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Muscle-invasive bladder cancer (MIBC) is a sex-biased cancer with a higher incidence in men but worse outcomes in women. The root cause behind these observations remains unclear. To investigate whether sex-specific tumor biology could explain the differences in clinical behavior of MIBC, we analyzed the transcriptome profiles from transurethral resected bladder tumors of 1000 patients. Female tumors expressed higher levels of basal- and immune-associated genes, while male tumors expressed higher levels of luminal markers. Using molecular subtyping, we found that the rates of the basal/squamous subtype were higher in females than in males. Males were enriched with tumors of the luminal papillary (LumP) and neuroendocrine-like subtypes. Male MIBC tumors had higher androgen response activity across all luminal subtypes and male patients with LumP tumors were younger. Taken together, these data confirm differences in molecular subtypes based on sex. The role of the androgen response pathway in explaining subtype differences between men and women should be studied further. PATIENT SUMMARY: We explored the sex-specific biology of bladder cancer in 1000 patients and found that women had more aggressive cancer with higher immune activity. Men tended toward less aggressive tumors that showed male hormone signaling, suggesting that male hormones may influence the type of bladder cancer that a patient develops.

ImportanceBladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches.ObjectiveTo evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis.Design, Setting, and ParticipantsThis prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020.ExposuresTrimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy.Main Outcomes and MeasuresMRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio.ResultsOf 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44).Conclusions and RelevanceHigher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)–derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery (P = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival (P = 0.02), as does persistent CTC signal after 4 weeks of treatment (P = 0.01). In the subset with estrogen receptor (ER)–positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression (P = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer. Significance: Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. Cancer Discov; 8(10); 1286–99. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195

Background Erythroderma is a severe manifestation of pemphigus foliaceus (PF), a blistering disease mediated by IgG autoantibodies against desmoglein 1. Increasing evidence supports the contribution of angiogenic mediators in the pathogenesis of erythroderma. Objective To evaluate the in situ expression of vascular endothelial growth factor (VEGF) and endoglin in patients with PF with erythroderma. Methods Formalin-fixed paraffin-embedded skin samples obtained from patients with erythrodermic PF (n = 19; 12 patients with endemic PF), non-erythrodermic PF (n = 17), pemphigus vulgaris (PV; n = 10), psoriasis (n = 10) and healthy individuals (HI; n = 10) were processed in an automated immunohistochemistry platform utilizing anti-VEGF and anti-endoglin as primary antibodies. Reactivity was evaluated both manually (0 = negative; 1+ = mild; 2+ = intense) and through an automated microvessel analysis algorithm. Results Vascular endothelial growth factor expression in erythrodermic PF was higher than in non-erythrodermic PF (P = 0.034) and in HI (P = 0.004), and similar to psoriasis (P = 0.667) and PV (P = 0.667). In non-erythrodermic PF, VEGF positivity was similar to HI (P = 0.247), and lower than psoriasis (P = 0.049) and PV (P = 0.049). Both erythrodermic and non-erythrodermic PF presented similar endoglin expression (P = 0.700). In addition, endoglin positivity during erythrodermic PF was similar to psoriasis (P = 0.133) and lower than PV (P = 0.0009). Increased expression of in situVEGF suggests that healing processes are triggered in response to tissue damage led by autoantibodies in PF, especially during erythroderma. Reduced endoglin positivity suggests that an unbalanced angiogenesis may occur during erythrodermic PF. Further studies may help to confirm if the regulation of VEGF and endoglin expression in patients with PF can contribute to control the healing process and enable disease remission. Conclusion Overexpression of VEGF in erythrodermic PF as well as in PV and psoriasis points out a dysregulated repair process in severe forms of these diseases and suggests VEGF and endoglin could act as prognostic markers and future therapeutic targets to enable proper healing in PF.

Objective: To demonstrate the safety and effectiveness of the MED-EL Electric-Acoustic Stimulation (EAS) System, for adults with residual low-frequency hearing and severe-to-profound hearing loss in the mid to high frequencies. Study Design: Prospective, repeated measures. Setting: Multicenter, hospital. Patients: Seventy-three subjects implanted with PULSAR or SONATA cochlear implants with FLEX24 electrode arrays. Intervention: Subjects were fit postoperatively with an audio processor, combining electric stimulation and acoustic amplification. Main Outcome Measures: Unaided thresholds were measured preoperatively and at 3, 6, and 12 months postactivation. Speech perception was assessed at these intervals using City University of New York sentences in noise and consonant–nucleus–consonant words in quiet. Subjective benefit was assessed at these intervals via the Abbreviated Profile of Hearing Aid Benefit and Hearing Device Satisfaction Scale questionnaires. Results: Sixty-seven of 73 subjects (92%) completed outcome measures for all study intervals. Of those 67 subjects, 79% experienced less than a 30 dB HL low-frequency pure-tone average (250–1000 Hz) shift, and 97% were able to use the acoustic unit at 12 months postactivation. In the EAS condition, 94% of subjects performed similarly to or better than their preoperative performance on City University of New York sentences in noise at 12 months postactivation, with 85% demonstrating improvement. Ninety-seven percent of subjects performed similarly or better on consonant–nucleus–consonant words in quiet, with 84% demonstrating improvement. Conclusion: The MED-EL EAS System is a safe and effective treatment option for adults with normal hearing to moderate sensorineural hearing loss in the low frequencies and severe-to-profound sensorineural hearing loss in the high frequencies who do not benefit from traditional amplification.

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288–303. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269. This article is highlighted in the In This Issue feature, p. 253

Significance Identifying predictive biomarkers of therapeutic response for melanoma patients treated with immune checkpoint inhibitors is a major challenge. By combining microfluidic enrichment for melanoma circulating tumor cells (CTCs) together with RNA-based droplet digital PCR quantitation, we have established a highly sensitive and robust platform for noninvasive, blood-based monitoring of tumor burden. Serial monitoring of melanoma patients treated with immune checkpoint inhibitors shows rapid changes in CTC score, which precede standard clinical assessment and are highly predictive of long-term clinical outcome. Early on-treatment digital monitoring of CTC dynamics may thus help identify patients likely to benefit from immune checkpoint inhibition therapy., A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.

