bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of TRPA1 Agonists Mustard Oil and Cinnamaldehyde on Lumbar Spinal Wide-Dynamic Range Neuronal Responses to Innocuous and Noxious Cutaneous Stimuli in Rats
Authors: Merrill Austin W. , Cuellar Jason M. , Judd Justin H. , Carstens Mirela Iodi , Carstens E.
Published: October 2007

Mustard oil [allyl isothiocyanate (AITC)] and cinnamaldehyde (CA), agonists of the ion channel TRPA1 expressed in sensory neurons, elicit a burning sensation and heat hyperalgesia. We tested whether these phenomena are reflected in the responses of lumbar spinal wide-dynamic range (WDR) neurons recorded in pentobarbital-anesthetized rats. Responses to electrical and graded mechanical and noxious thermal stimulation were tested before and after cutaneous application of AITC or CA. Repetitive application of AITC initially increased the firing rate of 52% of units followed by rapid desensitization that persisted when AITC was reapplied 30 min later. Responses to noxious thermal, but not mechanical, stimuli were significantly enhanced irrespective of whether the neuron was directly activated by AITC. Windup elicited by percutaneous or sciatic nerve electrical stimulation was significantly reduced post-AITC. These results indicate that AITC produced central inhibition and peripheral sensitization of heat nociceptors. CA did not directly excite WDR neurons, and significantly enhanced responses to noxious heat while not affecting windup or responses to skin cooling or mechanical stimulation, indicating a peripheral sensitization of heat nociceptors.
Synaptic Vesicle Endocytosis at a CNS Nerve Terminal: Faster Kinetics at Physiological Temperatures and Increased Endocytotic Capacity During Maturation
Authors: Renden Robert , von Gersdorff Henrique
Published: October 2007

Synaptic vesicle membrane must be quickly retrieved and recycled after copious exocytosis to limit the depletion of vesicle pools. The rate of endocytosis at the calyx of Held nerve terminal has been measured directly using membrane capacitance measurements from immature postnatal day P7–P10 rat pups at room temperature (RT: 23–24°C). This rate has an average time constant of tens of seconds and becomes slower when the amount of exocytosis (measured as capacitance jump) increases. Such slow rates seem paradoxical for a synapse that can operate continuously at high-input frequencies. Here we perform time-resolved membrane capacitance measurements from the mouse calyx of Held in brain stem slices at physiological temperature (PT: 35–37°C), and also from more mature calyces after the onset of hearing (P14–P18). Our results show that the rate of endocytosis is strongly temperature dependent, whereas the endocytotic capacity of a nerve terminal is dependent on developmental stage. At PT we find that endocytosis accelerates due to the addition of a kinetically fast component (time constant: τ = 1–2 s) immediately after exocytosis. Surprisingly, we find that at RT the rate of endocytosis triggered by short (1- to 5-ms) or long (≥10-ms) depolarizing pulses in P14–P18 mice are similar (τ ≈ 15 s). Furthermore, this rate is greatly accelerated at PT (τ ≈ 2 s). Thus endocytosis becomes faster and less saturable during synaptic maturation, making the calyceal terminal more capable of sustaining prolonged high-frequency transmitter release.
Hyperdiploidy Is a Common Finding in Monoclonal Gammopathy of Undetermined Significance and Monosomy 13 Is Restricted to These Hyperdiploid Patients
Authors: Brousseau Maud , Leleu Xavier , Gerard Jérémie , Gastinne Thomas , Godon Alban , Genevieve Franck , Dib Mamoun , Lai Jean-Luc , Facon Thierry , Zandecki Marc ,   for the Intergroupe Francophone du Myélome
Published: October 2007

Purpose: Two pathways, hyperdiploid and nonhyperdiploid, are proposed for progression to plasma cell neoplasia. Implication of monosomy 13 (Δ13) is unclear in monoclonal gammopathy of undetermined significance (MGUS), and data on DNA content of plasma cells [DNA index (DI)] are rare.

Experimental Design: We ascertained DI in 169 multiple myeloma (MM) and 96 MGUS patients. Interphase fluorescence in situ hybridization (FISH) coupled to cytoplasmic staining of specific Ig (cIg-FISH) was done to look for trisomies and to ascertain Δ13.

Results: Hyperdiploidy and hypodiploidy were found in 54% and 11.5% of MGUS patients and in 59.5% and 25% of MM patients, respectively. In MGUS patients tested using probes for odd chromosomes, cIg-FISH showed association between trisomies for chromosomes 3, 7, 9, 11, or 15 and hyperdiploidy. Δ13 was found in 45.3% and 24.6% of MM and MGUS patients, respectively. Most Δ13 cases observed in MGUS were found within hyperdiploid clones, 38% versus 11% in hypodiploid cases, in sharp contrast with the occurrence of Δ13 in MM patients, 31.9% and 76.3%, respectively. That peculiar distribution of Δ13 according to DI persisted with other thresholds used to ascertain hyperdiploidy, such as DI ≥ 1.05. A strong relationship between IgA peak and hypodiploidy (P = 0.007) was only observed in MM, whereas λ light chain was significantly associated with hypodiploidy in MGUS (P = 0.001) and MM (P = 0.05). Hyperdiploidy shows similar pattern in MGUS and MM.

