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Background and Purpose: An "unwound" or "offset" cochlea has been described as a characteristic imaging feature in patients with branchio-oto-renal syndrome, and recently recognized to be associated in particular to those with EYA1 gene mutations. Determination of this feature has traditionally relied on subjective visual assessment. Our aim was to establish an objective assessment method for cochlear offset (the cochlear turn alignment ratio) and determine an optimal cutoff turn alignment ratio value that separates individuals with EYA1 -branchio-oto-renal syndrome from those with SIX1 -branchio-oto-renal syndrome and healthy controls., Materials and Methods: Temporal bone CT or MR imaging from 40 individuals with branchio-oto-renal syndrome and 40 controls was retrospectively reviewed. Cochlear offset was determined visually by 2 independent blinded readers and then quantitatively via a standardized technique yielding the cochlear turn alignment ratio. The turn alignment ratio values were compared between cochleae qualitatively assessed as "not offset" and "offset." Receiver operating characteristic analysis was used to determine the ability of the turn alignment ratio to differentiate between these populations and an optimal cutoff turn alignment ratio value. Cochlear offset and turn alignment ratio values were analyzed for each branchio-oto-renal syndrome genotype subpopulation and for controls., Results: The turn alignment ratio can accurately differentiate between cochleae with and without an offset ( P  < .001). The optimal cutoff value separating these populations was 0.476 (sensitivity = 1, specificity = 0.986, J = 0.986). All except 1 cochlea among the EYA1 -branchio-oto-renal syndrome subset and all with unknown genotype branchio-oto-renal syndrome had a cochlear offset and a turn alignment ratio of <0.476. All except 1 cochlea among the SIX1 -branchio-oto-renal syndrome subset and all controls had no offset and a turn alignment ratio of >0.476., Conclusions: There is a statistically significant difference in turn alignment ratios between offset and nonoffset cochleae, with an optimal cutoff of 0.476. This cutoff value allows excellent separation of EYA1 -branchio-oto-renal syndrome from SIX1 -branchio-oto-renal syndrome and from individuals without branchio-oto-renal syndrome or sensorineural hearing loss. The turn alignment ratio is a reliable and objective metric that can aid in the imaging evaluation of branchio-oto-renal syndrome., (© 2022 by American Journal of Neuroradiology.)

Background and Purpose: Temporal bone imaging plays an important role in the work-up of branchio-oto-renal syndrome. Previous reports have suggested that the unwound or offset cochlea is a highly characteristic marker for branchio-oto-renal syndrome. Our goals were to examine the prevalence of this finding in a branchio-oto-renal syndrome cohort and analyze genetic-phenotypic associations not previously established., Materials and Methods: This multicenter retrospective study included 38 ears in 19 unrelated individuals with clinically diagnosed branchio-oto-renal syndrome and confirmed mutations in the EYA1 or SIX1 genes. Two blinded neuroradiologists independently reviewed and documented temporal bone imaging findings in 13 categories for each ear. Imaging phenotypes were correlated with genotypes., Results: There was excellent interrater agreement for all 13 phenotypic categories (κ ≥ 0.80). Of these, 9 categories showed statistically significant differences between patients with EYA1 -branchio-oto-renal syndrome and SIX1 -branchio-oto-renal syndrome. Cochlear offset was present in 100% of patients with EYA1 -branchio-oto-renal syndrome, but in only 1 ear (12.5%) among patients with SIX1 -branchio-oto-renal syndrome. A short thorny appearance of the cochlear apical turn was observed in most patients with SIX1 -branchio-oto-renal syndrome., Conclusions: An offset cochlea is associated with the EYA1 -branchio-oto-renal syndrome genotype. The SIX1 -branchio-oto-renal syndrome genotype is associated with a different cochlear phenotype that almost always is without offset and has a short thorny tip as the apical turn. Therefore, cochlear offset is not a characteristic marker for all patients with branchio-oto-renal syndrome. The lack of a cochlear offset in a patient with clinically suspected branchio-oto-renal syndrome does not exclude the diagnosis and, in fact, may be predictive of the SIX1 genotype., (© 2022 by American Journal of Neuroradiology.)