To assess compliance with the Japanese antiemetic guidelines for chemotherapy-induced nausea and vomiting (CINV), the frequencies of CINV occurrence and use of antiemetic rescue medications were examined in patients with hematological malignancy. A total of 40 patients with hematologic malignancy were eligible in this study. This study was performed in the Department of Hematology, Kyushu University Hospital, as a subgroup analysis from a nationwide, multicenter prospective cohort study conducted by the CINV Study Group of Japan. In the patients with hematological malignancy, the guideline compliance rate was 45 %. Five patients (22.7 %) experienced vomiting during the observation period after receiving non-guideline-consistent antiemetic prophylaxis, whereas no patient experienced vomiting after receiving guideline-consistent antiemetic prophylaxis. The study was not sufficiently powered to reach a statistical significance in its frequency of occurrence between the compliance and non-compliance groups. In the entire study period, 8 out of 40 patients required rescue medication, but there was no association between the status of compliance and the antiemetic guidelines. A total of 22 (55.0 %) patients achieved complete response, which was defined as no vomiting and no use of antiemetic rescue medication, during the study period. The rate of compliance with the prophylactic antiemetic treatment guidelines seemed to be low in patients with hematological malignancy, although the status of the guideline compliance did not always influence the antiemetic effects.

Inpatients who had been in close contact with patients with influenza were given oseltamivir [75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children] for three days as postexposure prophylaxis (PEP). The index patients with influenza were prescribed a neuraminidase inhibitor and were discharged immediately or transferred to isolation rooms. The protective efficacy of oseltamivir for three days was 93% overall [95% confidence interval (CI) 53-99%; P = 0.023] and 94% for influenza A (95% CI 61-99%; P = 0.017), which is comparable to that of seven- to 10-day regimens of oseltamivir as PEP.

The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency.A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation.The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 GA and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate.POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0-1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Using the Cluster-Chip, we identify CTC-clusters in 30–40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis.

Background Cancer patients treated with pelvic radiation therapy (RT) often experience sexual health–related side effects during and following treatment. A clinical needs assessment was used to evaluate sexual health needs and to determine how needs differed between patients receiving and who had completed RT. Methods and materials A questionnaire was used to evaluate sexual health needs among patients treated with pelvic RT. All answers were rated using a 4-point Likert scale. Convenience sampling was used, and patients were stratified by whether they were on-treatment or in follow-up. Charts were reviewed for demographic, diagnostic, and treatment information. Pearson's χ 2 test and logistic regression analysis were used to analyze the associations between sexual health–related topics and clinical variables. Results A total of 107 of 109 (98%) invited patients completed the questionnaire (46 females, 61 males; 52 undergoing RT, 54 completed RT). Most (75%) reported some degree of change in sexual health from the effects of cancer and/or treatment; 22% and 28% reported "quite a bit" or "very much" change, respectively. Sixty-nine percent reported that they experienced some degree of distress from sexual health changes (28% reported "very much" or "quite a bit" of distress). Seventy-six percent "agreed" or "strongly agreed" that they were interested in access to a multidisciplinary sexual health clinic (MSHC). Compared with patients currently receiving RT, patients in follow-up were significantly more likely to report worsening degrees of "change" ( P = .008) and "distress" ( P = .04) and to express interest in having access to an MSHC ( P = .03). Conclusion The majority of patients receiving pelvic RT reported a change in sexual health with associated distress, with more reports among those in follow-up. Patients undergoing pelvic RT expressed a high interest in attending a radiation oncology MSHC. Our findings emphasize the important role radiation oncologists can play in the quality of life of our patients.

SummaryCirculating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they greatly contribute to the metastatic spread of cancer.

TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1. While TGF-β-induced mitotic defects in proliferating cells are reversible upon its withdrawal, the acquired genomic abnormalities persist, leading to increased tumorigenic phenotypes. In metastatic breast cancer patients, increased mesenchymal marker expression within single circulating tumor cells is correlated with genomic instability. These observations identify a mechanism whereby microenvironment-derived signals trigger heritable genetic changes within cancer cells, contributing to tumor evolution.

Purpose Verbal short-term memory (STM) and working memory (WM) skills predict speech and language outcomes in children with cochlear implants (CIs) even after conventional demographic, device, and medical factors are taken into account. However, prior research has focused on single end point outcomes as opposed to the longitudinal process of development of verbal STM/WM and speech-language skills. In this study, the authors investigated relations between profiles of verbal STM/WM development and speech-language development over time. Method Profiles of verbal STM/WM development were identified through the use of group-based trajectory analysis of repeated digit span measures over at least a 2-year time period in a sample of 66 children (ages 6–16 years) with CIs. Subjects also completed repeated assessments of speech and language skills during the same time period. Results Clusters representing different patterns of development of verbal STM (digit span forward scores) were related to the growth rate of vocabulary and language comprehension skills over time. Clusters representing different patterns of development of verbal WM (digit span backward scores) were related to the growth rate of vocabulary and spoken word recognition skills over time. Conclusion Different patterns of development of verbal STM/WM capacity predict the dynamic process of development of speech and language skills in this clinical population.

Purpose To compare clinical outcomes of image-based versus non-image-based interstitial brachytherapy (IBBT) for vaginal cancer. Methods and materials Of 72 patients with vaginal cancer treated with brachytherapy (BT), 47 had image guidance (CT=31, MRI=16) and 25 did not. Kaplan–Meier (KM) estimates were generated for any recurrence, local control (LC), disease-free interval (DFI), and overall survival (OS) and Cox models were used to assess prognostic factors. Results Median age was 66 and median follow-up time was 24months. Median cumulative EQD2 dose was 80.8Gy in the non-IBBT group and 77Gy in the IBBT group. For non-IBBT versus IBBT, the 2-year KM LC was 71% vs. 93% ( p =0.03); DFI was 54% vs. 86% ( p =0.04); and OS 52% vs. 82% ( p =0.35). On multivariate analysis, IBBT was associated with better DFI (HR 0.24, 95% CI 0.07–0.73). Having any 2 or more of chemotherapy, high-dose-rate (HDR) BT or IBBT (temporally correlated variables) significantly reduced risk of relapse (HR=0.33, 95% CI=0.13–0.83), compared to having none of these factors. Conclusion Over time, the use of chemotherapy, HDR, and IBBT has increased in vaginal cancer. The combination of these factors resulted in the highest rates of disease control. Image-guided brachytherapy for vaginal cancer patients maximizes disease control.