Conclusion: This fits well a hyperdiploid pathway leading to MM after a preceding MGUS stage. Yet-to-be-determined secondary event(s) needs to occur for the transition to MM, unrelated to changes in chromosome number or to loss of chromosome 13. In contrast, the “nonhyperdiploid” pathway needs to be clarified further because hypodiploidy is less common in MGUS than in MM and Δ13 is rare in hypodiploid MGUS patients compared with hypodiploid MM patients.
Identification of a Met-Binding Peptide from a Phage Display Library
Authors: Zhao Ping , Grabinski Tessa , Gao Chongfeng , Skinner R. Scot , Giambernardi Troy , Su Yanli , Hudson Eric , Resau James , Gross Milton , Vande Woude George F. , Hay Rick , Cao Brian
Published: October 2007

Purpose: Aberrant c-Met expression has been implicated in most types of human cancer. We are developing Met-directed imaging and therapeutic agents.

Experimental Design: To seek peptides that bind specifically to receptor Met, the Met-expressing cell lines S114 and SK-LMS-1 were used for biopanning with a random peptide phage display library. Competition ELISA, fluorescence-activated cell sorting analysis, an internalization assay, and a cell proliferation assay were used to characterize a Met-binding peptide in vitro. To evaluate the utility of the peptide as a diagnostic agent in vivo, 125I-labeled peptide was injected i.v. into nude mice bearing s.c. xenografts of the Met-expressing and hepatocyte growth factor (HGF)/scatter factor–expressing SK-LMS-1/HGF, and total body scintigrams were obtained between 1 and 24 h postinjection.

Results: One Met-binding peptide (YLFSVHWPPLKA), designated Met-pep1, reacts with Met on the cell surface and competes with HGF/scatter factor binding to Met in a dose-dependent manner. Met-pep1 is internalized by Met-expressing cells after receptor binding. Met-pep1 inhibits human leiomyosarcoma SK-LMS-1 cell proliferation in vitro. In SK-LMS-1 mouse xenografts, tumor-associated activity was imaged as early as 1 h postinjection and remained visible in some animals as late as 24 h postinjection.

Conclusions: Met-pep1 specifically interacts with Met: it is internalized by Met-expressing cells and inhibits tumor cell proliferation in vitro; it is a potential diagnostic agent for tumor imaging.
Canonical Nuclear Factor κB Pathway Inhibition Blocks Myeloma Cell Growth and Induces Apoptosis in Strong Synergy with TRAIL
Authors: Romagnoli Mathilde , Desplanques Grégoire , Maïga Sophie , Legouill Steven , Dreano Michel , Bataille Régis , Barillé-Nion Sophie
Published: October 2007

Purpose: Intrinsic activation of nuclear factor κB (NF-κB) characterizes various hematologic malignancies. In this study, we specifically address the role of NF-κB blockade in mediated antimyeloma activity using the IκB kinase-2 pharmacologic inhibitor, AS602868.

Experimental Design: Human myeloma cell lines (n = 16) and primary myeloma cells (n = 10) were tested for their sensitivity to AS602868 in terms of proliferation and apoptosis. Both in vitro and in vivo experiments were conducted. Functional mechanisms regarding the apoptotic pathways triggered by AS602868 were studied. The potential proapoptotic synergy between AS602868 and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) was also evaluated.

Results: Our results show that AS602868 efficiently targeted the canonical NF-κB pathway in myeloma cells and potently inhibited their growth in inducing apoptosis through Bax and caspase-3 activation. AS602868 also induced apoptosis in primary myeloma cells even in the presence of bone marrow mononuclear cells. Moreover, the IκB kinase-2 inhibitor targeted the paracrine effect on the bone marrow environment. Indeed, it decreased the intrinsic and myeloma-induced secretion of interleukin-6 from bone marrow stromal cells. In addition, AS602868 inhibited myeloma cell growth in the MM.1S xenograft myeloma model. Of particular interest, AS602868 strongly increased myeloma sensitivity to TRAIL in blocking TRAIL-induced NF-κB activation and in decreasing the expression of antiapoptotic proteins such as cFLIP and cIAP-1/2.

Conclusions: Taken together, our data point out the interest to inhibit the canonical NF-κB pathway in myeloma and clearly encourage clinical evaluation of novel therapies based on targeting NF-κB, especially in combination with TRAIL.
Evaluation of an 111In-Radiolabeled Peptide as a Targeting and Imaging Agent for ErbB-2 Receptor–Expressing Breast Carcinomas
Authors: Kumar Senthil R. , Quinn Thomas P. , Deutscher Susan L.
Published: October 2007

Purpose: The cellular targeting and tumor imaging properties of a novel ErbB-2-avid peptide, discovered from bacteriophage display, were evaluated in human breast carcinoma cells and in breast carcinoma–xenografted mice.

Experimental Design: The affinity of the ErbB-2 targeting peptide KCCYSL and its alanine substituted counterparts for the extracellular domain (ECD) of purified recombinant ErbB-2 (ErbB-2-ECD) was assessed by fluorescence titration. Binding of the KCCYSL peptide to breast and prostate carcinoma cells was analyzed by confocal microscopy. A DOTA(GSG)-KCCYSL peptide conjugate was radiolabeled with 111In, and stability, target binding, and internalization were analyzed in vitro. In vivo biodistribution and single-photon emission computed tomography imaging studies were done with the radiolabeled peptide in MDA-MB-435 human breast tumor–bearing severe combined immunodeficient mice.

