Impact of Sonic Hedgehog-dependent sphenoid bone defect on craniofacial growth.

OBJECTIVES: The main objective of this study was to evaluate how an apparently minor anomaly of the sphenoid bone, observed in a haploinsufficient mouse model for Sonic Hedgehog (Shh), affects the growth of the adult craniofacial region. This study aims to provide valuable information to orthodontists when making decisions regarding individuals carrying SHH mutation. MATERIALS AND METHODS: The skulls of embryonic, juvenile and adult mice of two genotypes (Shh heterozygous and wild type) were examined and measured using landmark-based linear dimensions. Additionally, we analysed the clinical characteristics of a group of patients and their relatives with SHH gene mutations. RESULTS: In the viable Shh+/ - mouse model, bred on a C57BL/6J background, we noted the presence of a persistent foramen at the midline of the basisphenoid bone. This particular anomaly was attributed to the existence of an ectopic pituitary gland. We discovered that this anomaly led to premature closure of the intrasphenoidal synchondrosis and contributed to craniofacial deformities in adult mice, including a longitudinally shortened skull base. This developmental anomaly is reminiscent of that commonly observed in human holoprosencephaly, a disorder resulting from a deficiency in SHH activity. However, sphenoid morphogenesis is not currently monitored in individuals carrying SHH mutations. CONCLUSION: Haploinsufficiency of Shh leads to isolated craniofacial skeletal hypoplasia in adult mouse. This finding highlights the importance of radiographic monitoring of the skull base in all individuals with SHH gene mutations.

An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis.

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumor­initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission.

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011-Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient's pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36-68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2-39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.

A Phase 2, Single Arm Study of Iniparib in Patients With BRCA1 or BRCA2 Associated Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

OBJECTIVE: The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS AND MATERIALS: Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks. Treatment continued until disease progression or adverse events (AEs) prohibited further therapy. Common Terminology Criteria for AEs v3.0 was used to grade AEs. The primary endpoint was tumor response. The study was conducted with a Simon 2-stage design with 12 and 23 patients planned in the first and second stage, respectively. The study was designed to distinguish between 10% and 30% responding with types 1 and 2 error of 0.10. RESULTS: Twelve patients were treated on study, with median exposure to iniparib of 7.5 weeks. The median number of previous chemotherapeutic regimens was 7. Treatment-related AEs (≥10%) included asthenia (83.3%), constipation (25%), diarrhea (25%), nausea (25%), abdominal pain (16.7%), and decreased hemoglobin (16.7%). All treatment-related AEs were grades 1 or 2 with the following 2 exceptions: 1 grade 3 diarrhea and 1 grade 3 hypertension. One patient had stable disease lasting 2 cycles; the remaining 11 patients had progressive disease. The study did not proceed to second stage enrollment. CONCLUSIONS: Iniparib did not show significant activity in this heavily pretreated ovarian cancer population, all of whom had BRCA1 or BRCA2 mutations.

Is It Time to Centralize Ovarian Cancer Care in the United States?

PURPOSE: The purpose of this article was to broadly review the most up-to-date information pertaining to the centralization of ovarian cancer care in the United States (US) and worldwide. METHODS: Much of the present literature pertaining to disparities in, and centralization of, ovarian cancer care in the US and internationally was reviewed, and specifically included original research and review articles. RESULTS: Data show improved optimal debulking rates, National Comprehensive Cancer Network (NCCN) guideline adherence, and overall survival rates in higher-volume, more specialized hospitals, and amongst higher-volume providers. CONCLUSIONS: Patients with invasive epithelial ovarian cancer, especially those with higher stages (III and IV), are better served by centralized care in high-volume hospitals and by high-volume physicians, who adhere to NCCN guidelines wherever possible. More research is needed to determine the policy changes that can increase NCCN guideline adherence in low-volume hospitals and low-provider caseload scenarios. Policy and future research should be aimed at increasing patient access, either directly or indirectly, to high-volume hospital and high-volume providers, especially amongst Medicare, lower socioeconomic status, and minority patients.

Annexin A2 is required for the early steps of cytokinesis.