Whereas acute pneumocephalus has been well characterized in the literature: typically seen postoperatively after neurosurgical and neurotological procedures, a chronic pneumocele developing several years after surgery is highly unusual. Most otogenic pneumocephali develop in an acute or subacute fashion, presenting with focal neurological symptoms, headache or signs of meningitis secondary to translocation of bacteria into the cavity. We describe a patient with a supra-auricular soft-tissue swelling as the only presenting symptom of a large chronic epidural pneumocele with extension into the extracranial subcutaneous tissues. It presented several years after surgical resection of a meningioma that involved the temporal bone.

To investigate visual-motor integration (VI) skills of prelingually deaf (PLD) children before and after cochlear implantation (CI) and investigate correlations with spoken-language and related processing measures.Study 1 was a longitudinal study in which VI was tested preimplant. Study 2 was a cross sectional study of school-age children who used a CI for2 years.In study 1, a standardized design-copying task was administered preimplant, and spoken-language data were obtained at intervals up to 4 years postimplantation. Analyses were conducted to determine if preimplant VI scores were predictive of various spoken-language measures. In study 2, standardized design copying and speeded maze tracing tasks were administered along with speech perception, vocabulary, and related processing measures.Whereas preimplant VI scores for children in study 1 fell within the typical range based on age-equivalent norms, postimplant VI standard scores in study 2 were low compared to the normative sample. Postimplant VI scores were inversely related to age at implantation. Preimplant VI scores were robustly predictive of most, but not all, spoken-language outcome scores. Postimplant design copying scores were also correlated with spoken-language and related processing measures whereas maze-tracing scores were less robustly related to these measures.Early auditory and linguistic experience may impact the development of VI skills. VI is a preimplant predictor of later spoken language outcomes. Design copying and speeded maze tracing tasks appear to tap different sets of cognitive resources in PLD children with CIs.

Lipoid proteinosis (LiP) (OMIM 247100) is a rare autosomal recessive disease caused by loss of function mutations in the extracellular matrix protein 1 gene, ECM1, on chromosome 1q21. LiP is characterized clinically by hoarseness in early infancy, followed by waxy papules and plaques on the face and body along with pox-like and acneiform scars. We studied a 20-year-old Japanese woman with LiP. She was born of consanguineous parents. Biopsy specimens obtained from a nodule on the elbow were used for histopathology, immunohistology and electron microscopy. Exons 6 and 7 of ECM1 were amplified by polymerase chain reaction (PCR) from genomic DNA from the proband, her parents, her brother and an unrelated person. PCR products were sequenced to detect the mutation. Histopathological examination revealed an irregular mass of calcium beneath deposits of a hyaline material in the dermis. Immunofluorescence double staining showed that the CD31-positive microvascular density was increased but that staining for the lymphatic-specific hyaluronan receptor LYVE-1 was drastically diminished in lesional compared with nonlesional skin of the patient and with normal skin. Electron microscopy revealed marked concentric reduplication of basal laminae not only around blood vessels but also around solitary dermal cells positive for Weibel-Palade bodies scattered in the hyaline material. Sequencing of the PCR products revealed a homozygous frameshift mutation, 507delT, in exon 6. This led to a premature stop codon 23 bp downstream. The results of immunopathological and ultrastructural characterization suggest that a failure of mucocutaneous lymphangiogenesis may underlie the clinical features of LiP. Identification of mutation 507delT in a Japanese patient with LiP further supports the thesis that this mutation represents a recurrent mutation in ECM1 in patients with LiP. To our knowledge, this case represents the first report of calcinosis cutis occurring in LiP.

The sound pressure levels (SPLs) of common infant humidifiers were determined to identify the likely sound exposure to infants and young children. This primary investigative research study was completed at a tertiary-level academic medical center otolaryngology and audiology laboratory. Five commercially available humidifiers were obtained from brick-and-mortar infant supply stores. Sound levels were measured at 20-, 100-, and 150-cm distances at all available humidifier settings. Two of 5 (40%) humidifiers tested had SPL readings greater than the recommended hospital infant nursery levels (50 dB) at distances up to 100 cm. In this preliminary study, it was demonstrated that humidifiers marketed for infant nurseries may produce appreciably high decibel levels. Further characterization of the effect of humidifier design on SPLs and further elucidation of ambient sound levels associated with hearing risk are necessary before definitive conclusions and recommendations can be made.

Objectives/Hypothesis: Individual speech and language outcomes of deaf children with cochlear implants (CIs) are quite varied. Individual differences in underlying cognitive functions may explain some of this variance. The current study investigated whether behavioral inhibition skills of deaf children were related to performance on a range of audiologic outcome measures. Design: Retrospective analysis of longitudinal data collected from prelingually and profoundly deaf children who used CIs. Methods: Behavioral inhibition skills were measured using a visual response delay task that did not require hearing. Speech and language measures were obtained from behavioral tests administered at 1-year intervals of CI use. Results: Female subjects showed higher response delay scores than males. Performance increased with length of CI use. Younger children showed greater improvement in performance as a function of device use than older children. No other subject variable had a significant effect on response delay score. A series of multiple regression analyses revealed several significant relations between delay task performance and open set word recognition, vocabulary, receptive language, and expressive language scores. Conclusions: The present results suggest that CI experience affects visual information processing skills of prelingually deaf children. Furthermore, the observed pattern of relations suggests that speech and language processing skills are closely related to the development of response delay skills in prelingually deaf children with CIs. These relations may reflect underlying verbal encoding skills, subvocal rehearsal skills, and verbally mediated self-regulatory skills. Clinically, visual response delay tasks may be useful in assessing behavioral and cognitive development in deaf children after implantation.

Although mitotic and meiotic spindles maintain a steady-state length during metaphase, their antiparallel microtubules slide toward spindle poles at a constant rate. This “poleward flux” of microtubules occurs in many organisms and may provide part of the force for chromosome segregation. We use quantitative image analysis to examine the role of the kinesin Eg5 in poleward flux in metaphase Xenopus laevis egg extract spindles. Pharmacological inhibition of Eg5 results in a dose–responsive slowing of flux, and biochemical depletion of Eg5 significantly decreases the flux rate. Our results suggest that ensembles of nonprocessive Eg5 motors drive flux in metaphase Xenopus extract spindles.

