Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer.

The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.

The effects of socioeconomic status on baseline neurocognitive testing scores.

Baseline neurocognitive testing has been recommended to provide a more accurate representation of the pre-concussion cognitive status of individual athletes. Socioeconomic status is not typically controlled for when obtaining baseline scores, which may lead to inaccurate findings if post-injury scores are compared to normative data. Understanding the role of socioeconomic status in baseline testing is important for the accurate analysis of test scores and proper evaluation of patients if individualized baseline data are not available. Our purpose was to investigate the effects of socioeconomic status, as determined by eligibility for free or reduced cost lunch on baseline neurocognitive test scores in secondary school athletes. 1,788 secondary school athletes (females = 778, males = 1,010, age = 14.96 ± 1.11 years, height = 171.25 ± 17.83 cm, mass = 66.82 ± 21.63 kg) completed the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) upon starting scholastic athletics. ImPACT components (symptom severity scores and composite scores of verbal memory, visual memory, visual motor speed, and reaction time) served as the dependent variables. School administration coded free or reduced cost lunch eligibility (N = 1255 not eligible, N = 563 eligible) for each participant (group), which served as the independent variable. Free or reduced cost lunch eligibility significantly altered the combined dependent variables (multivariate F5,1780=14.41, p < .001, ɳ2 = .04) when sex and age were controlled. Follow up ANOVAs showed that participants eligible for free or reduced cost lunch scored significantly worse on verbal memory (F1,1784 = 24.81, p < .001, ɳ2 = .01), visual memory (F1,1784 = 24.90, p < .001, ɳ2 = .01), and visual motor speed (F1,1784 = 50.54, p < .001, ɳ2 = .03). In addition, slower reaction times (F1,1784 = 35.10, p < .001, ɳ2 = .02) and higher symptom severity scores (F1,1784 = 10.37, p < .01, ɳ2 = .01) were observed in those eligible for free or reduced cost lunch. If normative data are used instead of individual baselines, potential modifiers such as socioeconomic status should be taken into account when analyzing concussion scores to provide accurate diagnoses.

Standardization of the Punch Technique for the Implantation of Bone Anchored Auditory Devices: Evaluation of the MIPS Surgical Set.

OBJECTIVE: To describe and assess intraoperative and postoperative outcomes in the insertion of osseointegrated auditory implants with a newly designed surgical instrumentation set through a punch type technique. STUDY DESIGN: Retrospective case series. METHODS: Patients who underwent bone anchored auditory implant surgery using the Minimally Invasive Ponto Surgery (Oticon Medical, Somerset, NJ) surgical set through a punch technique at nine neurotology tertiary referral based practices were identified. Demographic data, skin thickness at implant site, implant used, duration of surgery, adverse intraoperative events, and postoperative outcomes were recorded. RESULTS: Seventy-five patients comprised the study cohort (32 males, 43 females). Most patients (57. 3%) were aged 51 to 75 years while 30.7% of the cohort comprised those aged 18 to 50 years and 12% were over 75 years. All but two patients received 4 mm fixtured implants and 68% received the Oticon Medical BioHelix implant. Two patients received 3 mm fixture implants and 32% received the Oticon Medical Wide Ponto implant. Mean surgical time was 12.2 minutes (6-45 min, standard deviation of 6.88 min). In three instances, surgery was converted to a linear incision to control brisk bleeding. Skin condition was Holgers 0 to 1 in 91.8%, while 5.5% had Holgers 2, and 2.7% had Holgers 3 at the first postoperative visit. At second postoperative visit, 94.3% had Holgers 0 to 1, 4.3% had Holgers 2, and 1.4% had Holgers 3. All instances of adverse skin reactions were treated with topical or systemic antibiotics and/or local debridement. There were no instances of implant loss. One patient had his implant traumatically displaced to a 45-degree angle necessitating implant replacement at a second site. CONCLUSION: Punch technique placement of osseointegrated auditory implants using the Minimally Invasive Ponto Surgery surgical set represents a safe technique that further simplifies a progressively minimally invasive surgery.

Novel Monoclonal Antibodies Recognizing Human Prostate-Specific Membrane Antigen (PSMA) as Research and Theranostic Tools.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a validated target for the imaging and therapy of prostate cancer. Here, we report the detailed characterization of four novel murine monoclonal antibodies (mAbs) recognizing human PSMA as well as PSMA orthologs from different species. METHODS: Performance of purified mAbs was assayed using a comprehensive panel of in vitro experimental setups including Western blotting, immunofluorescence, immunohistochemistry, ELISA, flow cytometry, and surface-plasmon resonance. Furthermore, a mouse xenograft model of prostate cancer was used to compare the suitability of the mAbs for in vivo applications. RESULTS: All mAbs demonstrate high specificity for PSMA as documented by the lack of cross-reactivity to unrelated human proteins. The 3F11 and 1A11 mAbs bind linear epitopes spanning residues 226-243 and 271-288 of human PSMA, respectively. 3F11 is also suitable for the detection of PSMA orthologs from mouse, pig, dog, and rat in experimental setups where the denatured form of PSMA is used. 5D3 and 5B1 mAbs recognize distinct surface-exposed conformational epitopes and are useful for targeting PSMA in its native conformation. Most importantly, using a mouse xenograft model of prostate cancer we show that both the intact 5D3 and its Fab fragment are suitable for in vivo imaging. CONCLUSIONS: With apparent affinities of 0.14 and 1.2 nM as determined by ELISA and flow cytometry, respectively, 5D3 has approximately 10-fold higher affinity for PSMA than the clinically validated mAb J591 and, therefore, is a prime candidate for the development of next-generation theranostics to target PSMA. Prostate 77:749-764, 2017. © 2017 Wiley Periodicals, Inc.