Cytokinesis requires the formation of an actomyosin contractile ring between the two sets of sister chromatids. Annexin A2 is a calcium- and phospholipid-binding protein implicated in cortical actin remodeling. We report that annexin A2 accumulates at the equatorial cortex at the onset of cytokinesis and depletion of annexin A2 results in cytokinetic failure, due to a defective cleavage furrow assembly. In the absence of annexin A2, the small GTPase RhoA-which regulates cortical cytoskeletal rearrangement-fails to form a compact ring at the equatorial plane. Furthermore, annexin A2 is required for cortical localization of the RhoGEF Ect2 and to maintain the association between the equatorial cortex and the central spindle. Our results demonstrate that annexin A2 is necessary in the early phase of cytokinesis. We propose that annexin A2 participates in central spindle-equatorial plasma membrane communication.

A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. METHODS: This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. RESULTS: From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age ≥ 60 years (p=0.01); CA-125 ≥ 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and ≥ 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. CONCLUSIONS: We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment.

Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer.

PURPOSE: Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. PATIENTS AND METHODS: Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. RESULTS: Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. CONCLUSION: The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.

Effects of estradiol in adult neurogenesis and brain repair in zebrafish.

The brain of the adult teleost fish exhibits intense neurogenic activity and an outstanding capability for brain repair. Remarkably, the brain estrogen-synthesizing enzyme, aromatase B, is strongly expressed, particularly in adult fishes, in radial glial cells, which act as progenitors. Using zebrafish, we tested the hypothesis that estrogens affect adult neurogenesis and brain regeneration by modulating the neurogenic activity of radial glial cells. To investigate this, the estrogenic environment was modified through inhibition of aromatase activity, blockade of nuclear estrogen receptors, or estrogenic treatments. Estrogens significantly decreased cell proliferation and migration at the olfactory bulbs/telencephalon junction and in the mediobasal hypothalamus. It also appears that cell survival is reduced at the olfactory bulbs/telencephalon junction. We also developed a model of telencephalic lesion to assess the role of aromatase and estrogens in brain repair. Proliferation increased rapidly immediately after the lesion in the parenchyma of the injured telencephalon, while proliferation at the ventricular surface appeared after 48 h and peaked at 7 days. At this time, most proliferative cells express Sox2, however, none of these Sox2 positive cells correspond to aromatase B-positive radial glial cells. Interestingly, aromatase B expression was significantly reduced 48 h and 7 days after the injury, but surprisingly, at 72 h after lesion, aromatase B expression appeared de novo expressed in parenchyma cells, suggesting a role for this ectopic expression of aromatase in brain repair mechanisms. Altogether these data suggest that estrogens modulate adult, but not reparative neurogenesis, in zebrafish.

Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma.

PURPOSE: To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. PATIENTS AND METHODS: Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16-120 mg/m(2)). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m(2). RESULTS: Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m(2). PK data were linear from 16 to 100 mg/m(2), with proportional increases in mean C(max) and AUC(tot) as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m(2) revealed the following: half-life (t (½)) = 9.1 ± 2.2 h; volume of distribution (V(z)) = 119 ± 41 L/m(2); clearance (CL) = 9.3 ± 3.2 L/h/m(2). MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m(2). Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed. CONCLUSION: KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m(2) weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.

Nuclear progesterone receptors are up-regulated by estrogens in neurons and radial glial progenitors in the brain of zebrafish.

In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr) has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation.

Activity and expression of steroidogenic enzymes in the brain of adult zebrafish.

The brain of adult teleost fish exhibits several unique and interesting features, notably an intense neurogenic activity linked to persistence of radial glial cells acting as neural progenitors, and a high aromatase activity supported by strong expression of the cyp19a1b gene. Strikingly, cyp19a1b expression is restricted to radial glial cells, suggesting that estrogens are able to modulate their activity. This raises the question of the origin, central or peripheral, of C19 androgens available for aromatization. This study aimed to investigate the activity and expression of other main steroidogenic enzymes in the brain of adult zebrafish. We demonstrate by high-performance liquid chromatography that the zebrafish brain has the ability to convert [³H]-pregnenolone into a variety of radiolabeled steroids such as 17OH-pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydro-testosterone, estrone, estradiol, progesterone, and dihydro- and tetrahydro-progesterone. Next, we show by in situ hybridization that messengers for key steroidogenic enzymes, such as Cyp11a1 (P450(SCC)), 3ß-Hsd, Cyp17 and Cyp19a1b, are widely expressed in the forebrain where they exhibit an overall similar pattern. By combining aromatase B immunohistochemistry with in situ hybridization, we show that cyp11a1, 3ß-hsd and cyp17 messengers are found in part in aromatase B-positive radial processes, suggesting mRNA export. This set of results provides the first demonstration that the brain of fish can produce true neurosteroids, possibly in radial glial cells. Given that radial glial cells are brain stem cells during the entire lifespan of fish, it is suggested that at least some of these neurosteroids are implicated in the persisting neurogenic process.