Objectives/Hypothesis: To examine the hypothesis that the newer generations of cochlear implants could provide considerable speech understanding to late-implanted, prelingually deaf adult patients. Study Design: Retrospective review. Methods: Speech perception scores of 103 patients with long-term prelingual deafness obtained from the recent clinical trials were compared with other previously published results. Results: Unlike patients receiving implants in early childhood, the audiologic performance of most patients with long-term prelingual deafness rapidly approached asymptotic levels within 1 year after implantation. Beginning at 3 months postimplantation, statistically significant improvement was noted in their speech perception scores compared with their preimplant levels. However, the average performance plateau achieved by this group of patients was significantly below the levels published for postlingual patients. No statistically significant differences were observed between the test scores at any testing interval among patients with different devices. Conclusions: Most patients with long-term prelingual deafness achieve their performance plateau within 1 year after implantation. The results suggest that patient characteristics, rather than device properties, are likely to be the major contributing factor responsible for the observed audiologic outcomes.

The purpose of the present study was to translate and adapt the Berg balance scale, an instrument for functional balance assessment, to Brazilian-Portuguese and to determine the reliability of scores obtained with the Brazilian adaptation. Two persons proficient in English independently translated the original scale into Brazilian-Portuguese and a consensus version was generated. Two translators performed a back translation. Discrepancies were discussed and solved by a panel. Forty patients older than 65 years and 40 therapists were included in the cultural adaptation phase. If more than 15% of therapists or patients reported difficulty in understanding an item, that item was reformulated and reapplied. The final Brazilian version was then tested on 36 elderly patients (over age 65). The average age was 72 years. Reliability of the measure was assessed twice by one physical therapist (1-week interval between assessments) and once by one independent physical therapist. Descriptive analysis was used to characterize the patients. The intraclass correlation coefficient (ICC) and Pearson's correlation coefficient were computed to assess intra- and interobserver reliability. Six questions were modified during the translation stage and cultural adaptation phase. The ICC for intra- and interobserver reliability was 0.99 (P < 0.001) and 0.98 (P < 0.001), respectively. The Pearson correlation coefficient for intra- and interobserver reliability was 0.98 (P < 0.001) and 0.97 (P < 0.001), respectively. We conclude that the Brazilian version of the Berg balance scale is a reliable instrument to be used in balance assessment of elderly Brazilian patients.

Purpose: autoimmunity has been proposed as one of the pathogenesis of abdominal aortic aneurysm (AAA). There is also a likelihood that when aorto-iliac occlusive disease (AIOD) coexists with AAA, some other occlusive atherosclerotic diseases, such as ischemic heart disease and cerebrovascular disease, may develop, leading to a very poor long-term prognosis. Previous studies using serological HLA typing showed that HLA-DR15 was a risk factor for AAA. In this study, we performed HLA-DNA typing by PCR to clarify the relationship between AAA and HLA genotypes in Japanese patients with AAA. In addition, we analyzed whether HLA genotypes are involved in the pathogenesis of AIOD. Results: we examined 78 HLA genotypes of class I (HLA-A and -B) and class II (HLA-DR) and found that 60.4 and 30.4% of 49 AAA patients had HLA-A2 and HLA-B61, respectively. These frequencies were significantly higher than those in control individuals (HLA-A2, p < 0.05; HLA-B61, p < 0.005). We also found that 55.6% of nine AAA patients with AIOD had both HLA-B52 and HLA-DR B1*1502. In contrast, only 10.0% each of 40 AAA patients without AIOD showed HLA-B53 or HLA-DR B1*1502. Conclusions: this study showed that HLA A-2 and HLA B-61, but not HLA DR-15, were important genetic risk factors for the development of AAA among the Japanese population. We also found high frequencies of HLA-B52 and HLA-DR B1*1502 in the AAA patients with AIOD than in those without, although this must be confirmed using a larger number of AAA patients with AIOD.Eur J Vasc Endovasc Surg 26, 215-218 (2003)

The aim of the present study was to examine whether Doppler tissue imaging demonstrated comparable diagnostic performance for the detection of viable myocardium compared to myocardial perfusion imaging with 99m Tc hexakis-2-methoxyisobutylisonitrile (MIBI). We studied 30 patients with old myocardial infarction who underwent percutaneous transluminal coronary angioplasty (PTCA). Myocardial single photon emission computed tomography (SPECT) with 99m Tc-MIBI and two-dimensional echocardiography were carried out within 7 days before PTCA. We measured regional 99m Tc-MIBI uptake for each myocardial segment from SPECT and peak systolic velocity and a ratio of regional pre-ejection period to regional ejection time (PEP/ET) from pulsed Doppler tissue imaging. Biplane left ventriculography was performed before interventional procedures and repeated 3 months after PTCA. Myocardial viability was determined when wall motion was improved at least one grade after PTCA. The peak systolic velocity was positively correlated with regional 99m Tc-MIBI uptake (R =0.59, P

Objectives In this investigation, we report the outcomes of 14 adults (age >18 y) and 9 children (age

Background The Parkinson's Disease Sleep Scale (PDSS)-2 is a recently developed tool for evaluating disease-related nocturnal disturbances in patients with Parkinson's disease (PD). However, its cutoff score has not been clinically assessed. We determined the optimal cutoff score of the Japanese version of the PDSS-2. Methods Patients with PD (n = 146) and controls (n = 100) completed the PDSS-2 and the Pittsburgh Sleep Quality Index (PSQI). Poor sleepers were defined as having global PSQI scores >5. Optimal cutoff scores for determining poor sleepers were assessed using the receiver operating characteristic curve. Results A PDSS-2 total score ≥14 exhibited 82.0% sensitivity and 70.6% specificity, whereas a PDSS-2 total score ≥15 provided 72.1% sensitivity and 72.9% specificity in distinguishing poor sleepers (PSQI score >5) from good sleepers (PSQI ≤5). Nocturnal disturbances were more frequently observed in patients with PD than in controls (PDSS-2 total score ≥14 or ≥15; 51.4% vs 20%; 45.9% vs 19%). Nocturnal disturbances were associated with higher Hoehn and Yahr stages and Unified Parkinson's Disease Rating Scale motor scores, impaired quality of life, daytime sleepiness, and depressive symptoms. Conclusion We suggest that PDSS-2 total scores ≥15 are useful for detecting poor sleepers among patients with PD.