Results: KCCYSL peptide exhibited high affinity (295 ± 56 nmol/L) to ErbB-2-ECD. Substitution of alanine for lysine, tryptophan, and cysteine reduced the peptide affinity ∼ 1- to 2.4-fold, whereas replacing leucine completely abolished binding. Both biotin-KCCYSL and 111In-DOTA(GSG)-KCCYSL were capable of binding ErbB-2–expressing human breast carcinoma cells in vitro. Approximately 11% of the total bound radioactivity was internalized in the carcinoma cells. Competitive binding studies indicated that the radiolabeled peptide exhibited an IC50 value of 42.5 ± 2.76 nmol/L for the breast carcinoma cells. 111In-DOTA(GSG)-KCCYSL was stable in serum and exhibited rapid tumor uptake (2.12 ± 0.32 %ID/g) at 15 min postinjection and extended retention coupled with rapid whole body disappearance, as observed by biodistribution and single-photon emission computed tomography imaging studies, respectively.

Conclusions: The DOTA(GSG)-KCCYSL peptide has the potential to be used as a tumor-imaging agent and a vehicle for specific delivery of radionuclide or cytotoxic agents for tumors overexpressing ErbB-2.
Enhancing Fraction Predicts Clinical Outcome following First-Line Chemotherapy in Patients with Epithelial Ovarian Carcinoma
Authors: O'Connor James P.B. , Jayson Gordon C. , Jackson Alan , Ghiorghiu Dana , Carrington Bernadette M. , Rose Chris J. , Mills Samantha J. , Swindell Ric , Roberts Caleb , Mitchell Claire L. , Parker Geoffrey J.M.
Published: October 2007

Purpose: To define a simple radiologic biomarker of prognosis in patients with advanced epithelial ovarian carcinoma on first-line chemotherapy.

Experimental Design: Twenty-seven patients receiving platinum-based chemotherapy with >2 cm residual disease [International Federation of Gynecology and Obstetrics (FIGO) stages IIIC or IV] after surgery were identified. The proportion of enhancing tumor tissue—the enhancing fraction—was calculated on pre-chemotherapy computed tomography scans at four Hounsfield unit (HU) thresholds and assessed for correlation with CA125 response, Response Evaluation Criteria in Solid Tumors (RECIST) radiologic response, and time to progression. Discriminative power was assessed by leave-one-out discriminant analysis.

Results: Pre-chemotherapy residual tumor volume did not correlate with clinical outcome. Pre-chemotherapy enhancing fraction at all thresholds significantly correlated with CA125 response (P < 0.001, ρ = 0.553 for 50 HU; P < 0.001, ρ = 0.565 for 60 HU; P < 0.001, ρ = 0.553 for 70 HU; P = 0.001, ρ = 0.516 for 80 HU). Significant correlations were also shown for radiologic response at all thresholds. Enhancing fraction predicted CA125 response with 81.9% to 86.4% specificity and Response Evaluation Criteria in Solid Tumors response with 74.9% to 76.8% specificity at 95% sensitivity (dependent on threshold). Enhancing fraction correlated with time to progression at the 60 HU (P = 0.045, ρ = 0.336) and 70 HU (P = 0.042; ρ = 0.340) thresholds.

Conclusion: Pre-chemotherapy enhancing fraction is a simple quantitative radiologic measure. Further evaluation in larger trials is required to confirm the potential of enhancing fraction as a predictive factor, particularly for patients who may benefit from the addition of antiangiogenic therapy.
Combination Treatment of Prostate Cancer Cell Lines with Bioactive Soy Isoflavones and Perifosine Causes Increased Growth Arrest and/or Apoptosis
Authors: Vinall Ruth L. , Hwa Kimberley , Ghosh Paramita , Pan Chong-Xian , Lara Primo N. , de Vere White Ralph W.
Published: October 2007

Purpose: To determine whether targeting the androgen receptor (AR) and Akt pathways using a combination of genistein combined polysaccharide (GCP) and perifosine is more effective at inducing growth arrest/apoptosis in prostate cancer cells compared with treatment with GCP or perifosine as single agents.

Experimental Design: The effect of GCP and perifosine treatment was assessed in five prostate cancer cell lines: LNCaP (androgen sensitive), LNCaP-R273H, C4-2, Cds1, and PC3 (androgen insensitive). A clonogenic assay assessed the long-term effects on cell growth and survival. Flow cytometry and Western blot analysis of poly(ADP)ribose polymerase cleavage were used to assess short-term effects. Preliminary studies to investigate mechanism of action included Western blot for P-Akt, Akt, P-p70S6K, p70S6K, p53, and p21; prostate-specific antigen analysis; and the use of myristoylated Akt and AR-specific small interfering RNA.

Results: Combination treatment with GCP and perifosine caused a decrease in clonogenic potential in all cell lines. In short-term assays, growth arrest was observed in the majority of cell lines, as well as increased inhibition of Akt activity and induction of p21 expression. Increased apoptosis was only observed in LNCaP. Knockdown of AR caused a further increase in apoptosis.

Conclusion: Combination treatment with GCP and perifosine targets the Akt pathway in the majority of the prostate cancer cell lines and causes increased inhibition of cell growth and clonogenicity. In LNCaP, combination treatment targets both the Akt and AR pathways and causes increased apoptosis. These data warrant clinical validation in prostate cancer patients.
PrLZ Is Expressed in Normal Prostate Development and in Human Prostate Cancer Progression
Authors: Wang Ruoxiang , Xu Jianchun , Mabjeesh Nicola , Zhu Guodong , Zhou Jianguang , Amin Mahul , He Dalin , Marshall Fray F. , Zhau Haiyen E. , Chung Leland W.K.
Published: October 2007

Purpose: We previously reported the isolation and characterization of PrLZ, a novel prostate-specific and androgen-responsive gene of the tumor protein D52 family at chromosome 8q21.1. PrLZ is the only known gene in this locus with prostate specificity. Expression level of PrLZ was elevated specifically in cancer cells, suggesting its association with malignancy.