Implementation of evidence-based guidelines for thyroid nodule biopsy: a model for establishment of practice standards.

OBJECTIVE: Multiple studies have defined criteria for the selection of thyroid nodules for biopsy. No set of criteria is sufficiently sensitive and specific. The aim of this study is to develop a method for assessing consistency of practice in an ultrasound group and to determine whether a 5-point malignancy rating scale can be used to select patients for biopsy. MATERIALS AND METHODS: One hundred one nodules (50 benign and 51 malignant) were selected from a thyroid biopsy database. Seven radiologists were educated on evidence-based criteria used to select nodules for biopsy. Using this information, readers graded the likelihood of malignancy using a 5-point malignancy rating scale, where 1 equals the lowest probability of malignancy and 5 equals the highest probability of malignancy, on the basis of overall impression of sonographic findings. Interobserver agreement on biopsy recommendation, reader sensitivity, specificity, and accuracy were determined. RESULTS: The sensitivity and specificity of biopsy recommendation were 96.1% and 52%, respectively. The misclassification rate was 25.7%, and accuracy was 74.3%. Interobserver agreement on biopsy recommendation was fair to substantial (κ, 0.38-0.69). The proportion of agreement was excellent for malignant nodules (0.88-1.0). The risk of malignancy increased with increasing malignancy rating: 4.3% of nodules with a malignancy rating of 1 were malignant versus 93.4% of those assigned a rating of 5. CONCLUSION: Our study illustrates a method to evaluate the standard of practice for thyroid nodule assessment among radiologists within an ultrasound group. Application of a 5-point malignancy rating scale to select nodules for biopsy is feasible and shows good diagnostic accuracy.

Pleural effusion detected at CT prior to primary cytoreduction for stage III or IV ovarian carcinoma: effect on survival.

PURPOSE: To determine the prognostic importance of pleural effusions on preoperative computed tomographic (CT) images in patients with advanced epithelial ovarian cancer. MATERIALS AND METHODS: The institutional review board waived informed consent for this HIPAA-compliant study of 203 patients with International Federation of Obstetrics and Gynecology stage III (n = 172) or IV (n = 31) epithelial ovarian cancer who underwent CT before primary cytoreductive surgery between 1997 and 2004 (mean age, 61 years; range, 37-96 years). Two radiologists retrospectively evaluated chest and/or abdominal CT images for pleural malignancy and the presence, size, and laterality of pleural effusions. To evaluate survival, Kaplan-Meier methods were used, with log-rank P values for comparisons. Multivariate analyses were conducted by using Cox proportional hazards regression. κ Statistics were calculated for interreader agreement. RESULTS: Median survival was 50 months (95% confidence interval [CI]: 45, 55 months) for patients with stage III disease and 41 months (95% CI: 27, 58 months) for patients with stage IV disease. Readers 1 and 2 found pleural effusions in 40 and 41 stage III and 20 and 21 stage IV patients, respectively. At multivariate analysis, after controlling for stage, age at surgery, preoperative serum CA-125 level, debulking status, and ascites, moderate-to-large pleural effusion on CT images was significantly associated with worse overall survival (reader 1: hazard ratio = 2.27 [95% CI: 1.31, 3.92], P < .01; reader 2: hazard ratio = 2.25 [95% CI: 1.26, 4.01], P = .02). Preoperative CA-125 level, debulking status, and ascites were also significant survival predictors (P ≤ .03 for all for both readers). Readers agreed substantially in distinguishing small from moderate-to-large effusions (κ = 0.764). CONCLUSION: Moderate-to-large pleural effusion on preoperative CT images in patients with stage III or IV epithelial ovarian cancer was independently associated with poorer overall survival after controlling for age, preoperative CA-125 level, surgical stage, ascites, and cytoreductive status.

Thoracic metastasis in advanced ovarian cancer: comparison between computed tomography and video-assisted thoracic surgery.