Importance Children who receive a cochlear implant (CI) for early severe to profound sensorineural hearing loss may achieve age-appropriate spoken language skills not possible before implantation. Despite these advances, reduced access to auditory experience may have downstream effects on fundamental neurocognitive processes for some children with CIs. Objective To determine the relative risk (RR) of clinically significant executive functioning deficits in children with CIs compared with children with normal hearing (NH). Design, Setting, and Participants In this prospective, cross-sectional study, 73 children at a hospital-based clinic who received their CIs before 7 years of age and 78 children with NH, with average to above average mean nonverbal IQ scores, were recruited in 2 age groups: preschool age (age range, 3-5 years) and school age (age range, 7-17 years). No children presented with other developmental, cognitive, or neurologic diagnoses. Interventions Parent-reported checklist measures of executive functioning were completed during psychological testing sessions. Main Outcomes and Measures Estimates of the RR of clinically significant deficits in executive functioning (≥1 SDs above the mean) for children with CIs compared with children with NH were obtained based on 2 parent-reported child behavior checklists of everyday problems with executive functioning. Results In most domains of executive functioning, children with CIs were at 2 to 5 times greater risk of clinically significant deficits compared with children with NH. The RRs for preschoolers and school-aged children, respectively, were greatest in the areas of comprehension and conceptual learning (RR [95% CI], 3.56 [1.71-7.43] and 6.25 [2.64-14.77]), factual memory ( 4.88 [1.58-15.07] and 5.47 [2.03-14.77]), attention (3.38 [1.03-11.04] and 3.13 [1.56-6.26]), sequential processing (11.25 [1.55-81.54] and 2.44 [1.24-4.76]), working memory (4.13 [1.30-13.06] and 3.64 [1.61-8.25] for one checklist and 1.77 [0.82-3.83] and 2.78 [1.18-6.51] for another checklist), and novel problem-solving (3.93 [1.50-10.34] and 3.13 [1.46-6.67]). No difference between the CI and NH samples was found for visual-spatial organization (2.63 [0.76-9.03] and 1.04 [0.45-2.40] on one checklist and 2.86 [0.98-8.39] for school-aged children on the other checklist). Conclusions and Relevance A large proportion of children with CIs are at risk for clinically significant deficits across multiple domains of executive functioning, a rate averaging 2 to 5 times that of children with NH for most domains. Screening for risk of executive functioning deficits should be a routine part of the clinical evaluation of all children with deafness and CIs.

Reverse redistribution (RR) of 99mTc-sestamibi is observed after direct percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). The purpose of this study was to clarify the functional characteristics of myocardial segments with RR after direct PTCA in AMI. Thirty patients with AMI who had undergone direct PTCA were examined. Myocardial perfusion tomography with 99mTc-sestamibi and low dose dobutamine echocardiography were performed within 2 weeks of the onset. The 99mTc-sestamibi images were obtained 1 and 3 h after tracer administration. The left ventricle was divided into nine segments, and regional 99mTc-sestamibi uptake and clearance were quantitatively evaluated in each segment. RR was defined as a decrease in 99mTc-sestamibi uptake of >10% on 3 h delayed images compared with the 1 h early images. The left ventricle in the echocardiographic images was also divided into nine segments corresponding to the scintigraphic images, and regional wall motion was assessed in the resting condition as the baseline and during dobutamine administration (5-10 microg x kg(-1) x min(-1)). Out of a total of 270 myocardial segments, 111 segments were perfused by the culprit coronary artery and were defined as ischaemic segments. There were 25 segments with RR and 86 segments without RR in the ischaemic myocardium. Enhanced clearance of 99mTc-sestamibi was observed in ischaemic segments with RR (P

Although cochlear implants improve the ability of profoundly deaf children to understand speech, critics claim that the published literature does not document even a single case of a child who has developed a linguistic system based on input from an implant. Thus, it is of clinical and scientific importance to determine whether cochlear implants facilitate the development of English language skills. The English language skills of prelingually deaf children with cochlear implants were measured before and after implantation. We found that the rate of language development after implantation exceeded that expected from unimplanted deaf children (p < .001) and was similar to that of children with normal hearing. Despite a large amount of individual variability, the best performers in the implanted group seem to be developing an oral linguistic system based largely on auditory input obtained from a cochlear implant.

Among 155 cases of hemifacial spasm (HFS), the authors found two cases of atypical HFS (1.3%) in which spasm started with the orbicularis oris and buccinator muscles, and gradually spread upward to involve the orbicularis occuli muscle, whereas the reverse process is usually seen in cases of typical HFS. The compression site in cases of atypical HFS is the posterior/rostral aspect of the facial nerve (FN), whereas it was the anterior/caudal aspect of the FN in all cases of typical HFS except for one. The meatal loop of the anterior inferior cerebellar artery (AICA) compressed the FN when the vessel passed between the FN and the eighth cranial nerve (8th N). These findings suggest that the topographical organization in the FN in the cerebellopontine cistern may be reversed to a peripheral distribution: the fibres on the posterior/rostral side of the FN innervate the lower part of the facial muscles, and those in the anterior/caudal side of the nerve innervate the upper part of the facial muscles. When examining patients with HFS, we must very carefully determine whether patients have typical or atypical HFS, to determine whether blood vessels (usually the meatal loop of the AICA) between the FN and the 8th N as well as at the root exit zone of the FN are to be decompressed.

