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In this paper we present an argument for a psychoanalytic understanding of space. While Freud struggled to move away from his own early prepsychoanalytic attempts at mapping the psyche through cerebral localization, he nevertheless found himself compelled to use spatial language and topographical models throughout his career. In his ambivalence, Freud emphasized that the space of the psyche should be read as no more than metaphorical. We argue that the topographical models that Freud struggled with were constrained by the metrics of Euclidean space. The psyche is spatial, just not in topographical terms. For Jacques Lacan many of the psychic operations that Freud described (such as the transference) are better understood in terms of topological operations. Lacan uses such figures as the torus, the cross-cap, and the Möbius strip to demonstrate how the subject is formed through internal exclusions and external inclusions. Using Freud's famous case of the Rat Man, we argue that the neurotic's journey shows him seeking to overcome a psychospatial problem, one that resembles a topological conundrum. Through the Rat Man's story, we demonstrate how Lacan's topology of the subject (the R-schema as cross-cap) accounts for the Möbius twist that allows the neurotic to situate people, events, and places that are apparently separated in time and space in the same place. Ultimately, we consider the usefulness of topology over Euclidean space for building an understanding of space that is at once psychic and material.

Introduction Les capillarites purpuriques et pigmentees sont des dermatoses chroniques qui regroupent plusieurs entites d’etiopathogenie mal identifiee. Elles se caracterisent par des macules purpuriques et pigmentees non infiltrees avec a l’histologie une extravasation d’erythrocytes dans le derme, des depots d’hemosiderine et un infiltrat perivasculaire lymphocytaire. Nous en rapportons un cas chez une enfant revelant un syndrome du pool vide delta plaquettaire. Observations Une enfant de 11 ans consultait devant l’apparition depuis deux mois d’une dizaine de macules purpuriques et pigmentees fixes, non infiltrees, arrondies des membres inferieurs. Elle n’avait pas d’antecedents de saignement cutaneomuqueux, d’episode infectieux recent ni de prise medicamenteuse. La NFS (plaquettes : 179 000/mm3 sans anomalie morphologique), le TP et TCA etaient normaux. Le temps d’occlusion plaquettaire (TOP) coll/ADP etait normal et coll/epinephrine legerement allonge (200 sec, n Discussion Notre cas s’integre dans le cadre des capillarites purpuriques et pigmentees et se rapproche cliniquement d’une capillarite de Schamberg de mecanismes et causes mal connues. Il s’agit a notre connaissance du premier cas associe a une thrombopathie. Dans les cas rapportes, le TOP n’est pas realise systematiquement. Chez notre patiente, ce test a permis de mettre en evidence une thrombopathie constitutionnelle rare, le syndrome du pool vide delta plaquettaire. Il s’agit d’une maladie a transmission autosomique dominante, sous-diagnostiquee en raison de l’absence de signes cliniques severes, avec des ecchymoses ou saignements des muqueuses, des saignements excessifs lors de l’accouchement, chirurgie ou extraction dentaire. Chez ces patients, le bilan de l’hemostase (TP/TCA/NFS) est normal alors que le TOP est habituellement allonge en coll/epinephrine (sensibilite 75 %). Conclusion Nous suggerons que devant une dermatose purpurique et pigmentee et un contexte evocateur des explorations avec NFS, TP, TCA, TOP et test d’agregometrie plaquettaire, soient realisees pour ne pas meconnaitre une thrombopathie sous-jacente.

Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mode of action. EMBRACE was the first trial to compare overall survival (OS) of this new chemotherapeutic agent to real-life treatment choices (treatment of physician's choice; TPC) in heavily pretreated subjects with advanced breast cancer. TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. It was previously reported that the study met its primary endpoint with a significant improvement in OS by a median of 2.5 months with eribulin vs. TPC. That primary analysis was based on 422 of 762 events that occurred by May 12, 2009; here we present an updated survival analysis requested by the FDA of the pivotal Phase 3 study through March 3, 2010. Methods: This report is an updated survival analysis based on 589 of 762 (77.3%) events that occurred by March 3, 2010. Data were censored for subjects who were still alive, lost to follow-up, or withdrew consent on or before the date of data cut-off (March 3, 2010). A treatment arm comparison of OS was performed (with geographic region, HER2/neu status and prior capecitabine use as stratification factors for randomization) using a stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the magnitude of the treatment benefit. Results: Seven hundred sixty two women were randomized in the study; 508 to the eribulin arm and 254 to the TPC arm. 386 (76.0%) events occurred in the eribulin-treated arm while 203 (79.9%) events were recorded in the TPC-treated group. Nine (1. 8%) eribulin and 5 (2.0%) TPC patients were lost to follow-up or withdrew consent. OS was significantly longer in the eribulin treatment arm as compared with the TPC treated arm. (p=0.014; HR 0.805; 95% CI 0.677, 0.958). Median OS was 403 days (13.2 months) compared with 321 days (10.5 months) for TPC. A sensitivity analysis in the following 3 populations showed that the HR was similar to the primary (intent to treat) analysis and the treatment difference was statistically different: population of subjects treated (p = 0.016; HR 0.806; 95% CI 0.676, 0.960), at the cut-off of 572 (75%) deaths (p=0.008; HR 0.787; 95% CI 0.660, 0.939) and with no stratification terms (p=0.024; HR 0.822; 95% CI 0.694, 0.975). Based on the Kaplan-Meier analysis, eribulin-treated subjects had a 1-yr and 2-yr survival rate estimate of 54.5 and 21.9% compared with 42.8 and 19.2% for TPC, respectively. Conclusions: The OS advantage associated with eribulin treatment reported in the primary analysis was maintained throughout the observation period. The results of this OS-updated analysis support the initial OS analysis of the pivotal trial EMBRACE, demonstrating the superiority of eribulin over TPC in heavily pretreated women with advanced breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-18.

Recombinant methodologies have allowed the production of monoclonal antibodies (MAbs) with higher percentages of human content to decrease antibody immunogenicity and reduce or eliminate the anti-antibody response. Trastuzumab (Tz) is a humanized MAb approved for treatment of HER2-overexpressing breast cancer. We detected anti-Tz antibodies in the serum of patients treated with Tz. We initially studied the effects of these antibodies on the response to Tz in a transgenic mouse model of breast cancer. Twenty-two wild-type FVB mice were transplanted with mammary tumors arising in FVBMMTV/HER2 transgenic mice. Mice with established tumors were treated with Tz (n=12) or PBS (n=10) for 4 weeks. Five of 12 mice responded to treatment while 7/12 mice exhibited progressive disease (PD). All 5 responders had elevated anti-Tz antibodies, whereas in mice that had tumor progression anti-Tz levels were low or undetectable (p=0.002). These findings were confirmed in a second mouse cohort (n=16), in which anti-Tz antibodies were detected in responder mice as early as one week after starting treatment. MAbs produced by hybridomas stemming from spleen cells derived from responder mice bound Tz. These findings argue against the current understanding that an anti-xenoglobulin response to Tz would produce blocking antibodies. Therefore, we addressed if detectable anti-Tz antibodies would predict benefit from antibody therapy in patients with HER2+ breast cancer. Samples from 21 patients with stage IV HER2 positive breast cancer experiencing clinical response or disease stabilization upon treatment with Tz that had been enrolled in an anti-HER2 vaccine phase I trial (J Clin Oncol 2009;4685) were retrospectively analyzed in a blinded fashion. With a median follow-up of 36 months, 14 patients had had disease progression while on Tz plus the vaccine. The presence of anti-Tz F(ab')2 antibodies was quantified among the enrolled patients. A univariate Cox regression analysis of the progression free survival (PFS) was performed. Analysis revealed that higher anti-Tz F(ab')2 antibodies were significantly associated with lower risk of disease progression (p=0.023). Fine specificity studies confirm the presence of a human polyclonal response to Tz, directed to epitopes present in both its Fc and Fab regions. In conclusion, in mice, response to Tz was significantly associated with the presence of anti-Tz antibodies in serum, while in patients with stage IV breast cancer treated with Tz, the presence of anti-Tz F(ab')2 antibodies was associated with longer PFS. The fine specificity of anti-Tz antibodies reveals epitopes that could be potentially relevant for vaccination strategies. Information about cognate epitopes on Tz may be also useful in the design of new therapeutic antibodies. These data also support prospective evaluation of patients undergoing therapy with other chimeric or humanized antibodies to address if detectable anti-therapeutic antibodies would predict benefit from long antibody therapy regimens, especially in the adjuvant setting, in which clinical benefit can only be measured by survival rates. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-04.