OBJECTIVE: To determine which computed tomography (CT) imaging features predict pleural malignancy in patients with advanced epithelial ovarian carcinoma (EOC) using video-assisted thoracic surgery (VATS), pathology, and cytology findings as the reference standard. METHODS: This retrospective study included 44 patients with International Federation of Obstetrics and Gynecology (FIGO) stage III or IV primary or recurrent EOC who had chest CT ≤30 days before VATS. Two radiologists independently reviewed the CT studies and recorded the presence and size of pleural effusions and of ascites; pleural nodules, thickening, enhancement, subdiaphragmatic tumour deposits and supradiaphragmatic, mediastinal, hilar, and retroperitoneal adenopathy; and peritoneal seeding. VATS, pathology, and cytology findings constituted the reference standard. RESULTS: In 26/44 (59%) patients, pleural biopsies were malignant. Only the size of left-sided pleural effusion (reader 1: rho=-0.39, p=0.01; reader 2: rho=-0.37, p=0.01) and presence of ascites (reader 1: rho=-0.33, p=0.03; reader 2: rho=-0.35, p=0.03) were significantly associated with solid pleural metastasis. Pleural fluid cytology was malignant in 26/35 (74%) patients. Only the presence (p=0.03 for both readers) and size (reader 1: rho=0.34, p=0.04; reader 2: rho=0.33, p=0.06) of right-sided pleural effusion were associated with malignant pleural effusion. Interobserver agreement was substantial (kappa=0.78) for effusion size and moderate (kappa=0.46) for presence of solid pleural disease. No other CT features were associated with malignancy at biopsy or cytology. CONCLUSION: In patients with advanced EOC, ascites and left-sided pleural effusion size were associated with solid pleural metastasis, while the presence and size of right-sided effusion were associated with malignant pleural effusion. No other CT features evaluated were associated with pleural malignancy.

Cxcr4 and Cxcl12 expression in radial glial cells of the brain of adult zebrafish.

Unlike that of mammals, the brain of adult teleost fish exhibits an intense and widespread neurogenic activity as a result of the persistence of radial glial cells acting as neural progenitors throughout life. Because chemokines, notably CXCL12, and their receptors, such as CXCR4, play key roles in mammalian embryonic neurogenesis, we investigated Cxcr4 and Cxcl12 expressions in the brain of adult zebrafish and their potential relationships with cell proliferation. Cxcr4 expression was found to be restricted to radial glial cells in the adult zebrafish, where it is co-expressed with established radial glial cell markers, such as brain lipid-binding protein (Blbp) or the estrogen-synthesizing enzyme aromatase B (Cyp19a1b). Double stainings combining proliferating cell nuclear antigen (PCNA) and Cxcr4 immunolabelling indicated that there is no obvious association between Cxcr4 expression and radial glial cell proliferation. Interestingly, cxcl12a messengers were detected in ventricular regions, in cells corresponding to aromatase B-immunoreactive radial glial cells. Altogether, our data demonstrate Cxcl12 and Cxcr4 expression in radial glial cells of the brain of adult zebrafish, supporting important roles for the Cxcl12/Cxcr4 pair in brain development and functioning.

Prognostic significance of supradiaphragmatic lymphadenopathy identified on preoperative computed tomography scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer.

INTRODUCTION: It has been hypothesized that the supradiaphragmatic lymph nodes serve as the principal nodes for lymphatic drainage of the entire peritoneal cavity. The purpose of this study was to determine the prognostic significance of enlarged supradiaphragmatic nodes noted on preoperative computed tomographic (CT) scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer (EOC). METHODS: We performed a retrospective chart review of all patients with stage III and IV EOC according to the International Federation of Gynecology and Obstetrics who had preoperative CT scans, including the supradiaphragmatic region, and had undergone primary cytoreductive surgery at our institution between January 1997 and June 2004. Scans were retrospectively reviewed by a radiologist. We defined supradiaphragmatic adenopathy as nodes measuring greater than 5 mm on the largest of 2 perpendicular measurements on the CT scan. The Fisher exact test was used to compare proportions. Kaplan-Meier curves and log-rank tests were used for the survival analyses. RESULTS: A total of 212 evaluable patients were identified. All underwent attempted primary cytoreduction followed by systemic chemotherapy. None had any supradiaphragmatic nodes removed at primary cytoreduction. With a median follow-up time of 52 months, median overall survival for the entire cohort was 48 months. Of 212 patients, 92 (43%) had supradiaphragmatic adenopathy. Median survival was 50 months for patients without adenopathy and 45 months for patients with adenopathy (P = 0.09). Of the 212 patients, 155 (73%) underwent optimal cytoreduction. In these patients, median survival was 55 months for the 91 without adenopathy and 50 months for the 64 patients with supradiaphragmatic adenopathy (P = 0.09). CONCLUSIONS: We observed a trend toward worse survival in patients with enlarged supradiaphragmatic nodes. The prognostic impact of supradiaphragmatic adenopathy remains uncertain and deserves further study.