Purpose: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA)., Methods: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status., Results: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT , FGFR2 , IDH1 , and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input., Conclusion: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care., Competing Interests: Karthikeyan Murugesan Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Pharma AG Patents, Royalties, Other Intellectual Property: Antibiotic resistance causation identification (US10629291B2) filed with Koninklijke Philips NV, Analytic prediction of antibiotic susceptibility (US20190279738A1) filed with Koninklijke Philips NV, Methods and devices for characterizing and treating combined hepatocellular cholangiocarcinoma, with Foundation Medicine Inc Travel, Accommodations, Expenses: Foundation Medicine Radwa Sharaf Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Meagan Montesion Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jay A. Moore Employment: Foundation Medicine Stock and Other Ownership Interests: Roche James Pao Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Provisional patent submitted for Foundation Medicine, dealing with machine learning for gene predictions Dean C. Pavlick Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Vivek A. Upadhyay Employment: EQRx Stock and Other Ownership Interests: EQRx Consulting or Advisory Role: Foundation Medicine Brian M. Alexander Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Lilly, Puma Biotechnology, Celgene Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summary Vincent A. Miller Employment: Foundation Medicine, EQRx Leadership: Revolution Medicines Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics, Revolution Medicines, EQRx Patents, Royalties, Other Intellectual Property: Receives periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Milind M. Javle Consulting or Advisory Role: QED Therapeutics, Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono Other Relationship: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer Tanios S. Bekaii Saab Consulting or Advisory Role: Amgen, Ipsen, Lilly, Bayer, Roche/Genentech, AbbVie, Incyte, Immuneering, Seattle Genetics, Pfizer, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation Medicine Patents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687 Other Relationship: Exelixis, Merck, AstraZeneca, Lilly, Pancreatic Cancer Action Network Lee A. Albacker Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics, Tango Therapeutics Research Funding: Foundation Medicine Siraj M. Ali Employment: EQRx Consulting or Advisory Role: Elevation Oncology, In8bio, Pillar Biosciences, Takeda, ArcherDx Stock and Other Ownership Interests: In8bio, Pillar Biosciences, EQRx Patents: Foundation Medicine No other potential conflicts of interest were reported. Karthikeyan Murugesan Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Pharma AG Patents, Royalties, Other Intellectual Property: Antibiotic resistance causation identification (US10629291B2) filed with Koninklijke Philips NV, Analytic prediction of antibiotic susceptibility (US20190279738A1) filed with Koninklijke Philips NV, Methods and devices for characterizing and treating combined hepatocellular cholangiocarcinoma, with Foundation Medicine Inc Travel, Accommodations, Expenses: Foundation Medicine Radwa Sharaf Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Meagan Montesion Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jay A. Moore Employment: Foundation Medicine Stock and Other Ownership Interests: Roche James Pao Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Provisional patent submitted for Foundation Medicine, dealing with machine learning for gene predictions Dean C. Pavlick Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Vivek A. Upadhyay Employment: EQRx Stock and Other Ownership Interests: EQRx Consulting or Advisory Role: Foundation Medicine Brian M. Alexander Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Roche Research Funding: Lilly, Puma Biotechnology, Celgene Open Payments Link: https://openpaymentsdata.cms.gov/physician/854258/summary Vincent A. Miller Employment: Foundation Medicine, EQRx Leadership: Revolution Medicines Stock and Other Ownership Interests: Foundation Medicine, Mirati Therapeutics, Revolution Medicines, EQRx Patents, Royalties, Other Intellectual Property: Receives periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Milind M. Javle Consulting or Advisory Role: QED Therapeutics, Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono Other Relationship: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer Tanios S. Bekaii Saab Consulting or Advisory Role: Amgen, Ipsen, Lilly, Bayer, Roche/Genentech, AbbVie, Incyte, Immuneering, Seattle Genetics, Pfizer, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo/UCB Japan, AstraZeneca, Exact Sciences, Natera, Treos Bio, Celularity, SOBI, BeiGene, Foundation Medicine Patents, Royalties, Other Intellectual Property: Patent WO/2018/183488, Patent WO/2019/055687 Other Relationship: Exelixis, Merck, AstraZeneca, Lilly, Pancreatic Cancer Action Network Lee A. Albacker Employment: Foundation Medicine Stock and Other Ownership Interests: Roche Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Celsius Therapeutics, Tango Therapeutics Research Funding: Foundation Medicine Siraj M. Ali Employment: EQRx Consulting or Advisory Role: Elevation Oncology, In8bio, Pillar Biosciences, Takeda, ArcherDx Stock and Other Ownership Interests: In8bio, Pillar Biosciences, EQRx Patents: Foundation Medicine No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background: In correctional facilities, sexually transmitted infections (STIs) are common, are often asymptomatic, and may lead to adverse outcomes such as infertility and increased HIV acquisition. In January 2020, testing for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) was paired with routine urine pregnancy tests among women entering a large county jail to increase testing and detection of STIs., Methods: The results of all GC/CT urine tests in the Dallas County Jail were collected from October 2019 to February 2020. Medical records were reviewed to collect demographic factors and to determine the positivity of GC/CT infections, time to results, and time to treatment., Results: With paired testing, monthly testing rates increased 4.7-fold among incarcerated females from 125 to 589 tests without substantial change for males (174 to 163). The number of infections detected in females increased from 25 (7%) of 359 to 62 (5.3%) of 1171 for GC and 42 (11.2%) of 374 to 129 (11%) of 1177 for CT without a significant difference in GC (P = 0.23) or CT positivity (P = 0.66). Younger women (≤25 years) had the highest rates of CT (18.8% [66/350]), whereas GC was highest among women aged 31 to 35 years (9.9% [32/321]). Average time to results and treatment were 5.8 and 1.8 days, respectively., Conclusions: Pairing GC/CT testing with routine urine pregnancy tests resulted in a large (4.7-fold) increase in the number of STI tests and a comparable increase (3.7- to 4.6-fold) in the number of infections detected. Future efforts should focus on incorporating STI testing into routine jail practices and expediting treatment to further improve outcomes in this vulnerable population., Competing Interests: Conflict of Interest and Sources of Funding: The authors have no conflicts of interest to share. A.E.N. receives the following grant funding relevant to this project: NIH R34 DA045592 and U01 DA 053039., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Background: In response to Choosing Wisely recommendations that sentinel lymph node biopsy (slnb) should not be routinely performed in elderly patients with node-negative (cN0), estrogen receptor-positive (er+) breast cancer, we sought to evaluate how nodal staging affects adjuvant treatment in this population., Methods: From a prospective database, we identified patients 70 or more years of age with cN0 breast cancer treated with surgery for er+ her2-negative invasive disease during 2012-2016. We determined rates of, and factors associated with, nodal positivity (pN+), and compared the use of adjuvant radiation (rt) and systemic therapy by nodal status., Results: Of 364 patients who met the inclusion criteria, 331 (91%) underwent slnb, with 75 (23%) being pN+. Axillary node dissection was performed in 11 patients (3%). On multivariate analysis, tumour size was the only factor associated with pN+ ( p = 0.007). Nodal positivity rates were 0%, 13%, 23%, 33%, and 27% for lesions preoperatively sized at 0-0.5 cm, 0.5-1 cm, 1.1-2.0 cm, 2.1-5.0 cm, and more than 5.0 cm. Compared with patients assessed as node-negative, those who were pN+ were more likely to receive axillary rt (lumpectomy: 53% vs. 1%, p < 0.001; mastectomy: 43% vs. 2%, p < 0.001), and adjuvant systemic therapy (endocrine: 82% vs. 69%; chemotherapy plus endocrine: 7% vs. 2%, p = 0.002)., Conclusions: Of elderly patients with cN0 er+ breast cancer, 23% were pN+ on slnb. Size was the primary predictor of nodal status, and yet significant rates of nodal positivity were observed even in tumours preoperatively sized at 1 cm or less. The use of rt and systemic adjuvant therapies differed by nodal status, although the long-term oncologic implications require further investigation. Multidisciplinary input on a case-by-case basis should be considered before omission of slnb., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none., (2020 Multimed Inc.)