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Purpose: To localize the enzyme prolyl 4-hydroxylase in the crystalline lens and determine the ability of lens epithelial cells (LECs) to synthesize procollagen. Setting: Research laboratory, Department of Ophthalmology, Wakayama Medical College, Wakayama, Japan. Methods: Phacoemulsification and aspiration of the crystalline lens followed by implantation of a poly(methyl methacrylate) intraocular lens (IOL) were performed in 1 eye each of 6 albino rabbits; the eye was enucleated 1 or 2 months later. Crystalline lenses were also extracted from the eyes of 2 rabbits. These samples were processed for immunohistochemical detection of the α- and β-subunits of prolyl 4-hydroxylase. Results: A monolayer of LECs was detected on the inner surface of the intact anterior capsule. Antibodies directed against both subunits of prolyl 4-hydroxylase reacted strongly to LECs proliferating on capsules with IOLs, whereas little or no reaction was observed in quiescent LECs or in the regenerated lenticular structure. Conclusion: The presence of prolyl 4-hydroxylase in LECs proliferating on the inner surface of the lens capsule suggests that these cells are involved in the production of procollagen and fibrosis during capsular injury and repair. Suppression of prolyl 4-hydroxylase activity may prevent the capsule opacification that results from cataract removal and IOL implantation.

We report the skull radiograph, CT and MRI findings in three patients with lymphocytic adenohypophysitis mimicking pituitary adenoma. All cases were associated with pregnancy. CT demonstrated a pituitary mass but did not differentiate lymphocytic adenohypophysitis from pituitary adenoma. The skull radiographs showed either a normal sella turcica or minimal abnormalities; they did not show ballooning or destruction. The MRI appearances were distinctive: relatively low signal on T1-weighted images; preservation of the bright posterior pituitary lobe despite the presence of a relatively large pituitary mass, less common in macroadenomas; marked contrast enhancement compared with pituitary macroadenomas; and dural enhancement adjacent to a pituitary mass.

The transmastoid facial recess approach has become the standard technique for cochlear implantation. Although this approach has been used for implantation in patients with common cavity deformities, it is not without increased risk to the facial nerve. Using a direct approach to the common cavity that circumvents the facial recess, we have successfully implanted four patients with common cavity deformities. An aberrant facial nerve in one patient would have precluded placement of the electrode array using standard cochlear implant techniques. As demonstrated in these four patients, the direct approach to the common cavity is an effective approach for placement of the electrode array, minimizes risk to the facial nerve, and may decrease the likelihood of postoperative cerebrospinal fluid leaks. Intraoperative video footage demonstrates the feasibility and facility of this approach in patients with common cavity deformities.

Circulating tumor cells (CTCs) are shed into the bloodstream from primary and metastatic tumor deposits. Their isolation and analysis hold great promise for the early detection of invasive cancer and the management of advanced disease, but technological hurdles have limited their broad clinical utility. We describe an inertial focusing-enhanced microfluidic CTC capture platform, termed "CTC-iChip," that is capable of sorting rare CTCs from whole blood at 10(7) cells/s. Most importantly, the iChip is capable of isolating CTCs using strategies that are either dependent or independent of tumor membrane epitopes, and thus applicable to virtually all cancers. We specifically demonstrate the use of the iChip in an expanded set of both epithelial and nonepithelial cancers including lung, prostate, pancreas, breast, and melanoma. The sorting of CTCs as unfixed cells in solution allows for the application of high-quality clinically standardized morphological and immunohistochemical analyses, as well as RNA-based single-cell molecular characterization. The combination of an unbiased, broadly applicable, high-throughput, and automatable rare cell sorting technology with generally accepted molecular assays and cytology standards will enable the integration of CTC-based diagnostics into the clinical management of cancer.

Background Current experience with carotid body tumors suggesting a high prevalence of associated cervical paragangliomas prompted this review. Patients and methods An 8-year retrospective study of patients with carotid body tumors was undertaken, detailing presentation, diagnosis, and treatment. Results Eleven patients harboring 17 carotid body tumors were discovered. All patients had a neck mass. Seven patients (64%) had bilateral carotid body tumors. Six (55%) reported a positive family history-4 were first-generation relatives, 5 had bilateral tumors, and 3 had other head and neck paragangliomas. Angiography documented 4 associated vagal and 2 glomus jugulare paragangliomas in addition to the carotid body tumors. Precise surgical care limited blood loss to an average of 590 cc. The carotid artery was repaired during 5 resections (29%). Cranial nerve injury occurred in 3 cases, all following vagal body or glomus jugulare resection. Every patient is currently alive, stroke free, and functioning without major disability. Conclusions Patients with carotid body tumors have a propensity for multiple head and neck paragangliomas. Angiography is diagnostic. The need for associated paraganglioma resection dramatically increases the risk of cranial nerve injury.

Cochlear implants (CIs) help many deaf children achieve near-normal speech and language (S/L) milestones. Nevertheless, high levels of unexplained variability in S/L outcomes are limiting factors in improving the effectiveness of CIs in deaf children. The objective of this study was to longitudinally assess the role of verbal short-term memory (STM) and working memory (WM) capacity as a progress-limiting source of variability in S/L outcomes after CI in children.Longitudinal study of 66 children with CIs for prelingual severe-to-profound hearing loss. Outcome measures included performance on digit span forward (DSF), digit span backward (DSB), and four conventional S/L measures that examined spoken-word recognition (Phonetically Balanced Kindergarten word test), receptive vocabulary (Peabody Picture Vocabulary Test ), sentence-recognition skills (Hearing in Noise Test), and receptive and expressive language functioning (Clinical Evaluation of Language Fundamentals Fourth Edition Core Language Score; CELF).Growth curves for DSF and DSB in the CI sample over time were comparable in slope, but consistently lagged in magnitude relative to norms for normal-hearing peers of the same age. For DSF and DSB, 50.5% and 44.0%, respectively, of the CI sample scored more than 1 SD below the normative mean for raw scores across all ages. The first (baseline) DSF score significantly predicted all endpoint scores for the four S/L measures, and DSF slope (growth) over time predicted CELF scores. DSF baseline and slope accounted for an additional 13 to 31% of variance in S/L scores after controlling for conventional predictor variables such as: chronological age at time of testing, age at time of implantation, communication mode (auditory-oral communication versus total communication), and maternal education. Only DSB baseline scores predicted endpoint language scores on Peabody Picture Vocabulary Test and CELF. DSB slopes were not significantly related to any endpoint S/L measures. DSB baseline scores and slopes taken together accounted for an additional 4 to 19% of variance in S/L endpoint measures after controlling for the conventional predictor variables.Verbal STM/WM scores, process measures of information capacity, develop at an average rate in the years after cochlear implantation, but were found to consistently lag in absolute magnitude behind those reported for normal-hearing peers. Baseline verbal STM/WM predicted long-term endpoint S/L outcomes, but verbal STM slopes predicted only endpoint language outcomes. Verbal STM/WM processing skills reflect important underlying core elementary neurocognitive functions and represent potential intervention targets for improving endpoint S/L outcomes in pediatric CI users.