Recurrent ovarian cancer: use of contrast-enhanced CT and PET/CT to accurately localize tumor recurrence and to predict patients' survival.

PURPOSE: To compare accuracy and interobserver variability in the detection and localization of recurrent ovarian cancer with contrast material-enhanced (CE) computed tomography (CT) and positron emission tomography (PET)/CT and determine whether imaging findings can be used to predict survival. MATERIALS AND METHODS: Waiving informed consent, the institutional review board approved this HIPAA-compliant, retrospective study of 35 women (median age, 54.4 years) with histopathologically proven recurrent ovarian carcinoma who underwent CE CT and PET/CT before exploratory surgery. All CE CT and PET/CT scans were independently analyzed. Tumor presence, number of lesions, and the size and maximum standardized uptake value (SUV(max)) of the largest lesion were recorded for patient and region. Surgical histopathologic findings constituted the reference standard. Areas under the receiver operating characteristic curves (AUCs), κ statistics, and hazard ratios were calculated. RESULTS: Readers' AUCs in detection of recurrence for region were 0.85 (95% confidence interval [CI]: 0.81, 0.90) and 0.78 (95% CI: 0.72, 0.83) for CE CT and 0.84 (95% CI: 0.79, 0.89) and 0.74 (95% CI: 0.67, 0.81) for PET/CT (P = .76); 12 patients died. At PET/CT, size, number, and SUV(max) of peritoneal deposits were significantly associated with poor survival for readers 1 and 2 (P ≤ .01and ≤ .05, respectively), as were long- and short-axis diameters, number, and SUV(max) of distant lymph nodes for reader 1 (P ≤ .001). With CE CT, size (reader 1) and number (readers 1 and 3) of peritoneal deposits were significantly associated with poor survival (P ≤ .01), as were long- and short-axis diameters and number of distant lymph nodes for reader 1 (P ≤ .01). Interobserver agreement ranged from fair (patient, κ = 0.30) to moderate (region, κ = 0.55) for CE CT and fair (patient, κ = 0.24) to substantial (region, κ = 0.63) for PET/CT. CONCLUSION: Preliminary data suggest that CE CT and PET/CT may have similar accuracy in detection of recurrent ovarian cancer. Tumor size, number, and SUV(max) may have potential as prognostic biomarkers for patients with recurrent ovarian cancer.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller.

INTRODUCTION: We previously reported a 52% correlation between the primary surgeon's assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. METHODS: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). RESULTS: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeon's assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. CONCLUSIONS: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeon's assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.

Antibiotic use in the management of pulmonary nodules.

BACKGROUND: Pulmonary nodules are common incidental findings on thoracic imaging examinations. This study sought to determine whether antibiotic use is associated with any improvement in nodule appearance and to identify clinical findings and nodule characteristics potentially influencing the decision to prescribe antibiotics. METHODS: Electronic medical records were reviewed of outpatients referred to a metropolitan cancer center for pulmonary nodules seen on chest CT scans who did not undergo biopsy. The primary end point was the appearance of each nodule on the first follow-up scan. A subset analysis was performed for patients manifesting symptoms or radiographic findings suggesting infection. An analysis was performed to determine what clinical and radiographic findings were associated with the decision to prescribe antibiotics. RESULTS: Between January 2003 and December 2004, 143 evaluations were performed for 293 nodules. Antibiotics were prescribed to 34 (24%) evaluations. A trend toward improvement was seen with antibiotic use, which was not significant. The percentage of nodules that improved was 33% among those receiving antibiotics and 27% among those who did not (odds ratio 1.33; 95% CI, 0.55-3.27). Among 63 patients with pulmonary symptoms, 41% of nodules improved among those receiving antibiotics and 28% among those who did not (odds ratio 1.78; 95% CI, 0.42-7.78). The decision to prescribe antibiotics was associated only with larger nodule size and bronchiectasis. CONCLUSIONS: These data do not support antibiotic use for pulmonary nodules. However, the trend toward improved nodule appearance suggests that larger prospective trials are warranted to clarify the role of antibiotics in managing lung nodules.