Background and Purpose: Noncontrast head CTs are routinely acquired for patients with neurologic symptoms in the emergency department setting. Anecdotally, noncontrast head CTs performed in patients with prior negative findings with the same clinical indication are of low diagnostic yield. We hypothesized that the rate of acute findings in noncontrast head CTs performed in patients with a preceding study with negative findings would be lower compared with patients being imaged for the first time., Materials and Methods: We retrospectively evaluated patients in the emergency department setting who underwent noncontrast head CTs at our institution during a 4-year period, recording whether the patient had undergone a prior noncontrast head CT, the clinical indication for the examination, and the examination outcome. Positive findings on examinations were defined as those that showed any intracranial abnormality that would necessitate a change in acute management, such as acute hemorrhage, hydrocephalus, herniation, or interval worsening of a prior finding., Results: During the study period, 8160 patients in the emergency department setting underwent a total of 9593 noncontrast head CTs; 88.2% (7198/8160) had a single examination, and 11.8% (962/8160) had at least 1 repeat examination. The baseline positive rate of the "nonrepeat" group was 4.3% (308/7198). The 911 patients in the "repeat" group with negative findings on a baseline/first CT had a total of 1359 repeat noncontrast head CTs during the study period. The rate of positive findings for these repeat examinations was 1.8% (25/1359), significantly lower than the 4.3% baseline rate ( P  < .001). Of the repeat examinations that had positive findings, 80% (20/25) had a study indication that was discordant with that of the prior examination, compared with only 44% (593/1334) of the repeat examinations that had negative findings ( P < .001)., Conclusions: In a retrospective observational study based on approximately 10,000 examinations, we found that serial noncontrast head CT examinations in patients with prior negative findings with the same study indication are less likely to have positive findings compared with first-time examinations or examinations with a new indication. This finding suggests a negative predictive value of a prior noncontrast head CT examination with negative findings with the same clinical indication., (© 2020 by American Journal of Neuroradiology.)

