 22-year-old man was hospitalized for a second erythematous vesicular eruption with intense mucosal involvement. Histopathological examination confirmed the diagnosis of Stevens-Johnson syndrome. He also developed enlarged cervical lymph nodes that revealed Hodgkin's disease. The latter diagnosis was followed by two recurrent rashes. Treatment consisted of systemic chemotherapy. Complete remission was obtained with no signs of cutaneous recurrence after 24 months of regular follow-up. Case 2: a 29-year-old man was admitted for a generalized erythematous and bullous rash with intense mucosal involvement. Histopathological examination confirmed the diagnosis of Stevens-Johnson syndrome. He then developed muco-cutaneous icterus that was secondary to Hodgkin's disease. Under specific hematologic treatment, no cutaneous relapse was noticed. DISCUSSION: These cases illustrate the rare association of SSJ revealing Hodgkin's disease. In these cases, no evidence was found of infectious disease or drug-induced cutaneous effects. Only one case of toxic epidermal necrolysis associated with Hodgkin's disease had previously been reported. The link between both diseases may be immunosuppression induced by Hodgkin's disease, which could favor infection inducing SJS or secretion by tumor cells granulysin, a mediator responsible for damage to keratinocytes.

[Pseudolymphoma of the skin: ambiguous terminology: a survey among dermatologists and pathologists]. / Le pseudolymphome cutané: une sémantique ambiguë. Enquête auprès des dermatologues et des pathologistes.

BACKGROUND: Cutaneous pseudolymphomas (CPL) are diseases that simulate cutaneous lymphomas both clinically and histologically but have a benign course. It can be very difficult, if not impossible, to differentiate pseudolymphoma from lymphoma and there is some semantic ambiguity about the term pseudolymphoma. The aim of this study was to determine the exact meaning attributed to the term pseudolymphoma by a representative sample of French dermatologists and pathologists. MATERIALS AND METHODS: We designed two types of questionnaire, one for dermatologists and the other for pathologists, and sent them out to 274 dermatologists and to 110 pathologists. RESULTS: We received responses from 122 dermatologists (44.5%) and 64 pathologists (58.1%). In the dermatologist group, 56% consider that CPL is not a clearly defined entity, while 58% consider it a benign disease and only 18% feel that most CPLs are related to a precise cause; 72% of dermatologists perform a routine checkup, 58% initiate treatment and 84% conduct follow-up in the case of CPL. Among pathologists, 61% consider that CPL is not a clearly defined entity, 82% feel that cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia and cutaneous lymphocytoma are the same entity, and 75% consider that CPL are benign; 92% perform routine immunohistochemistry studies and only 26% screen for clonality. Bivariate statistical analysis showed that pathologists consider pseudolymphomas as benign entities frequently than dermatologists (χ(2) test: P=0.02; Fisher's exact test: P=0.01) and that there are more pathologists than dermatologists who see more than four pseudolymphomas per year (χ(2) test: P<0.001; Fisher's exact test: P<0.001). Multivariate analysis clearly identified a tendency among doctors viewing pseudolymphomas as a distinct entity to also consider them benign (Odds Ratio 0.29, CI 97.5% 0.14-0.58), irrespective of speciality or type of practice (hospital practice, private practice or both). DISCUSSION: This study demonstrates that, in France, the term pseudolymphoma is an ambiguous notion. We believe that cases in which it is impossible to differentiate pseudolymphoma from cutaneous lymphoma should be referred to as lymphoproliferations of undetermined significance, since more than 50% of physicians consider that the term pseudolymphoma designates a resolutely benign entity.

Association between genetic variants in the HNF4A gene and childhood-onset Crohn's disease.

Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4α genetic variants and Crohn's disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the HNF4A gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case-control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33; P<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P<2.09 × 10(-4) for combined cohorts). This is the first report showing that the HNF4A locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD.

Combined metallothioneins and p53 proteins expression as a prognostic marker in patients with Dukes stage B and C colorectal cancer.

Our study aimed to evaluate metallothionein and p53 expression in colorectal cancer and to correlate their combined expression with selected clinical and pathologic variables of the disease, to define their prognostic significance. Colorectal cancer specimens from 99 patients were retrospectively analyzed by immunohistochemistry for metallothionein and p53 expression. Survival curves were generated according to the Kaplan-Meier method, and univariate survival distributions were compared with the use of the log-rank test. Multivariate models were computed using Cox proportional hazards regression. This research was approved by the institutional review boards of all centers. Tumors showing concomitant high metallothionein expression and negative p53 (metallothionein(H)/p53(-)) were significantly inversely related to depth of invasion, frequency of nodal metastasis, and Dukes stage (P < .01). In univariate analysis, patients with metallothionein(H)/p53(-) phenotype showed a better overall survival (hazard ratio [HR], 2.83; P < .05) and disease-free survival (HR, 2.03; P < .05). In multivariate analysis, considering staging, metallothionein, and metallothionein + p53 variables, in 83 patients with Dukes stages B and C, metallothionein(H)/p53(-) combination was the sole factor showing an independent prognostic value for overall survival (HR, 3.88; P < .1) and disease-free survival (HR, 2.56; P < .1). In conclusion, the combined analysis of metallothionein and p53 may enhance the prognostic power of each individual marker by predicting the progression of the disease and contributing to a better identification of patients at low risk for mortality, especially for those with Dukes stage B and C colorectal cancer.

Myotax: a phase II trial of docetaxel plus non-pegylated liposomal doxorubicin as first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines.