Background: The randomized, controlled, open-label, phase III EMBRACE study compared the efficacy and safety of eribulin mesylate (E7389) vs. treatment of the physician's choice (TPC) in heavily pretreated subjects with late-stage breast cancer. The study met its primary endpoint by showing that eribulin significantly prolonged OS vs. TPC (HR: 0.809; 95% CI: 0.660-0.991; p=0.041). This exploratory subgroup analysis aimed to determine the influence of the number of prior regimens on OS among eribulin-treated subjects. Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects had to show progression on or within 6 months of the last chemotherapy regimen. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment and then randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. Results: A total of 762 subjects in 135 centers worldwide were randomized to receive either eribulin (n=508) or TPC (n=254). Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81 % had taxane-refractory disease. Overall, 47% and 53% of subjects had received ≥3 and >3 prior chemotherapy regimens in total, respectively. Seventy-five percent and 25% of subjects received ≥3 and >3 prior chemotherapy regimens in total for locally recurrent or metastatic disease, respectively. Subgroup analysis identified consistently longer median OS with eribulin vs. TPC in subjects who received ≥3 prior chemotherapy regimens, both in total and specifically for locally recurrent or metastatic disease (Table). Lesser improvements in OS with eribulin vs. TPC were observed in subjects who received >3 prior chemotherapy regimens. The study was not powered to show statistical significance for this subgroup analysis. Conclusion: In this retrospective subgroup analysis, the OS benefit with eribulin appears greater for subjects with locally recurrent or metastatic breast cancer who received fewer previous therapies. Additional studies are underway to confirm these findings in less heavily pretreated patients. Table. Overall survival by treatment history vs. TPC Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-01.

We sought to determine if an association exists between age and capecitabine efficacy among patients with metastatic breast cancer (MBC). Pooled analysis of five phase II or III registration trials of capecitabine 2,500-2,510 mg/m(2)/day for 2 weeks and 1 week off, or combination therapy was performed. Four trials enrolled patients previously exposed to other chemotherapy, generally a taxane. Of 570 patients, 193 (34%) were 18-49 years old, 246 (43%) were 50-64, and 131 (23%) were ≥ 65. Median average daily dose was 2,067 mg/m² in the 18- to 49-year-old group and 2,105 mg/m² in the 50-64 and ≥ 65 year groups. Overall survival (OS) in all groups was similar by log-rank test for the individual trials (P = 0.71-0.95) and Cox regression of the pooled trials. Univariate analysis demonstrated no difference in clinical benefit or objective response between groups. Treatment failure analysis showed 283 (50%) patients experienced progressive disease, while 114 (20%) withdrew for safety. Serious adverse events (AEs) occurred in 71 (36.8%), 85 (34.6%), and 59 (45.0%) patients in the 18-49, 50-64, and ≥ 65 years groups, respectively. There was no statistically significant association between age and OS, clinical benefit, or objective response in patients with MBC treated with capecitabine. Frequency of AEs and serious AEs was not related to age at treatment, although women ≥ 65 years were more likely to withdraw from treatment because of an AE than younger women.

Purpose This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. Methods Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles followed by paclitaxel 175 mg/m2 every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m2 plus paclitaxel 200 mg/m2 every 3 weeks for four cycles followed by paclitaxel 80 mg/m2 weekly for 12 weeks. Results Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC→P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor–positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. Conclusion The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.

1069Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. Methods: EMBRACA (NCT01945775) is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA (1 mg/day) with standard single-agent PCT (capecitabine, eribulin, gemcitabine, or vinorelbine) in pts with advanced breast cancer (aBC) and a germline BRCA1/2 mutation (gBRCAmut). PFS by blinded independent central review (BICR) and ORR by investigator were investigated in clinically important subgroups. Results: Of 431 pts randomized, 287 were assigned to receive TALA and 144 to PCT. PFS and ORR are shown (Table). Conclusions: In pts with advanced gBRCAmut breast cancer, TALA demonstrated a statistically significant improvement in both ORR and PFS in clinically relevant subgroups compared with PCT, including pts with CNS metastases, poor performance status, younger age, and visceral disease. Clinical trial information: NCT0194...

1070Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA in BRCA1/2-mutated cells, preventing DNA damage repair and causing cell death. Methods: EMBRACA (NCT01945775) is a ran...

We undertook a retrospective study of 50 consecutive patients (41 male, 9 female) with an infected nonunion and bone defect of the femoral shaft who had been treated by radical debridement and distraction osteogenesis. Their mean age was 29.9 years (9 to 58) and they had a mean of 3.8 (2 to 19) previous operations. They were followed for a mean of 5.9 years (2.0 to 19.0). The mean duration of the distraction osteogenesis was 24.5 months (2 to 39). Pin-track infection was observed in all patients. The range of knee movement was reduced and there was a mean residual leg-length discrepancy of 1.9 cm (0 to 8) after treatment. One patient required hip disarticulation to manage intractable sepsis. In all, 13 patients had persistant pain. Bony union was achieved in 49 patients at a mean of 20.7 months (12 to 35). Although distraction osteogenesis is commonly used for the treatment of infected femoral nonunion with bone defects, it is associated with a high rate of complications.