Objective: To evaluate prospective surveillance and targeted physiotherapy (PSTP) compared to education (EDU) on the prevalence of arm morbidity and describe the associated program cost., Design: Pilot randomized single-blinded controlled trial., Setting: Urban with assessments and treatment delivered in hospitals., Participants: Women scheduled for breast cancer surgery., Interventions: Participants were randomly assigned (1:1) to PSTP ( n = 21) or EDU ( n = 20) and assessed presurgery and 12 months postsurgery. All participants received usual care, namely, preoperative education and provision of an education booklet with postsurgical exercises. The PSTP group was monitored for arm morbidity every three months and referred for physiotherapy if arm morbidity was identified. The EDU group received three education sessions on nutrition, stress and fatigue management., Main Outcome Measures: Arm morbidity was based on changes in the surgical arm(s) from presurgery in four domains: (1) shoulder range of motion, (2) strength, (3) volume, and (4) upper body function. Complex arm morbidity indicated ≥2 domains impaired. Second, the cost of the PSTP program was described., Results: At 12 months, 18 (49%) participants (10 PSTP and 8 EDU) had arm morbidity, with EDU participants presenting more complex arm morbidity compared to PSTP participants. PSTP participants attended 4.4 of 5 assessments with 90% retention. The PSTP program cost was $150 covered by the Health Care Provider and the Patient Out-of-Pocket Travel cost was CAN$40., Conclusion: Our results suggest that PSTP is feasible among women with breast cancer for early identification of arm morbidity. A larger study is needed to determine the cost and effectiveness benefits.

Introduction: Breast Conserving Surgery (BCS) is considered standard of care for women with early stage breast cancer. Between 20 and 50% of women treated with BCS will require re-operation for positive or close margins and it has been suggested that routine cavity shave margins may reduce the frequency of positive margins., Methods: Retrospective chart review of a prospectively maintained surgical database of patients undergoing BCS for early stage breast cancer, at a single institution, between January 2012 and December 2015. Cohort was followed until June 2016 to capture re-operations., Results: Among 2096 patients with stage 0-III breast cancers, 872 (42%) underwent primary mastectomies and 1224 (58%) underwent primary BCS. Margins were positive in 128 (11%) and close in 442 (36%). Re-operation rate for patients after BCS was 19%., Conclusion: A lower than predicted positive margin rate suggests that routine shave margins are not warranted at our institution., (Copyright © 2018. Published by Elsevier Inc.)