Experimental Design: To define its biological function in the morphogenesis, development, and functional maturation of the prostate gland and to gain further insight into its role in prostate cancer, we examined PrLZ expression in prostate specimens during early embryonic development and in adult tissue.

Results: PrLZ first appears in the nuclei of the prostate epithelia at 16 weeks of gestation before its distribution in the cytoplasm at later ages. Its expression peaks at 24 years of age, declines at 31 years of age, and maintains a minimal level in later age. On prostate cancer development, PrLZ expression is reactivated, and its expression increases from primary localized tumor to bone metastasis. Overexpression of PrLZ in prostate cancer cells accelerates their growth in vitro and tumor formation in vivo.

Conclusion: This work identifies PrLZ as a marker for prostate cancer progression and metastasis, and its pattern of expression is suggestive of a proto-oncogene.
The Universal Character of the Tumor-Associated Antigen Survivin
Authors: Andersen Mads Hald , Svane Inge Marie , Becker Jürgen C. , Straten Per thor
Published: October 2007

Survivin is expressed in most human neoplasms, but is absent in normal, differentiated tissues. Survivin is a bifunctional inhibitor of apoptosis protein that has been implicated in protection from apoptosis and regulation of mitosis. Several clinical trials targeting survivin with a collection of different approaches from small molecule antagonists to immunotherapy are currently under way. With regard to the latter, spontaneous anti-survivin T-cell reactivity has been described in cancer patients suffering from a huge range of cancers of different origin, e.g., breast and colon cancer, lymphoma, leukemia, and melanoma. Thus, survivin may serve as a universal target antigen for anticancer immunotherapy. Accordingly, down-regulation of survivin as a means of immune escape would severely inflict the survival capacity of tumor cells, which highlights this protein as a prime target candidate for therapeutic vaccinations against cancer. Data from several ongoing phase I/II trials targeting survivin for patients with advanced cancer will provide further information about this idea.
Phase I Trial of Toll-Like Receptor 9 Agonist PF-3512676 with and Following Rituximab in Patients with Recurrent Indolent and Aggressive Non–Hodgkin's Lymphoma
Authors: Leonard John P. , Link Brian K. , Emmanouilides Christos , Gregory Stephanie A. , Weisdorf Daniel , Andrey Jeffrey , Hainsworth John , Sparano Joseph A. , Tsai Donald E. , Horning Sandra , Krieg Arthur M. , Weiner George J.
Published: October 2007

Purpose: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9–activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab.

Experimental Design: Patients with relapsed/refractory CD20+ B cell non–Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks.

Results: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease.

Conclusion: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non–Hodgkin's lymphoma.
Expression of X-Linked Inhibitor of Apoptosis Protein Is a Strong Predictor of Human Prostate Cancer Recurrence
Authors: Seligson David B. , Hongo Fumiya , Huerta-Yepez Sara , Mizutani Yoichi , Miki Tsuneharu , Yu Hong , Horvath Steve , Chia David , Goodglick Lee , Bonavida Benjamin
Published: October 2007

Purpose: The X-linked inhibitor of apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We examined the expression patterns of XIAP with regard to human prostate cancer, predicting that XIAP status may predict cancer recurrence and/or clinical outcome.

Experimental Design: Immunohistochemistry was done on tissue microarrays constructed from 226 primary prostate cancer specimen. The protein expression distribution was examined across the spectrum of epithelial tissues and its association with standard clinicopathologic covariates and tumor recurrence was examined in 192 outcome-informative patients.

Results: The mean XIAP expression was significantly higher in prostate cancer compared with prostatic intraepithelial neoplasia (PIN), normal, and benign prostatic hyperplasia. We observed that XIAP is an independent predictor of tumor recurrence in multivariate Cox proportional hazards analysis in all patients as well as after substratifying by Gleason score. Interestingly, patients with high XIAP levels had a much lower probability of tumor recurrence than those with lower XIAP expression. Even patients with high-grade tumors who had higher XIAP levels had a lower risk of recurrence compared with any patient whose tumors express lower XIAP.

Conclusions: XIAP is expressed at higher levels in prostate cancers compared with matched normal tissues. High XIAP expression is strongly associated with a reduced risk of tumor recurrence and is not directly associated with Gleason score, tumor stage, capsular involvement, or preoperative prostate-specific antigen status, suggesting that it is a novel prognosticator and a potential target for prostate cancer diagnosis and therapy. Significantly, these findings provide important and extensive validation of previous results.
Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil–Based Chemotherapy
Authors: Shen Lanlan , Catalano Paul J. , Benson Al B. , O'Dwyer Peter , Hamilton Stanley R. , Issa Jean-Pierre J.
Published: October 2007

Purpose: There are no good genomic markers of survival in patients with advanced colorectal cancer. The CpG island methylator phenotype (CIMP) marks a distinctive pathway in colorectal cancer. We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial.

Experimental Design: We studied 188 patients enrolled on protocol E2290, a five-arm trial comparing 5-FU, 5-FU in combination with N-phosphonoacetyl-l-aspartic acid, oral leucovorin, i.v. leucovorin, or IFNα-2a in patients with advanced colorectal cancer. Methylation of MINT1, MINT31, hMLH1, p14ARF, and p16INK4a in DNA extracted from formalin-fixed paraffin-embedded specimens was evaluated by combined bisulfite restriction analysis, and methylation of MINT2 was studied by methylation-specific PCR.