Like many signaling pathways in development, the Notch receptor pathway plays an important role in cancer pathobiology when it is dysregulated. Potential ligand-binding sites within the epidermal growth factor (EGF)–like repeats of Notch1 have been identified, but the ligand-binding domains in Notch3, which is implicated in lung cancer, are not known. In screening a library of 155 peptides representing all 34 EGF-like repeats in Notch3, we discovered two distinct ligand-binding regions involving the 7–10 and 21–22 repeats that are distinct from the putative ligand-binding domain of Notch1. In cell-based assays, peptides from these regions induced apoptosis and reduced expression of the Notch3-dependent gene Hey1. They also bound directly to the Notch ligand Jagged1, suggesting that their mechanism of action involves disrupting interactions between Notch3 and Jagged1. Recombinant Fc fusion peptides engineered for in vivo testing showed that the Notch3 peptides defined could trigger apoptosis and suppress tumor growth in tumor xenograft assays. These findings rationalize a mechanistic approach to lung cancer treatment based on Notch3 receptor–targeted therapeutic development. Cancer Res; 70(2); 632–8

Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]

We discuss the incommensurate adsorption of an ad layer on a crystalline substrate. We show that in the case of Pb adsorbed on Ag (111) the size considerations are not enough to determine the angle of epitaxy: A special form of the adsorbing potential is required. The necessary conditions for this potential is discussed. An explicit form for the pb/Ag(111) case is given. (jes)

Purpose We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were ≥ 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity. Patients and Methods Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m2; n = 510), or TC (75/600 mg/m2; n = 506), administered by intravenous infusion every 3 weeks. Results The median age in women younger than 65, was 50 years (range, 27 to 64) and for women ≥ 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio [HR], 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC. Conclusion With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Purpose: Stratifying patients who have a high risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer.Experimental Design: In a nested case-control study, 82 subjects developed biochemical recurrence within 5 years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrence-free following prostatectomy in the same period were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex ELISA to identify the expression of three chemokines to discriminate the two patient populations.Results: The expression of CX3CL1 and IL-15 in prostate tissue was associated with 5-year biochemical recurrence-free survival following prostatectomy. However, the expression of chemokine ligand 4 (CCL4) was associated with biochemical recurrence. Multivariable logistic regression model combining preoperative prostate-specific antigen, Gleason score, surgical margin, and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared with use of the clinicopathologic variables alone (P < 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy.Conclusions: Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.

This study describes the validation of a computer program for automated analysis of ambulatory 24-hour two-channel esophageal manometry. The program's ability to characterize contractions and to calculate their duration and amplitude was validated against manual evaluation. An independent reference standard for the identification and classification of contractions was established by submitting representative recordings to a group of 14 experts in upper gastrointestinal motility; the program's ability to identify and classify contractions was then validated against the majority verdict of the experts. The results show an excellent correlation between the manual and computer evaluations of both contraction amplitude (p = 0.9957) and duration (p = 0.8241). The concordance between the experts was also excellent: 97 (72%) of 135 pressure events were classified identically by 12 or more experts. Computer-aided manometry analysis (CAMA) had a sensitivity of 98.9% and a specificity of 93.5% for the detection of contractions, with sensitivities of 94.7% and 84.4% and specificities of 94.9% and 94.2% for the classification of propagated and nonpropagated contractions, respectively.

Contains fulltext : 70697.pdf (Publisher’s version ) (Closed access) Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

To discover and develop a xylanase enzyme that can significantly enhance wood pulp bleachability under typical kraft process conditions (high temperature and alkaline pH), close to 200 xylanases from diverse environments were discovered and screened using a 3-stage (XDEp) pulp biobleaching assay. Four xylanases belonging to a new clade of glycosyl hydrolase family 11 outperformed all other enzymes by reducing bleaching chemical consumption by 15–25% on softwood and hardwood pulps. During the screening process, many thermostable and alkali-tolerant family 10 xylanases were also identified, however, family 10 xylanases in general were not as effective as those from family 11 in enhancing wood pulp bleachability. The candidate selected for developing a prebleaching xylanase enzyme product, Xyn11a, retained 80% of its maximum activity after incubation at 65 °C for 30 min.