Word-learning skills were tested in normal-hearing 12- to 40-month-olds and in deaf 22- to 40-month-olds 12 to 18 months after cochlear implantation. Using the Intermodal Preferential Looking Paradigm (IPLP), children were tested for their ability to learn two novel-word/novel-object pairings. Normal-hearing children demonstrated learning on this task at approximately 18 months of age and older. For deaf children, performance on this task was significantly correlated with early auditory experience: Children whose cochlear implants were switched on by 14 months of age or who had relatively more hearing before implantation demonstrated learning in this task, but later implanted profoundly deaf children did not. Performance on this task also correlated with later measures of vocabulary size. Taken together, these findings suggest that early auditory experience facilitates word learning and that the IPLP may be useful for identifying children who may be at high risk for poor vocabulary development.

Background: Accounting for outcome variability among pediatric cochlear implant (CI) recipients is an enduring clinical challenge. Short-term memory and working memory (STM/WM), as indexed by digit span forward (DSF) and digit span backward (DSB), have been shown to be strongly correlated with speech and language (S/L) outcomes. The enormous variability observed in conventional outcome measures of S/L may reflect individual differences in STM/WM. Methods: Repeated measure auditory digit spans were obtained from 110 children (age 3–15 years; mean 7.2 years) with at least 2 years of CI use. Growth curves were computed for each child, and linear functions were fit to both DSF and DSB. Slopes and intercepts were used as parameters in mixed-models to assess relations between STM/WM capacity change over time and S/L outcome measures including vocabulary (PPVT), open-set set spoken word recognition (PBK), and sentence perception (HINT-C). Results: For DSF, the percent of the sample more than 1 SD below the norm at each age ranged from 54 to 90% (mean = 66.5%). For DSB, the percent of the sample more than 1 SD below the norm at each age ranged from 23 to 42% (mean = 34.5%) at ages where there were at least five children. Four subgroups within our CI sample emerged: (Subgroup 1) children demonstrating age-appropriate growth in both DSF and DSB scores over time (49/110, 44.55%); (Subgroup 2) children demonstrating age appropriate growth in DSF over time but below average growth in DSB over time (23/110, 20.91%); (Subgroup 3) children demonstrating below average growth in DSF over time but age-appropriate growth in DSB over time (19/110, 17.27%); and (Subgroup 4) children demonstrating below average growth in both DSF and DSB over time (19/110, 17.27%). For all tests except CELF-3, Subgroup 4 demonstrated the poorest performance among the four DS slope subgroups. Significant differences were observed between Subgroup 1 and Subgroup 4 on last visit PBK-Word (P = 0.029), PPVT (P = 0.018), and HINT-C in Quiet (P = 0.001), but not CELF-3 (P = 0.433). Conclusion: The findings from this longitudinal study suggest that differences in the rate of development of STM/WM may influence S/L outcomes in children with CIs. The clinical implications of these findings are significant because they indicate that the rate of development of STM/WM, and not just the actual level of STM/WM at a single time point, predicts later S/L development in this clinical population. Targeted interventions to improve developmental rate of verbal STM/WM may hold promise for enhancing S/L skills in children with CIs.

BACKGROUND AND PURPOSE: Neurological manifestations, such as benign convulsions and encephalitis/encephalopathy have been reported in patients with rotavirus gastroenteritis. However, cerebellitis has not attracted much attention. The purpose of this study was to identify and report the clinical and radiologic features of rotavirus cerebellitis. MATERIALS AND METHODS: Records of patients with rotavirus gastroenteritis exhibiting cerebellar lesions on MR imaging were collected from multiple centers in Japan. Their clinical, laboratory, and radiologic data were reviewed retrospectively. RESULTS: A diagnosis of acute cerebellitis concurrent with encephalitis was made for 11 of 13 patients identified. Two patients who were diagnosed as having injury due to hypovolemic shock were excluded from the study. All 11 patients with acute cerebellitis had disorders of consciousness with onset on days 2 to 4, followed by mutism in 10 patients. Other cerebellar symptoms included dysarthria following the mutism, hypotonia, ataxia, tremor, nystagmus, and dysmetria. MR imaging lesions in the vermis or cerebellar cortex were seen at some point (day 5 to 1 year) in 10 patients. A reversible splenial lesion (3 isolated and 3 with concurrent cerebellar lesions) was found in 6 patients scanned between days 4 and 6. Transient lesions in the cerebellar white matter/nuclei manifesting reduced diffusion were seen in 6 patients during days 5 through 7. The final MR imaging performed after 1 month showed cerebellar atrophy in 10 patients. CONCLUSIONS: The 11 patients with rotavirus cerebellitis exhibited nearly identical clinical and MR imaging features. Involvement of the cerebellar white matter/nuclei may be associated with the mutism. An isolated splenial lesion with homogeneously reduced diffusion is not always a benign sign indicative of complete clinical and radiologic recovery in patients with rotavirus gastroenteritis.