Background: In 2009, a Rapid Access Breast Clinic (rabc) was opened at our urban hospital. Compared with the traditional system (ts), the navigated care through the clinic was associated with a significantly shorter time to surgical consultation. Since 2009, many radiology facilities have introduced facilitated-care pathways for patients with breast pathology. Our objective was to determine if that change in diagnostic imaging pathways had eliminated the advantage in time to care previously shown for the rabc., Methods: All patients seen in the rabc and the office-based ts in November-December 2012 were included in the analysis. A retrospective chart review tabulated demographic, surgeon, pathology, and radiologic data, including time intervals to care for all patients. The results were compared with data from 2009., Results: In 2012, time from presentation to surgical consultation was less for the rabc group than for the ts group (36 days vs. 73 days, p < 0.001) for both malignant (31 days vs. 55 days, p = 0.008) and benign diagnoses (43 days vs. 79 days, p < 0.001). Comparing the 2012 results with results from 2009, a decline in mean wait time was observed for the ts group (86 days vs. 73 days, p = 0.02). Compared with patients having investigations in the ts, rabc patients with cancer were more likely to undergo surgery within 60 days of presentation (33% vs. 15%, p = 0.04)., Conclusions: The coordination of radiology and clinical care reduces wait times for diagnosis and surgery in breast cancer. To achieve recommended targets, we recommend implementation of more systematic coordination of care for a breast cancer diagnosis and of navigation to surgeons for patients needing surgical care.

Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently needed. This study was designed to evaluate chimeric antigen receptor (CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R) or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.

Skin cancer is a serious concern whose incidence is increasing at an alarming rate. Allyl sulfides-i.e., sulfur metabolites in garlic oil-have been demonstrated to have anticancer activity against several cancer types, although the mechanisms underlying these effects remain enigmatic. Our previous study showed that diallyl trisulfide (DATS) is more potent than mono- and disulfides against skin cancer. DATS inhibits cell growth of human melanoma A375 cells and basal cell carcinoma (BCC) cells by increasing the levels of intracellular reactive oxygen species (ROS) and DNA damage and by inducing G2/M arrest, endoplasmic reticulum (ER) stress, and mitochondria-mediated apoptosis, including the caspase-dependent and -independent pathways. This short review focuses on the molecular mechanisms of garlic-derived allyl sulfides on skin cancer prevention., (© 2012 New York Academy of Sciences.)

Background: Accumulating evidence indicates that oestrogens have significant direct effects on normal prostate development and carcinogenesis. The majority of the biological activities of oestrogens are mediated through the oestrogen receptor (ER), which functions as a hormone-inducible transcription factor to regulate target gene expression by binding to oestrogen response elements (EREs) in the regulatory regions of target genes. Sequence variants in EREs might affect the ER-ERE interaction and subsequent physiological activities. Therefore, we tested whether common single-nucleotide polymorphisms (SNPs) inside EREs are related to the clinical outcomes of androgen-deprivation therapy (ADT) in men with prostate cancer., Methods: We systematically evaluated 49 ERE SNPs predicted using a genome-wide database in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed using Kaplan-Meier analysis and a Cox regression model., Results: Based on multiple hypothesis testing, BNC2 rs16934641 was found to be associated with disease progression; in addition, TACC2 rs3763763 was associated with PCSM, and ALPK1 rs2051778 and TACC2 rs3763763 were associated with ACM. These SNPs remained significant in multivariate analyses that included known clinicopathological predictors. Moreover, a combined genotype effect on ACM was observed when ALPK1 rs2051778 and TACC2 rs3763763 were analysed in combination. Patients with a greater number of unfavourable genotypes had a shorter time to ACM during ADT (P for trend <0.001)., Conclusion: The incorporation of ERE SNPs into models with known predictors might improve outcome prediction in patients with prostate cancer receiving ADT., (© 2011 The Association for the Publication of the Journal of Internal Medicine.)