Gastro-oesophageal reflux was examined by taped long-term pH monitoring in 31 healthy subjects (16 men, 15 women; average age 28 years). The following was found: (1) reflux during the day is normal in health subjects, occurring predominantly after meals; (2) healthy persons have practically no reflux at night, after reaching the phase of deep sleep, the decisive difference between the healthy subject and those with reflux concerning the sleep phase, during which the patient with reflux has significantly increased reflux; (3) gastro-oesophageal reflux during the night is dependent upon depth of sleep, while position-dependent reflux was not observed.

The effectiveness of a single, morning oral dose of 40 mg omeprazole or a twice daily oral dose of 150 mg ranitidine was compared in a randomized endoscopically controlled double-blind trial at 37 clinics in Austria, Germany and Switzerland. A total of 178 out-patients in stages I-IVa (after Savary and Miller) were entered into the trial: 78 in stage I, 60 in stage II, 27 in stage III, and in 13 in stage IVa. As early as at the end of the third treatment week there was a significantly higher rate of complete healing or reduction into a lower stage with omeprazole than ranitidine (85% vs 67%; P less than 0.02). After six treatment weeks, healing tendency after omeprazole compared with ranitidine was 85% vs 45% (P less than 0.04). Omeprazole also brought earlier improvement in symptoms. The difference was statistically significant for heartburn (pyrosis): P less than 0.01. Both drugs were equally well tolerated and there were no clinically significant side-effects. This is the first demonstration that the ATPase inhibitor omeprazole is superior to the H2-receptor antagonist ranitidine in the treatment of reflux oesophagitis.

134 outpatients with acute benign gastric ulcer confirmed by endoscopic biopsy received either 1 g sucralfate suspension four times daily or one 150 mg ranitidine tablet twice daily for six to 12 weeks in a multicentre therapy study (double-blind study according to the double-dummy technique). After six to 12 weeks, respectively, 56% and 82% of the ulcers had healed in the sucralfate group. The rates of healing in the ranitidine group were 72% and 88%, respectively. The differences in the rates of healing between sucralfate and ranitidine were not statistically significant. Ranitidine was superior to the sucralfate suspension in corpus ulcer. In the distally located ulcers, the two kinds of treatment were equivalent. There were no appreciable differences between the medications with regard to antacid consumption and compliance. Gastric pain was influenced better by ranitidine than by sucralfate.

In a multi-centre double-blind (double-dummy) trial the effectiveness of low-dose antacid gel (6 X 12 ml/d; neutralisation capacity 120 mmol) was compared with that of a standard dose of cimetidine (1 g/d) in the curative treatment of gastric ulcer. Antacid gel was given to 65 patients, cimetidine to 60. Diagnosis was confirmed by endoscopic biopsy, which was also employed in a serial follow-up. After 4 weeks antacid gel and cimetidine produced cures in 43% and 52%, respectively; after 8 weeks 76% and 89%, respectively, the difference between the two methods not being statistically significant. There was also no statistically significant difference with regard to ulcer pain. In one case each in the antacid and cimetidine groups, the treatment had to be stopped because of side effects. Diarrhoea was more common on cimetidine than on antacid gel. It is concluded that both low-dose antacids gels and cimetidine are suitable in the treatment of gastric ulcers.

Purpose Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers. Patients and Methods A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. Results During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance. Conclusion The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.

SummaryA Brazilian orthopaedic company designed a stainless steel plate called Synthesis Pengo System (S.P.S.), which has one fixed and one changeable extremity. According to the assembly of the changeable extremity, it is possible to obtain dynamization or neutralization of the fracture site. Since the S.P.S. plate was developed for use in human patients, the aim of this study was to evaluate this system in long-bone diaphyseal fractures in dogs. Eight dogs with closed diaphyseal fractures of the femur (n= 1), radius and ulna (n=5), and tibia (n=2) were used. Patients were aged seven months to three years and weighed 18 to 31.2 kg. The S.P.S. plate was assembled with one fixed extremity and one changeable extremity in dynamization mode. The trail bar was positioned for synthesis modules with holes for cortical screws. The modules were positioned close to one another in two fractures and far away from the fracture site in the others. The bone healing occurred by external callus. Since motion at the fracture site determines the amount of callus required, the secondary bone healing that was observed in all of the cases indicated less rigid fixation of this system. A potential benefit of this system was a lesser interface contact with the bone since it was only done by trail bar. The major disadvantage was the prominence of the implant. It was possible to conclude that the S.P.S. plate appears to be a suitable method for the treatment of diaphyseal fractures in dogs.