Enhanced dopamine uptake in the striatum following repeated restraint stress.

In mice administered chronic stress--repeated overnight restraint stress for 7 days--there was a prolonged enhancement of dopamine (DA) uptake into synaptosomes. The mRNA for the DA transporter (DAT) was found to be concomitantly increased in the midbrain, as was the binding of the transporter ligand mazindol to DAT in the nucleus accumbens and caudate-putamen. Kinetic analysis showed an increase in Vmax for DA, with little change in Km. No changes in tyrosine hydroxylase activity and tissue DA or 3,4-dihydroxyphenylacetic acid (DOPAC) content were observed. However, homovanillic acid (HVA) was found to be increased in the striatum of the stressed animals. Enhanced DAT activity attributable to chronic stress was still observed in animals treated with the DA D2 receptor antagonist haloperidol or the glucocorticoid receptor antagonist mifepristone. Modulation of DAT activity may be a physiological mechanism for regulating the concentration of DA that reaches receptors, following periods of stress.

The accuracy of computer-aided surgery in neurotologic approaches to the temporal bone: a cadaver study.

OBJECTIVE: To assess the accuracy of computer-aided surgery for common neurotologic approaches to the temporal bone. STUDY DESIGN AND SETTING: Cadaveric heads were dissected by using standard neurotologic approaches to the temporal bone including translabyrinthine, middle fossa, and retrosigmoid. Dissected anatomic landmarks from each approach were compared with CT images that were obtained before dissection on the VectorVision 2 system (BrainLAB Corp, Munich, Germany) and the variability measured from digital images. Each approach was performed 5 times, with each anatomic landmark measured 3 times from each approach. RESULTS: The accuracy of the computer-aided surgery system was less than 1 mm for all anatomic points measured. Forty-two of the 49 measured points were accurate to less than 0.5 mm. CONCLUSIONS: Computer-aided surgery of the temporal bone using common neurotologic approaches can be performed accurately and reliably in cadaver specimens. SIGNIFICANCE: The utility and limitations of computer-aided surgery in the temporal bone are discussed. EBM RATING: B-2.

Prospective evaluation of intraoperative cochlear implant radiographs.

OBJECTIVE: To investigate the clinical utility of intraoperative plain radiographs in cochlear implant surgery. STUDY DESIGN: Prospective. SETTING: Tertiary referral center. PATIENTS: Eighty consecutive adult and pediatric cochlear implant operations at a facility capable of intraoperative radiographs were evaluated over 12 months. INTERVENTIONS: Intraoperative plain radiographs to assess implant location and surgeon questionnaire. MAIN OUTCOME MEASURES: Plain radiographic image interpretation and surgeon questionnaire. RESULTS: In one revision surgery, the intraoperative plain radiograph was useful for confirming the cochleostomy site. In the remaining 79 operations, no changes in the electrode arrays were made on the basis of the information provided by intra-operative plain radiographs. CONCLUSIONS: In this cohort, intraoperative plain radiographs were not useful for uncomplicated implant operations; however, they may be useful for complicated operations. These results may have implications for surgical cost and patient radiation exposure.

Cochlear implantation in children with congenital inner ear malformations.

OBJECTIVE/HYPOTHESIS: To assess the audiologic and surgical outcomes for pediatric cochlear implant patients with inner ear malformations. STUDY DESIGN: Retrospective review of 315 pediatric cochlear implant cases from 1994 to 2002. METHODS: Twenty-eight pediatric cochlear implant patients with known inner ear malformations determined on high-resolution computed tomography (HRCT) of the temporal bone were the subjects of review. Results of HRCT findings, intraoperative findings, postoperative complications, and objective measures of both closed- and open-set testing of speech perception were analyzed. RESULTS: Patients with the constellation of an incompletely partitioned (IP) cochlea, enlarged vestibular aqueduct (EVA), and a dilated vestibule (i.e., Mondini's malformation) as well as those with an isolated EVA or partial semicircular canal aplasia have relatively good levels of speech perception. Patients with total semicircular canal aplasia, isolated IP, cochlear hypoplasia, or common cavity demonstrated lower levels of performance. Poor performance may be related to associated developmental delays rather than labyrinthine anatomy alone. Complications of surgery were relatively limited. CONCLUSIONS: Cochlear implantation can be successfully performed in children with inner ear malformations. These children and their parents can expect significant auditory benefits from this intervention. The various types of inner ear malformations may have quite different prognoses for good auditory performance.

Cochlear implantation for the treatment of deafness.

Cochlear implants have dramatically changed the treatment and prognosis for patients with profound sensorineural hearing loss. Deaf adults and children can be successfully (re)integrated into the hearing world through a multidisciplinary approach involving otolaryngologists, audiologists, and speech/language pathologists. As the technology of the cochlear prosthesis advances, the candidacy for these devices continues to broaden. This review addresses the basic technology, candidacy criteria, and important issues in the fields of adult and pediatric cochlear implantation. Cost utility and future directions in the treatment of the profoundly hearing impaired are discussed.

Management of labyrinthine fistulae in chronic ear surgery.

The appropriate management of labyrinthine fistulae has been debated in the literature for years. After several recent cases of labyrinthine fistulae at our institution, a review of the published data regarding hearing outcome with fistula management was undertaken. Results of this critical review were presented at departmental grand rounds. The grand rounds presentation, data and discussion are presented to better illuminate the topic of labyrinthine fistula management.