Results: Methylation frequencies were 21% for MINT1, 23% for MINT2, 24% for MINT31, 4% for hMLH1, 11% for p14ARF, and 17% for p16INK4a. Methylation of MINT1, MINT31, p14ARF, and p16INK4a were correlated, as expected. There was no association between methylation and clinicopathologic factors or response to therapy. Methylation of MINT1, MINT31, p14ARF, or p16INK4a was associated individually with shortened overall survival. Hazard ratios were 1.51 (P = 0.05) for MINT1, 1.70 (P = 0.006) for MINT31, 2.22 (P = 0.001) for p14ARF, and 1.51 (P = 0.05) for p16INK4a. Concurrent methylation of two or more genes of the CIMP-associated subset (MINT1, MINT31, p14ARF and p16INK4a) defined a group of cases with markedly reduced overall survival and hazard ratio was 3.22 (P < 0.0001 in multivariate analyses).

Conclusions: CIMP is associated with poor survival in advanced colorectal cancer patients.
Magnetic Resonance Imaging of the Breast Improves Detection of Invasive Cancer, Preinvasive Cancer, and Premalignant Lesions during Surveillance of Women at High Risk for Breast Cancer
Authors: Riedl Christopher C. , Ponhold Lothar , Flöry Daniel , Weber Michael , Kroiss Regina , Wagner Teresa , Fuchsjäger Michael , Helbich Thomas H.
Published: October 2007

Purpose: To assess the diagnostic accuracy of mammography, ultrasound, and magnetic resonance imaging (MRI) of the breast in the surveillance of women at high risk for breast cancer.

Experimental Design: In this prospective comparison study, women at high risk for breast cancer were offered annual surveillance examinations, consisting of mammography, ultrasound, and MRI, at a single tertiary care breast center. The sensitivity and specificity of each modality was based on the histopathologic evaluation of suspicious findings from all modalities plus the detected interval cancers.

Results: Three hundred and twenty-seven women underwent 672 complete imaging rounds. Of a total of 28 detected cancers, 14 were detected by mammography, 12 by ultrasound, and 24 by MRI, which resulted in sensitivities of 50%, 42.9%, and 85.7%, respectively (P < 0.01). MRI detected not only significantly more invasive but also significantly more preinvasive cancers (ductal carcinoma in situ). Mammography, ultrasound, and MRI led to 25, 26, and 101 false-positive findings, which resulted in specificities of 98%, 98%, and 92%, respectively (P < 0.05). Thirty-five (35%) of these false-positive findings were atypical ductal hyperplasias, lesions considered to be of premalignant character. Nine (26%) of those were detected by mammography, 2 (6%) with ultrasound, and 32 (91%) with MRI (P < 0.01).

Conclusion: Our results show that MRI of the breast improves the detection of invasive cancers, preinvasive cancers, and premalignant lesions in a high-risk population and should therefore become an integral part of breast cancer surveillance in these patients.
Emerging Therapies for Neovascular Age-Related Macular Degeneration: State of the Art
Authors: Donati Guy
Published: October 2007

The cornerstone of pharmacotherapeutic treatment for age-related macular degeneration (AMD) is photodynamic therapy with verteporfin. The recently approved pegaptanib sodium, which targets vascular endothelial growth factor (VEGF), reduces vision loss in AMD when given by intravitreal injection every 6 weeks. The early promise of monotherapy with the corticosteroid triamcinolone acetonide has yet to be borne out in larger clinical trials, but outcomes may be improved when it is used in combination with verteporfin therapy. The angiostatic cortisone anecortave acetate was recently reported to have failed to meet the primary efficacy criterion in two large, placebo-controlled trials, and its clinical utility is uncertain. Other potential treatments with varying mechanisms of action are currently under investigation. To date, no agent has been shown to significantly restore lost vision in patients with AMD. Future treatment strategies are likely to include a combination of treatments to better manage AMD-associated choroidal neovascularisation and preserve patients’ visual acuity.
Impact of Nuclear Cataract Density on Postoperative Refractive Outcome: IOL Master versus Ultrasound
Authors: Ueda Tetsuo , Taketani Futoshi , Ota Takeo , Hara Yoshiaki
Published: October 2007

Purpose: To evaluate the effect of cataract density on the postoperative refractive outcome. Methods: For 59 nuclear cataract eyes, the axial length was preoperatively measured by the IOL Master (Zeiss, Germany) and ultrasound (US; UD-6000, Tomey, Japan) and the cataract density by EAS-1000 (Nidek, Japan). The prediction error was used as evaluation of the accuracy of ocular biometry. Results: There were significant differences between IOL Master and US in the mean error (0.24 ± 0.63 vs. 0.69 ± 0.64 dpt, p < 0.001) and the mean absolute error (0.57 ± 0.36 vs. 0.79 ± 0.53 dpt, p < 0.001). The cataract density was significantly correlated with the prediction error with IOL Master (r = 0.24, p = 0.03) and US (r = 0.29, p = 0.01). Conclusions: Measurements with the IOL Master are slightly affected by the cataract density due to the refractive index change, but its accuracy is less affected than US.
Clinical Effectiveness of Balloon Dacryocystoplasty in Circumscribed Obstructions of the Nasolacrimal Duct
Authors: Lüchtenberg Marc , Bartel Jan Hendrik , Bink Andrea , Kuhli-Hattenbach Claudia , Berkefeld Joachim
Published: October 2007