AIM: Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumour activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as a single agent or in combination with cyclophosphamide. This phase II trial was performed to evaluate the efficacy and the safety of NPLD and docetaxel combination in patients with metastatic breast cancer previously exposed to adjuvant anthracyclines. PATIENTS AND METHODS: Thirty-four patients received NPLD 60 mg/m(2) and docetaxel 75 mg/m(2) in a 21-day cycle as first-line therapy of metastatic breast cancer. Treatment was planned for six cycles and was continued until progression or toxicity. RESULTS: Objective response rate among response-assessable patients was 79% (95% CI (confidence interval), 64-94%) and 27% (95% CI, 11-43%) presented a complete response. Median progression free survival was 11.3 months (95% CI, 6.2-13.3 months) and median overall survival was 28.2 months (95% CI, 16-36.4 months). Symptomatic grade 3 cardiotoxicity occurred in 15% of cases and febrile neutropenia in 47% of the patients. CONCLUSIONS: The combination of NPLD and docetaxel demonstrated high antitumour activity in a population of metastatic breast cancer patients exposed to adjuvant anthracyclines and showed an unexpected and unexplained 15% symptomatic left ventricular systolic dysfunction rate.

Analysis of the effects of iron and vitamin C co-supplementation on oxidative damage, antioxidant response and inflammation in THP-1 macrophages.

OBJECTIVES: The aims of the study were to test the susceptibility of THP-1 macrophages to develop oxidative stress and to deploy antioxidant defense mechanisms that insure the balance between the pro- and antioxidant molecules. DESIGN AND METHODS: Differentiated THP-1 were incubated in the presence or absence of iron-ascorbate (Fe/As) (100/1000µM) and the antioxidants Trolox, BHT, α-Tocopherol and NAC. RESULTS: Fe/As promoted the production of lipid peroxidation as reflected by the formation of malondialdehyde and H(2)O(2) along with reduced PUFA levels and elevated glutathione disulfide/total glutathione ratio, a reliable index of cellular redox status. THP-1 macrophages developed an increase in cytoplasmic SOD activity due in part to high cytoplasmic SOD1. On the other hand, a decline was noted in mRNA and protein of extra-cellular SOD3, as well as the activity of GSH-peroxidase, GSH-transferase and ATOX-1 expression. CONCLUSIONS: Macrophages activated under conditions of oxidative stress do not adequately deploy a powerful endogenous antioxidant response, a situation that can lead to an enhanced inflammatory response.

IL-15 and IL-2 increase Cetuximab-mediated cellular cytotoxicity against triple negative breast cancer cell lines expressing EGFR.

Triple negative breast cancer (TNBC) patients are not likely to benefit from anti-estrogen or anti-HER2 therapy and this phenotype is associated with a more aggressive clinical course and worse clinical outcome. Taking into account the limited treatment possibilities in TNBC, the aim of the present work was to study a potential therapy based on Cetuximab-mediated immune activity by natural killer (NK) cells. We performed in vitro studies on human breast cancer (BC) cell lines, IIB-BR-G, and the in vivo metastatic variant IIB-BR-G MT. The immunohistochemical analysis showed a TNBC phenotype with high but different levels of EGFR expression on each cell line, measured by flow cytometry. DNA sequencing showed that both cell lines have a mutated K-RAS status, 38 G > A at codon 13. Consequently, Cetuximab did not inhibit cellular proliferation or induce apoptosis. We investigated if Cetuximab could trigger immune mechanisms, and we determined that both cell lines treated with 1 µg/ml Cetuximab were susceptible to antibody dependent cellular cytotoxicity (ADCC), mediated by peripheral blood mononuclear cells (PBMC). At 50:1 effector:target ratio, lytic activity was 34 ± 2% against IIB-BR-G and 27 ± 6% against IIB-BR-G MT cells. PBMC pretreatment with IL-2 allowed reaching 65 ± 3% of Cetuximab-mediated ADCC against IIB-BR-G and 63 ± 6.5% against IIB-BR-G MT. Furthermore, IL-15 pretreatment increased the ADCC up to 71 ± 3% in IIB-BR-G and 79 ± 3.5% in IIB-BR-G MT. We suggest that NK cells are the effectors present in PBMC since they were able to induce ADCC at lower effector:target ratios. Besides, IL-2- and mainly IL-15-induced upregulation of NK activating receptors CD16 and NKG2D and enhanced IFN-γ production. EGFR-expressing TNBC could be killed by Cetuximab-mediated ADCC at clinically achievable concentrations. IL-15 could advantageously replace IL-2 in most of its immunologic activities, stimulating the ability to produce IFN-γ, and paralleling the up-regulation of activating receptors.

Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients.

BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

Susceptibility loci reported in genome-wide association studies are associated with Crohn's disease in Canadian children.

BACKGROUND: Recent genome-wide association studies based on adult and paediatric populations have implicated >30 genes/loci as susceptibility loci for Crohn's disease (CD). AIMS: To investigate whether reported genes/loci were also associated with CD in Canadian children. DESIGN AND METHODS: A case-control design was implemented at three paediatric gastroenterology clinics in Canada. Children < or =18 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in five genome-wide association studies reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. RESULTS: A total of 406 cases and 415 controls were studied. The mean (+/-s.d.) age of the cases was 12.3 (+/-3.2) years. Most cases were male (56.6%), had ileo-colonic disease (L3 +/- L4, 52.0%) and inflammatory behaviour (B1 +/- p, 86.9%) at diagnosis. Allelic association analysis (two-tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01). Associations with SNP rs4613763 in the PTGER4 locus were marginally nonsignificant (P = 0.07). The ZNF365 and STAT3 SNPs were predominantly associated with ileal disease with or without colonic involvement. CONCLUSION: The identified susceptibility genes/loci for adult-onset CD also confer risk for paediatric-onset CD.