Background: Activated androgen receptor binds to androgen-responsive elements (AREs) in genome to regulate target gene transcription and, consequently, mediates physiological or tumorigenic processes of the prostate. Our aim was to determine whether genetic variants in AREs are associated with clinical outcomes after androgen-deprivation therapy (ADT) in prostate cancer patients., Patients and Methods: We systematically investigated 55 common single-nucleotide polymorphisms (SNPs) in the genome-wide insilico-predicted AREs in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed by Kaplan-Meier analysis and Cox regression model., Results: In univariate analysis, two, five, and four SNPs were associated with disease progression, PCSM, and ACM, respectively. After adjusting for known prognostic factors, ARRDC3 rs2939244, FLT1 rs9508016, and SKAP1 rs6504145 remained as significant predictors for PCSM and FBXO32 rs7830622 and FLT1 rs9508016 remained as significant predictors for ACM in multivariate analysis. Moreover, strong combined genotype effects on PCSM and ACM were also observed (P(trend) < 0.001)., Conclusion: Our results suggest that SNPs in AREs influence prostate cancer survival and may further advance our understanding of the disease progression.

Autophagy is a pathway in eukaryotes by which nutrient remobilization occurs through bulk protein and organelle turnover. Autophagy not only aides cells in coping with harsh environments but also plays a key role in many physiological processes that include pollen germination and tube growth. Most autophagic components are conserved among eukaryotes, but phylum-specific molecular components also exist. We show here that Arabidopsis thaliana PTEN, a protein and lipid dual phosphatase homologous to animal PTENs (phosphatase and tensin homologs deleted on chromosome 10), regulates autophagy in pollen tubes by disrupting the dynamics of phosphatidylinositol 3-phosphate (PI3P). The pollen-specific PTEN bound PI3P in vitro and was localized at PI3P-positive vesicles. Overexpression of PTEN caused accumulation of autophagic bodies and resulted in gametophytic male sterility. Such an overexpression effect was dependent upon its lipid phosphatase activity and was inhibited by exogenous PI3P or by expression of a class III phosphatidylinositol 3-kinase (PI3K) that produced PI3P. Overexpression of PTEN disrupted the dynamics of autophagosomes and a subpopulation of endosomes, as shown by altered localization patterns of respective fluorescent markers. Treatment with wortmannin, an inhibitor of class III PI3K, mimicked the effects by PTEN overexpression, which implied a critical role for PI3P dynamics in these processes. Despite sharing evolutionarily conserved catalytic domains, plant PTENs contain regulatory sequences that are distinct from those of animal PTENs, which might underlie their differing membrane association and thereby function. Our results show that PTEN regulates autophagy through phylum-specific molecular mechanisms., (© 2011 Shandong Agricultural University. The Plant Journal © 2011 Blackwell Publishing Ltd.)

Prosthetic joint infection with Candida is uncommon. Only 28 cases have been reported in the English literature. Successful reimplantation after eradication of Candida infection has been reported in 3 hip joints and only 1 knee. We present the case of a 68-year-old woman with chronic Candida parapsilosis infection of a prosthetic knee joint. Removal of the prosthesis, thorough débridement, and antifungal therapy treated the infection successfully. Antifungal therapy included 6 weeks of parenteral administration of fluconazole followed by 4 weeks of oral fluconazole. The involved knee joint was reimplanted 3 months after initial treatment. The prosthetic joint was pain free and functioned satisfactorily during the ensuing 4 years. No recurrence of infection was noted. The principle in treating Candida prosthetic infection generally has been the same as that of bacterial prosthetic infection. In chronic cases, removal of implants, thorough débridement, and effective antifungal therapy are mandatory for the eradication of infection. Reimplantation of the prosthesis can be performed successfully in a staged surgical procedure with the interval between the 2 stages shortened to 3 months.