The purpose of this study was to determine the mechanisms by which the pesticide, methoxychlor (MXC), acts as an environmental endocrine disruptor through interaction with the three largemouth bass (Micropterus salmoides) estrogen receptors (ERs) alpha, betaa, and betab. MXC is a less-environmentally persistent analog of DDT that behaves as a weak estrogen. Using transient transfection assays in HepG2 cells, we have previously shown that each receptor is responsive to the endogenous ligand 17beta-estradiol (E(2)) in a dose-dependent manner. The parent compound, MXC, showed dose-dependent stimulation of transcriptional activation through all three ERs. In addition to the parent molecule, each of the metabolites was also estrogenic with all three ERs. The order of potency for ERalpha and ERbetab was HPTEOH-MXCMXC, while the opposite order was seen for ERbetaa. HepG2 cells did not substantially metabolize MXC to the active metabolites, thus the activity of MXC was not due to metabolism. When examining the effects of increasing concentrations of MXC at a fixed concentration of E(2), all three ERs show increased activity compared to that with E(2) alone, showing that the effects of MXC and E(2) are additive. However, when this experiment was repeated with increasing concentrations of HPTE at a fixed concentration of E(2), the activity of ERalpha was decreased, that of ERbetab was increased, while that of ERbetaa was unaffected compared to E(2) alone. These experiments suggest that HPTE functions as an E(2) antagonist with ERalpha, an E(2) agonist with ERbetab and does not perturb E(2) stimulation of ERbetaa. While it is clear the ERbeta subtypes are the products of different genes (due to a gene duplication in teleosts) the differences in their responses to MXC and its metabolites indicate that their functions diverge, both in their in vivo molecular response to E(2), as well as in their interaction with endocrine disrupting compounds found in the wild.

Purpose Nanoparticle albumin-bound paclitaxel, a solvent-free, albumin-bound paclitaxel, demonstrated antitumor activity in patients with taxane-naive metastatic breast cancer (MBC). We examined albumin-bound paclitaxel (100 mg/m2 or 125 mg/m2 administered weekly) to determine the antitumor activity in patients with MBC whose disease progressed despite conventional taxane therapy. Patients and Methods Women with MBC that was previously treated with taxanes were eligible for participation. Taxane failure was defined as metastatic disease progression during taxane therapy or relapse within 12 months of adjuvant taxane therapy. Primary objectives were response rates (RRs) and the safety/tolerability of albumin-bound paclitaxel. Results Women were treated with albumin-bound paclitaxel 100 mg/m2 (n = 106) or 125 mg/m2 (n = 75) on days 1, 8, and 15 of a 28-day cycle. Response rates were 14% and 16% for the 100-mg/m2 and 125-mg/m2 cohorts, respectively; an additional 12% and 21% of patients, respectively, had stable disease (SD) ≥ 16 weeks. Median progression-free survival times were 3 months at 100 mg/m2 and 3.5 months at 125 mg/m2; median survival times were 9.2 months and 9.1 months, respectively. Survival was similar for responding patients and those with SD. No severe hypersensitivity reactions were reported. Patients who developed treatment-limiting peripheral neuropathy typically could be restarted on a reduced dose of albumin-bound paclitaxel after a 1-2–week delay. Grade 4 neutropenia occurred in Conclusion Albumin-bound paclitaxel 100 mg/m2 given weekly demonstrated the same antitumor activity as albumin-bound paclitaxel 125 mg/m2 weekly and a more favorable safety profile in patients with MBC that had progressed with previous taxane therapy. Survival of patients with SD ≥ 16 weeks was similar to that of responders.

Purpose Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Patients and Methods Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Results Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. Conclusion At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

SUMMARY Analysis of clinical data obtained in a double-blind randomized study, which compared liquid antacid (neutralizing capacity 120 mmol per day) with 1 g cimetidine in the treatment of 125 patients with gastric ulcer, revealed that, before starting treatment 71 % of the patients complained of epigastric pain, approximately 50% of bloating, and approximately 30 % of nausea, heartburn, constipation or vomiting. Epigastric pain before treatment was significantly more frequent in patients with large ulcers (P < 0.05) and in patients with ulcers unhealed after 4 weeks of therapy (P < 0.05). This finding was the result of a highly significant correlation between diurnal epigastric pain and ulcer size and delayed healing (P < 0.005). Nocturnal pain did not correlate with prognosis. In contrast to this correlation between pain before therapy and healing, the disappearance of epigastric pain with therapy did not signify ulcer healing. Only 14 (38%) of the 37 patients with healed ulcer were free from pain after the 4 weeks of therapy, whereas 25 (49%) of the 52 patients with persistent ulcers had no pain at this time. Placebo pain tablets relieved ulcer pain effectively in more than 85% of the patients, irrespective of whether the ulcer was healing or not. The other symptoms (bloating, nausea, heartburn, constipation or vomiting) were also alleviated by 4 weeks of therapy but no correlation was found with ulcer size or prognosis. The loss of the prognostic significance of ulcer pain is probably due to a complex interaction of the trial schedule on the patient's level of consciousness. The highly effective placebo pain tablets and improvement of symptoms, which are unlikely to be due to gastric ulcer symptoms that are also unlikely to be affected by a decrease in gastric acidity such as bloating and constipation), suggest that ulcer treatment in a controlled trial changes pain perception. We conclude that treatment trials have effects that go beyond the rates of healing.