Purpose: Balloon dacryocystoplasty (DCP) is known to have limited clinical success rates. In a previous publication, we tried to define subgroups that could benefit from interventional treatment of tear duct stenoses. The purpose of this study was to evaluate the clinical effectiveness of DCP performed with limited indication confined to patients with circumscribed stenosis or distal occlusion of the nasolacrimal duct (NLD). Patients and Methods: Twenty-nine patients with severe epiphora due to dacryocystographically proven postsaccal obstruction of the lacrimal draining system were treated by means of DCP and were available for a telephone interview after a median follow-up period of 40 months (5–75 months). A standardized questionnaire covered the individual history of epiphora before and after interventional treatment. All patients had circumscribed stenoses of the lower lacrimal sac or the NLD or presented with short-distance occlusions of the distal NLD. Patients with canalicular, high saccal or diffuse lesions as well as cases with active dacryocystitis, suspicion of dacryocystolithiasis or posttraumatic stenosis were excluded from DCP. Failures or recurrences with no major improvement compared with the initial status were taken as a study endpoint. Results: We dilated 21 partial and 8 complete obstructions and post-DCP control dacryocystograms showed a widening of the ductal lumen or improvement of flow. In 25 out of 29 patients, regression of clinical symptoms occurred during the first week after treatment, 4 cases remained unchanged. Ten out of 25 patients with initial improvement reported recurrence of severe epiphora after a median period of 5 months. Five patients of all treated patients (n = 29) received additional operative dacryocystorhinostomy (DCR) after failure of DCP or due to severe recurrences. One patient received DCR during the 1st week after DCP (n = 1). Four out of 25 patients with initial improvement underwent DCR. Overall, 15 of the 29 treated patients had durable improvement of epiphora by DCP alone. Conclusion: Even patients with circumscribed obstructions of the NLD and exclusion of factors potentially associated with poor outcome of tear duct stenosis after DCP balloon dilatation showed a limited clinical success and high recurrence rate. The main argument to continue DCP as first or second line treatment in selected patients with duct obstructions is its lack of invasiveness. Even patients with increased risk of general anesthesia can be treated and approximately half of the operations may be avoided.
Upper Eyelid Localisation of Tunga penetrans
Authors: Kaimbo Wa Kaimbo D. , Bifuko A. , Parys-Van Ginderdeuren R.
Published: October 2007

Purpose: This report describes two cases of palpebral localisation of Tunga penetrans.Methods: Two Congolese patients (a 17-year-old black man and a 12-year-old black girl) presented with a history of itching and oedema of the left upper eyelid. Results: On inspection and slit lamp examination, the patients manifested the characteristic lesion of a white translucent papule with a central black pit. Scraping of the lesion revealed a gravid adult female flea, allowing the diagnosis of infection with the flea T. penetrans. After removal of the parasite, a complete local recovery occurred over a 1-week period with local application of tetracycline. Conclusion: With the increase in international travelling, it is useful to know that eyelid localisation of T. penetrans is possible.
Lymphadenectomy in Bladder Cancer: A Review
Authors: Buscarini Maurizio , Josephson David Y. , Stein John P.
Published: October 2007

Background: Radical cystectomy is the standard treatment for muscle invasive bladder cancer, however the role and appropriate extent of an associated lymphadenectomy continues to change. Methods: We performed a detailed review of the medical literature pertaining to the development and rationale for an extended lymphadenectomy in patients undergoing radical cystectomy. Results: A perspective of lymphadenectomy and an anatomic account of bladder lymphatic drainage are presented. The technique of an extended lymphadenectomy is also highlighted. Autoptic contemporary clinical data are presented to suggest that a more extensive lymphadenectomy has both prognostic and therapeutic utility. Furthermore, the stage of the primary bladder tumor, total number of lymph nodes removed, and the lymph node tumor burden are shown to be important prognostic variables in patients undergoing cystectomy with pathologic evidence of lymph node metastasis. Conclusions: Radical cystectomy provides excellent local cancer control with the Lowe’s pelvic recurrence rates and the best long-term survival. Radical cystectomy with an appropriate extended lymphadenectomy, while surgically more challenging, does not significantly increase the morbidity or mortality of the procedure. The limits of lymph node dissection are still subject to dabate and there is growing evidence that an extended lymphadenectomy provides further diagnostic and therapeutic benefit.
Physiological Considerations of the Morphologic Changes of the Testicles during Erection and Ejaculation: A Canine Study
Authors: Shafik Ahmed , Shafik Ali A. , Shafik Ismail A. , El Sibai Olfat
Published: October 2007

Purpose: We investigated the hypothesis that testicles and scrotal skin undergo morphologic changes that would servethe mechanism of erection and ejaculation. Materials and Methods: Testicular and scrotal skin changes during erection and ejaculation were studied in 9 dogs. Testicular volume was measured by ultrasound, testicular temperature by digital thermometer and testicular vascularity by color duplex Doppler ultrasonography. Dartos muscle activity was studied by electromyography. Results: Testicular volume increased during erection and diminished at ejaculation. Testicular consistency became softer during erection and firmer at ejaculation. During erection and ejaculation the testicles were elevated closer to abdominal wall. Testicular temperature increased in the erectile phase followed by reduction during ejaculation. Doppler ultrasonography recorded increased testicular vascularity during erection and diminished vascularity at ejaculation. A dartos muscle electromyogram exhibited increased activity in the erectile and ejaculatory phases. Conclusion: During erection and ejaculation, testicles underwent changes which apparently serve the erectile and ejaculatory functions of penis.
Stabilization of Calcium Oxalate Suspension by Urinary Macromolecules, Probably an Efficient Protection from Stone Formation
Authors: Baumann J.M. , Affolter B. , Caprez U. , Clivaz C. , Glück Z. , Weber R.
Published: October 2007