A rapid and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of the antiallergenic compound, trans-3-[6-(methylthio)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid, [I], in plasma. The assay involves acetonitrile protein precipitation followed by the analysis of an aliquot of the protein-free fraction by reversed-phase HPLC with fluorescence detection (excitation at 245 nm, with emission greater than 418 nm). The overall recovery of [I] from plasma was 103 +/- 10%. The sensitivity limit of the assay was 0.125 microgram/ml of plasma. The analogous compound, trans-3-[6-[(1-methylethyl)thio]-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid, [II], is used as the internal standard. The assay was used to monitor the plasma concentration--time fall-off profile of [I] in the dog and in man. The stability of [I] was demonstrated in dog plasma on long-term storage for up to 180 days at -17 degrees C and -70 degrees C.

Five groups of six healthy subjects received single oral doses of 150, 300, 450, 600 or 750 mg tiacrilast 150 mg capsules, followed 24 h later by the same dose given every 6 h for 7 days, in a study designed to assess the pharmacokinetics of single and multiple doses of tiacrilast. Plasma samples were obtained at specified times after the initial dose, after 4 days of multiple dosing and after the last dose of tiacrilast. Samples were assayed for unchanged drug by a specific HPLC method. Wide variability was seen in the plasma concentration-time data. Plasma concentrations and pharmacokinetic parameters were nearly proportional to dose over the 150 to 750 mg dose range studied. Moreover, there was no evidence of unexpected accumulation of the drug in the plasma during multiple dosing and food did not appear to alter the bioavailability of tiacrilast to any clinically significant extent. The apparent elimination half-life was similar after single and multiple doses and ranged from 1 to 3 h.

A rapid and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of the antiarrhythmic quinidine analog, 7'-trifluoromethyldihydrocinchonidine.2HCl ([I].2HCl) in plasma and urine. The overall recovery of [I] from plasma was 86 +/- 9% with a sensitivity limit of detection of 0.2 microgram/ml. The assay involves extraction of [I] into benzene--methylene chloride (9:1) from plasma or urine made alkaline with 0.1 N sodium hydroxide (pH 13) and saturated sodium chloride, the residue of which is dissolved in methylene chloride, an aliquot of which is analyzed by HPLC using adsorption chromatography on silica gel with UV detection at 254 nm. The mobile phase composed of methylene chloride--methanol--conc. ammonium hydroxide (95.5:4:0.5) yields baseline resolution of quinidine used as the internal (reference) standard, compound [I] and dihydroquinidine, a common contaminant in quinidine. The assay was applied to the analysis of plasma and urine samples taken from a dog administered a single 20 mg/kg dose via intravenous and oral routes. The stability of [I] in human plasma for up to 37 days of storage at -17 degrees C was also demonstrated.

The metabolic disposition of 14C-labeled carprofen [(+/-)-6-chloro-alpha-methylcarbazole-2-acetic acid] was investigated in rats, dogs, and humans. Carprofen is eliminated predominantly by biotransformation in these three species. In dogs and rats, the direct conjugation of carprofen to form an ester glucuronide and oxidation to the C-7 and the C-8 phenols followed by their conjugation represent the major metabolic pathways. Small amounts of the alpha-hydroxy derivative also are formed by these species and are excreted free in the urine. In dogs, biliary secretion predominates, and 70% of an intravenous dose of carprofen is excreted in the feces while 8--15% of the dose is excreted in the urine. In rats, fecal excretion due to biliary secretion varies from 60 to 75%, and urinary excretion accounts for 20--30% of an intravenous dose. In humans direct conjugation of carprofen represents the only significant pathway of metabolism. Between 65 and 70% of the orally administered carprofen was found to be excreted as the ester glucuronide in the urine, and most of the remaining dose was estimated to be secreted as this metabolite in the bile. Due to enterohepatic circulation, only a fraction of the biliary metabolite was recovered in the feces in humans. Less than 5% of the dose was excreted in human urine as free, intact carprofen. In dogs and humans, plasma levels of carprofen and of total radioactivity exhibit a multiphasic decline. In the three human subjects studied, the terminal component declined with a 13--26 hr half-life; the terminal half-life was approximately 40 hr in dogs.