Helicobacter pylori infection, a highly prevalent pathogen, is a major cause of chronic gastritis and peptic ulcer and a risk factor for gastric malignancies. Antibiotics-based H. pylori eradication treatment is 90% effective. However, it is expensive and causes side effects and antibiotic resistance. Probiotics could present a low-cost, large-scale alternative solution to prevent or decrease H. pylori colonization. A literature search of the MEDLINE database (1966-2006) has been performed selecting all in vitro, animal, and human fully published English-language studies dealing with H. pylori and probiotics. Probiotics had an in vitro inhibitory effect on H. pylori. Animal studies demonstrated that probiotic treatment is effective in reducing H. pylori-associated gastric inflammation. Seven of 9 human studies showed an improvement of H. pylori gastritis and decrease in H. pylori density after administration of probiotics. The addition of probiotics to standard antibiotic treatment improved H. pylori eradication rates (81% vs. 71%, with combination treatment vs. H. pylori-eradication treatment alone; chi(2)test: P=0.03). Probiotic treatment reduced H. pylori therapy-associated side effects (incidence of side effects: 23% vs. 46%, with combination therapy vs. H. pylori-eradication treatment alone; chi(2)test: P=0.04). No study could demonstrate the eradication of H. pylori infection by probiotic treatment. So long-term intake of products containing probiotic strains of probiotics may have a favorable effect on H. pylori infection in humans, particularly by reducing the risk of developing disorders associated with high degrees of gastric inflammation.

Purpose We conducted a multicenter phase II trial to determine the efficacy/safety of capecitabine and weekly paclitaxel, a combination with preclinical evidence of synergy, in patients with metastatic breast cancer (MBC) previously treated with a taxane. Patients and Methods Eligibility criteria included measurable MBC, history of every-3-week taxane therapy (adjuvant or for MBC), and no previous taxane on a weekly basis, capecitabine, or infusional 5-fluorouracil. Patients received capecitabine 825 mg/m2 per dose orally twice daily (1650 mg/m2 per day) on days 1–14 and weekly paclitaxel 80 mg/m2 intravenously on days 1 and 8, followed by a 1-week rest period (every-3-week cycle) until progression or intolerable toxicity. Fifty-four women were treated, most with previous every-3-week taxane exposure as adjuvant therapy (n = 43) rather than for MBC (n = 11). The median number of delivered cycles was 7, with dose modifications in 30 patients. The intent-to-treat objective response rate (primary study endpoint) was 59% (95% confidence interval, 46%–72%), including 7 complete and 25 partial responses. Results Three patients had stable disease for ≥ 6 months, for a clinical benefit rate of 65% (95% confidence interval, 51%–76%). Median objective response duration, time to progression, and overall survival were 8.1 months, 8.4 months, and 21.6 months, respectively. Grade 3/4 treatment-related adverse events consisted of neutropenia (13%), anemia (2%), hand-foot skin reaction (20%), fatigue (7%), diarrhea (4%), nausea/vomiting (4%), and pain (2%). No patients developed grade 3/4 neuropathy. Conclusion Capecitabine and weekly paclitaxel were highly active with acceptable tolerability in patients with MBC previously treated with a taxane, consistent with our recently published experience in taxane-naive women with MBC.

Objective To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Design A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer. Setting Genetic clinics. Patient(s) Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire. Intervention(s) None. Main Outcome Measure(s) Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment. Result(s) There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18–2.33) and the subsequent risk of ovarian cancer. Conclusion(s) Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.