Rare circulating tumor cells (CTCs) are present in the blood of patients with metastatic epithelial cancers but have been difficult to measure routinely. We report a quantitative automated imaging system for analysis of prostate CTCs, taking advantage of prostate-specific antigen (PSA), a unique prostate tumor–associated marker. The specificity of PSA staining enabled optimization of criteria for baseline image intensity, morphometric measurements, and integration of multiple signals in a three-dimensional microfluidic device. In a pilot analysis, we detected CTCs in prostate cancer patients with localized disease, before surgical tumor removal in 8 of 19 (42%) patients (range, 38 to 222 CTCs per milliliter). For 6 of the 8 patients with preoperative CTCs, a precipitous postoperative decline (

Purpose: Cochlear implantation has recently become available as an intervention strategy for young children with profound hearing impairment. In fact, infants as young as 6 months are now receiving cochlear implants (CIs), and even younger infants are being fitted with hearing aids (HAs). Because early audiovisual experience may be important for normal development of speech perception, it is important to investigate the effects of a period of auditory deprivation and amplification type on multimodal perceptual processes of infants and children. The purpose of this study was to investigate audiovisual perception skills in normal-hearing (NH) infants and children and deaf infants and children with CIs and HAs of similar chronological ages. Methods: We used an Intermodal Preferential Looking Paradigm to present the same woman's face articulating two words ("judge" and "back") in temporal synchrony on two sides of a TV monitor, along with an auditory presentation of one of the words. Results: The results showed that NH infants and children spontaneously matched auditory and visual information in spoken words; deaf infants and children with HAs did not integrate the audiovisual information; and deaf infants and children with CIs initially did not initially integrate the audiovisual information but gradually matched the auditory and visual information in spoken words. Conclusions: These results suggest that a period of auditory deprivation affects multimodal perceptual processes that may begin to develop normally after several months of auditory experience.

The present results demonstrated that all 3 factors --lexical difficulty, stimulus variability, and word length--significantly influenced spoken word recognition by children with multichannel cochlear implants. Lexically easy words were recognized significantly better than lexically hard words, regardless of talker condition or word length of the stimuli. These results support the earlier findings of Kirk et al(12) obtained with live-voice stimulus presentation and suggest that lexical effects are very robust. Despite the fact that listeners with cochlear implants receive a degraded speech signal, it appears that they organize and access words from memory relationally in the context of other words. The present results concerning talker variability contradict those previously reported in the literature for listeners with normal hearing(7,11) and for listeners with mild-to-moderate hearing loss who use hearing aids.(14) The previous investigators used talkers and word lists different from those used in the current study and found that word recognition declined as talker variability increased. In the current study, word recognition was better in the multiple-talker condition than in the single-talker condition. Kirk(15) reported similar results for postlingually deafened adults with cochlear implants who were tested on the recorded word lists used in the present study. Although the talkers were equally intelligible to listeners with normal hearing in the pilot study, they were not equally intelligible to children or adults with cochlear implants. It appears that either the man in the single-talker condition was particularly difficult to understand or that some of the talkers in the multiple-talker condition were particularly easy to understand. Despite the unexpected direction of the talker effects, the present results demonstrate that children with cochlear implants are sensitive to differences among talkers and that talker characteristics influence their spoken word recognition. We are conducting a study to assess the intelligibility of each of the 6 talkers to listeners with cochlear implants. Such studies should aid the development of equivalent testing conditions for listeners with cochlear implants. There are 2 possible reasons the children in the present study identified multisyllabic words better than monosyllabic words. First, they may use the linguistic redundancy cues in multisyllabic words to aid in spoken word recognition. Second, multisyllabic words come from relatively sparse lexical neighborhoods compared with monosyllabic tokens. That is, multisyllabic words have fewer phonetically similar words, or neighbors, competing for selection than do monosyllabic stimuli. These lexical characteristics most likely contribute to the differences in identification noted as a function of word length. The significant lexical and word length effects noted here may yield important diagnostic information about spoken word recognition by children with sensory aids. For example, children who can make relatively fine phonetic distinctions should demonstrate only small differences in the recognition of lexically easy versus hard words or of monosyllabic versus multisyllabic stimuli. In contrast, children who process speech using broad phonetic categories should show much larger differences. That is, they may not be able to accurately encode words in general or lexically hard words specifically. Further study is warranted to determine the interaction between spoken word recognition and individual word encoding strategies.

Randomized trials of chemoradiation for esophageal cancer have included very few patients ageor = 75. In this retrospective study, we describe the outcomes and toxicity of full-dose chemoradiation in elderly patients with esophageal cancer. Patients, ageor = 75, treated with full-dose chemoradiation for esophageal carcinoma from 2002 to 2008 were retrospectively reviewed. Thirty-four patients were identified with a median age of 79.5 (range 75-89). The median Eastern Cooperative Oncology Group performance status was 1 (range 0-3) and the median Adult Comorbidity Evaluation-27 score was 1 (range 0-3). Twenty-eight patients received definitive and six received neoadjuvant chemoradiation. The median radiation dose delivered was 50.4 Gray (range 3.6-68.4 Gray). Platinum-based chemotherapy was used in 79.4% of patients. Fifty percent of the patients completed all planned radiation therapy (RT) and chemotherapy; 85.3% completed RT. Acute toxicityor = grade 4 occurred in 38.2% of patients, and 70.6% of the patients required hospitalization, emergency department visit, and/or RT break. Median follow-up was 14.5 months among 7 survivors, and median survival was 12.0 months (95% confidence interval [CI]: 9.7 to 24.1 months). The actuarial overall survival at 2 years was 29.7% (95% CI: 16.6 to 52.6%). There were four treatment-related deaths. The median time to any recurrence was 10.4 months. Nineteen patients had a local and/or distant recurrence. In conclusion, elderly patients experienced substantial morbidity from chemoradiation, and long-term survival was low. Future efforts to improve treatment tolerability in the elderly are needed.

BACKGROUND The proximal acceleration flow region is a laminar flow field that is located immediately upstream from the leaking orifice. The purpose of this study was to evaluate whether cinemagnetic resonance imaging can provide information regarding the proximal acceleration flow region in patients with aortic regurgitation and to analyze the relation between the area of the proximal acceleration flow delineated by cinemagnetic resonance imaging and the severity of aortic regurgitation delineated by angiography. METHODS AND RESULTS Thirty-eight consecutive patients who underwent aortography were examined by cinemagnetic resonance imaging. The region of proximal flow acceleration was identified as a semicircular-shaped signal void in the aorta during diastole. Cinemagnetic resonance imaging detected the proximal acceleration flow region in 26 of the 30 patients who were proved to have this lesion (sensitivity, 87%). In eight patients without aortic regurgitation according to aortography, no proximal acceleration flow region was detected (specificity, 100%). The area of the acceleration flow signal void from the long-axis view was well correlated with angiographic degree of aortic regurgitation. CONCLUSIONS Cinemagnetic resonance imaging is useful in detecting the proximal acceleration flow region and permits noninvasive assessment of the severity of aortic regurgitation.