The compound 3-phenoxy-N-methylmorphinan (I) is under development as an analgesic agent. Studies on the biotransformation of the drug in the rat and in the dog have shown that I is extensively metabolized by N-demethylation to yield the nor-analogue (I-A), by para-hydroxylation of the 3-phenoxy ring to yield the phenolic analogue (I-B), cleavage of the ether linkage to yield levorphanol (I-C), and its N-demethylation to yield nor-levorphanol (I-D). The presence of these four metabolites (two of which, I-B and I-C, have analgesic potential) in addition to the parent drug, necessitated the development of sensitive and specific assays for their quantitation in plasma. This was accomplished by the development of (a) a high-performance liquid chromatographic assay using UV detection to obtain a qualitative/semi-quantitative profile of the metabolites present in plasma; (b) a gas chromatographic--nitrogen--phosphorus-specific detection method for the determination of the parent drug (I) for pre-clinical drug evaluation; and (c) a sensitive and specific gas chromatographic--positive chemical ionization mass spectrometric assay for eventual clinical evaluation for the determination of I and a key metabolite levorphanol (I-C). This report presents some preliminary pharmacokinetic data on I and I-C in the dog obtained during pre-clinical development.

A rapid, sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of midazolam, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]- benzodiazepine (I), and its four metabolites in plasma. The assay involves extraction into diethyl ether--methylene chloride (7:3) from plasma buffered to pH 9 and subsequent analysis by reversed-phase HPLC with ultraviolet detection at 254 nm. The overall recovery of I from dog plasma was 94.5 +/- 7.1% and greater than 89.0% for its metabolites. The sensitivity limit of the assay was 50 ng/ml of plasma for all compounds. The HPLC assay was used to determine plasma concentrations of I and its metabolites from selected samples taken from an oral toxicity study in the dog.

A rapid, sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of (E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methyl-2- phenylethenyl)naphthalene (I) and its phenolic metabolite, (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2- methylethenyl]phenol (II) in plasma. The assay for both compounds involves precipitation of the plasma proteins with acetonitrile, followed by extraction of the entire mixture into methyl tert.-butyl ether and subsequent analysis by reversed-phase HPLC. The overall recovery of I and II was 96.9 +/- 5.3 and 96.2 +/- 5.8% for dog plasma, 80.0 +/- 4.0 and 93.5 +/- 5.0% for human plasma and 97.4 +/- 2.9 and 97.6 +/- 9.6% for rat plasma, respectively. The sensitivity limit is 20 ng/ml of plasma for both compounds I and II using UV detection at 280 nm. The HPLC assay was used in studies in the dog and in the rat.

A method is described for measuring a trimethyl prostaglandin E2 analog, TM-PGE2, in human plasma. Trideuterated and monofluorinated analogs of TM-PGE2 and added to plasma as internal standard and carrier, respectively. The plasma is adjusted to pH 3.0 and is extracted with a mixture of benzene-dichloromethane (9:1). The residue, following removal of the extracting solvent, is reacted consecutively with pentafluorobenzyl bromide and bistrimethylsilyltrifluoroacetamide. The excess derivatizing reagents are removed by evaporation, and an aliquot of the reconstituted residue is analyzed by capillary column gas chromatography using methane as the carrier gas. A quadrupole mass spectrometer is set to monitor in the gas chromatographic effluent the (M - C7H2F5)-fragment ion of TM-PGE2 (m/e 449) and trideuterated TM-PGE2 (m/e 452) generated by methane negative chemical ionization. Quantitation of unknowns is based on a comparison of the m/e 449 to m/e 452 ion ratio in each unknown to that obtained from the analysis of control plasma spiked with known amounts of TM-PGE2 and fixed amounts of internal standard and carrier. The sensitivity limit of the assay is approximately 100 pg ml-1, which is equivalent to 1 pg injected. The assay was used to measure the concentration of TM-PGE2 in the plasma of two subjects following a single 10 micrograms kg-1 oral dose of the drug.