The concept of a systematic or predictive relationship between distant vertebral levels distinct from accumulative functional compensatory mechanisms, such as in scoliosis, has been perpetuated within chiropractic technique systems based on clinical observation and experience. This study seeks to investigate this relationship between the cervical and lumbar vertebrae.Patients (experimental group n=26 and control group n=12) were selected from the patient base of one office, and were limited to patients that had sensitivity at specific cervical reflex points. Using a pre and post outcome measurement and sacro occipital technique R + C protocols, the related lumbar vertebra was adjusted in the direction indicated by the cervical vertebral sensitivity.Statistical analysis revealed there was a statistically significant difference between pre- and post-VAS measurements and found that the notable difference in mean change in VAS scores were statistically significantly different between the experimental and control groups (p.001).The findings of this study suggest that further research into cervical and lumbar vertebra interrelationships, and the efficacy of orthopedic block treatment, may be warranted. Further studies are needed to confirm whether a causal relationship exists between lumbar manipulation and decreased cervical spine sensitivity.Le concept d’une relation systématique ou prédictive entre les niveaux distants vertébraux distincte des mécanismes compensatoires fonctionnels cumulatifs, comme en cas de scoliose, a été perpétué dans les systèmes de techniques chiropratiques fondés sur des observations cliniques et sur l’expérience. Cette étude cherche à examiner la relation entre les vertèbres cervicales et lombaires.Les patients (groupe expérimental n=26 et groupe de contrôle n=12) ont été choisis parmi la clientèle d’un bureau, et se limitaient à ceux qui avaient une sensibilité à certains points de réflexe cervical. À l’aide d’une mesure avant et après et des protocoles de technique sacro occipitale R + C, la vertèbre lombaire liée était ajustée dans la direction indiquée par la sensibilité vertébrale cervicale.Les analyses statistiques ont révélé une différence statistique importante entre les mesures avant et après VAS et ont indiqué que la différence de changement moyen des scores VAS étaient statistiquement très différente entre le groupe expérimental et le groupe de contrôle (p0,001).Les trouvailles de cette étude laissent entendre que des recherches supplémentaires sur les relations entre les vertèbres lombaires et cervicales, ainsi que l’efficacité du traitement de bloc orthopédique, peuvent être justifiées. D’autres études sont nécessaires pour confirmer s’il existe une relation de cause à effet entre la manipulation lombaire et la baisse de sensibilité de la colonne cervicale.

In this work, the impact of different ozone-based cleaning processes on the level of surface passivation achieved is determined and compared against the RCA cleaning processes. Two different passivation materials are used in this study, including hydrogenated amorphous silicon and silicon nitride plasma enhanced chemical vapor deposition (PECVD). Photoconductance measurements and calibrated photoluminescence imaging are used to evaluate the level of passivation achieved and spatial uniformity for the different cleaning processes.

Caudo-rostral whole-field visual motion elicits forward locomotion in many organisms, including larval zebrafish. Here, we investigate the dependence on the latency to initiate this forward swimming as a function of the speed of the visual motion. We show that latency is highly dependent on speed for slow speeds (1.5 s, which is much longer than neuronal transduction processes. What mechanisms underlie these long latencies? We propose two alternative, biologically inspired models that could account for this latency to initiate swimming: an integrate and fire model, which is history dependent, and a stochastic Poisson model, which has no history dependence. We use these models to predict the behavior of larvae when presented with whole-field motion of varying speed and find that the stochastic process shows better agreement with the experimental data. Finally, we discuss possible neuronal implementations of these models., Summary: Initiation of swimming is based on an instantaneous evaluation of whole-field visual sensory input as opposed to an accumulation of evidence over a prolonged time.

A new analytical theory is discussed that extends the range of the mean spherical approximation (MSA) to extreme situations where the asypmtotic limits are known. The MSA [J. K. Percus and G. Yevick, Phys. Rev. 110, 250 (1964); J. L. Lebowitz and J. K. Percus, Phys. Rev. 144, 251 (1966)] yields explicit thermodynamics and structure in terms of a single screening parameter [L. Blum, Mol. Phys. 30, 1559 (1975)] and gives the correct high density limiting behavior of the contact pair distribution function and thermodynamics [Y. Rosenfeld and L. Blum, J. Chem. Phys. 85, 1556 (1986), Y. Rosenfeld, J. Stat. Phys. 37, 215, (1984)] and has been very useful for practical applications. However, it misses the low density limiting behavior which is implicit in the second virial coefficient. The soft mean spherical approximation (SMSA), which was proposed over 30 years ago by Blum and Narten [L. Blum and A. H. Narten, J. Chem. Phys. 56, 5197 (1972), A. H. Narten, L. Blum, and R. H. Fowler, J. Chem. Phys. 60, 3378 (197...