Introduction: Crystal aggregation (AGN) destabilizes crystal suspensions and during crystalluria probably favors crystal apposition to kidney calcifications and preexisting stones. We analyzed inhibition of AGN and stabilization of calcium oxalate suspensions by urinary macromolecules (UM), urine and solutions with urinary citrate concentration. Materials and Methods: Solutions of UM (UMS) were obtained by a hemofiltration procedure from urine of 6 healthy men. Calcium oxalate suspensions were prepared in all solutions and urine by adjusting Ca2+ to 1.5 mM and by an oxalate titration to 1.0 mM. Crystallization was monitored measuring optical density (OD). Stability of suspensions (SS) was defined as the time without sedimentation and zeta potential (ZP) of crystals was measured. AGN was visualized by scanning electron microscopy and quantified by maximal OD. Results: UMS inhibited AGN and increased ZP and SS. Most inhibitory activity of urine could be attributed to UM. 3.3-fold dilution of UM reduced SS only by 30%. Conclusions: During crystalluria, UM of healthy men are supposed to protect from stone formation by inhibiting AGN and stabilizing crystal suspensions. As a probably important aspect, this protection was found to be limited in time and may favorably be influenced by an increase of diuresis.
Incisional Hernia in a 12-mm Non-Bladed Trocar Site following Laparoscopic Nephrectomy
Authors: Kouba Erik J. , Hubbard J. Slade , Wallen Eric , Pruthi Raj S.
Published: October 2007

Non-bladed trocars, radially-dilating systems, and conical blunt devices are considered less traumatic to the abdominal wall because they do not incise the fascia itself. Consequently, several authors have suggested that closure of the abdominal fascia may be unnecessary if such non-bladed laparoscopic trocars are used. We report of a case in whom a port-site hernia was diagnosed at the site of a 12-mm non-bladed trocar 11 days after laparoscopic nephrectomy.
Laparoscopic Heminephrectomy and Resection of Ectopic Ureter in an Adult
Authors: Brehmer Bernhard , Makris Antonio , Jakse Gerhard
Published: October 2007

We report a unique case of a duplex kidney and ectopic ureter presenting as a cystic tumor of the seminal vesicle with consecutive dysuria in an adult. The medical history of the patient, the diagnostic pathway and the laparoscopic treatment as well as the key points in laparoscopic surgery are described.
Functional Ureteral Obstruction due to Complex Pelvic Venous Anomaly
Authors: Huwyler Mirjam , Willmann Jürgen K. , John Hubert
Published: October 2007

Venous anomalies are rare causes of ureteral obstruction. We report the case of a 31-year-old woman with obstruction of the right distal ureter by a complex pelvic venous anomaly. Beside benign and malignant lesions of the retroperitoneum, venous anomalies should also be considered in the differential diagnosis of extrinsic ureteral obstruction. Due to its abilities of three-dimensional visualization, multi-detector row computed tomography is helpful in the depiction of venous anomalies.
Can We Identify the High-Risk Patients to Be Screened? A Genetic Approach
Authors: Gammon Amanda , Kohlmann Wendy , Burt Randall
Published: October 2007

Our understanding of the mechanisms that lead to colorectal cancer expands each year. Patients with a genetic predisposition to colorectal cancer have significantly increased risks for developing this malignancy over their lifetime. These risks can approach an 80 to nearly 100% likelihood of colorectal malignancy with some of the known cancer predisposition syndromes [Burt and Neklason: Gastroenterology 2005;128:1696–1716 and Rowley: Annu Rev Med 2005;56:539–554]. Although these inherited syndromes have a genetic basis, affected individuals are often initially seen by medical professionals outside the genetics realm. Gastroenterologists in particular have a key role in identifying patients at high risk for an inherited colorectal cancer predisposition syndrome and referring them on for directed genetics evaluation. In this review, we will focus on the presenting features and recommended screening and treatment protocols for six syndromes that predispose to colorectal carcinoma. The underlying genetic basis of each syndrome will be discussed, as well as specific guidelines for patient identification. Familial adenomatous polyposis will be covered first, followed by Lynch syndrome, attenuated familial adenomatous polyposis, MYH-associated polyposis, hereditary mixed polyposis, and hyperplastic polyposis. Other rare syndromes (the hamartomatous polyposis syndromes) will be summarized in table form. Finally, we will give some general guidelines for when to first suspect colorectal cancer syndromes, a summary of family history taking techniques that can be used in the primary care setting and a review of the referral, genetics appointment and postgenetics consultation process. Through this review, we hope to show that the identification of high-risk patients is possible, though sometimes difficult.
Colorectal Cancer Screening by Colonoscopy – Current Issues
Authors: Kaminski M.F. , Regula J.
Published: October 2007

Of all colorectal cancer screening methods, colonoscopy used as a primary screening tool is both the most promising and the most discussed in the current literature. Several countries have introduced colonoscopic screening on a national scale, but many issues still require further research. The practicality of using colonoscopic screening can be questionable given the huge target population, which requires a great increase in endoscopic resources. Limiting the target population by shifting the use of colonoscopy from low-risk to high-risk groups is a valid option. The quality of colonoscopy related to the individual colonoscopist’s skill has become a surprisingly considerable problem, and it is obvious that continuous quality improvement programs need to be established. The accuracy of detecting important colorectal lesions is also still influenced by the old problem of cleansing the large bowel, and further research would be welcome. Technological improvements in current endoscopic equipment will hopefully increase the diagnostic yield of colonoscopy and eventually strengthen its use in the setting of colorectal cancer screening.
New Stool Screening Tests for Colorectal Cancer
Authors: Young Graeme P. , Cole Stephen
Published: October 2007

Background/Aims: The purpose of this review is to clarify the place of new-technology stool tests in screening for colorectal neoplasia. Findings: New technologies have been based on blood and cellular products of neoplasia. Fecal occult blood tests (FOBTs) based on guaiac (i.e. GFOBTs) have been proved to be effective, but their impact on mortality is modest. When GFOBTs are reconfigured to provide improved sensitivity for cancer, their specificity often becomes unacceptable. Fecal immunochemical tests (FITs) targeting the human hemoglobin molecule have been shown to have better sensitivity for neoplasia without an unacceptable deterioration in specificity. The new stool-sampling technologies for FITs also improve population participation rates in screening. Most recently, quantitative FITs have become available; these provide flexibility for the end-user as a desired sensitivity: specificity ratio can be selected that is feasible in the context of available colonoscopic resources. A multi-target fecal DNA test, comprising a test for undegraded DNA and certain common mutations, was found more sensitive for cancer, but not for adenoma, than the early GFOBTs. A more recent version including an epigenetic marker for the vimentin gene has further improved sensitivity for cancer, but performance relative to GFOBT or FIT is not clear. These ‘fecal DNA tests’ have not proved to be more specific for neoplasia than tests that detect blood. Conclusions: FIT should replace GFOBT as the first test in two-step screening of large populations. It is not yet clear that tests targeting nonhemoglobin molecular events provide a clear advantage over FIT.
The New Scopes – Broadening the Colonoscopy Marketplace
Authors: Rösch T. , Eickhoff A. , Fritscher-Ravens A. , Eliakim R. , Arber N.
Published: October 2007

Colonoscopy has been established as a screening tool for colorectal cancer and precursors in some countries. Efforts to improve instrument performance as well as patient comfort, safety and compliance have led to modifications of existing endoscopes as well as to the development of new scopes with different working mechanisms, including the colon capsule. While the former have not substantially changed performance, the true value of new scopes – partially single use and/or self propelling – can not be fully assessed, since they are either still under development and/or tested only in animals and in small groups of patients or volunteers. The colon capsule holds promise but has a too complicated preparatory regimen and too low a sensitivity at the moment. Future developments and further studies will show which of these techniques may complement or even replace traditional screening colonoscopy.
Prevention of Colorectal Cancer in High-Risk Populations: The Increasing Role for Endoscopy and Chemoprevention in FAP and HNPCC
Authors: Lynch Patrick M.
Published: October 2007

Familial colorectal cancer (CRC) is heterogeneous. Screening recommendations do exist for individuals with a mild to moderate family history of CRC, with or without early age at onset. However, most attention has properly focused on the identification of individuals in whom a defined susceptibility gene mutation can be found. The past 20 years has seen the discovery genes for familial adenomatous polyposis (FAP), its variant forms (attenuated FAP and the recessive MYH-associated polyposis or MAP), nonadenomatous polyposes, and hereditary nonpolyposis CRC (HNPCC). A few retrospective and prospective studies support current recommendations for endoscopic surveillance in FAP and HNPCC, the main subjects of this paper. Where firm data have been lacking, various professional organizations have been very willing to provide consensus clinical practice guidelines. General guidelines need to be tailored to the peculiarities of a patient’s circumstances, a task best accomplished in the hands of practitioners familiar with the natural history of the condition. Improvements in the technology of endoscopic treatment of adenomas now enable increasingly aggressive nonsurgical intervention. To this may be added opportunities for chemoprevention, currently consisting mainly of nonsteroidal anti-inflammatory drugs. Surveillance, chemoprevention, and imaginative hybrid surveillance/endoscopic therapy/chemoprevention trials may gradually decrease the present dependence on prophylactic colectomy/proctocolectomy.
Combining Association Tests across Multiple Genetic Markers in Case-Control Studies
Authors: Zhou Huanyu , Wei Lee-Jen , Xu Xiping , Xu Xin
Published: October 2007

In the search to detect genetic associations between complex traits and DNA variants, a practice is to select a subset of Single Nucleotide Polymorphisms (tag SNPs) in a gene or chromosomal region of interest. This allows study of untyped polymorphisms in this region through the phenomenon of linkage disequilibrium (LD). However, it is crucial in the analysis to utilize such multiple SNP markers efficiently. In this study, we present a robust testing approach (TC) that combines single marker association test statistics or p values. This combination is based on the summation of single test statistics or p values, giving greater weight to those with lower p values. We compared the powers of TC in identifying common trait loci, using tag SNPs within the same haplotype block that the trait loci reside, with competing published tests, in case-control settings. These competing tests included the Bonferroni procedure (TB), the simple permutation procedure (TP), the permutation procedure proposed by Hoh et al. (TP-H) and its revised version using ‘deflated’ statistics (TP-H_def), the traditional χ2 procedure (TCHI), the regression procedure (Hotelling T2 test) (TR) and the haplotype-based test (TH). Results of these comparisons show that our proposed combining procedure (TC) is preferred in all scenarios examined. We also apply this new test to a data set from a previously reported association study on airway responsiveness to methacholine.