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Background: Cefazolin is the preferred antimicrobial for prevention of surgical-site infections in most procedures at our institution. Our first alternative is vancomycin which is associated with higher adverse events and infection rates. The presence of penicillin allergies can influence prescribing of vancomycin despite a low risk of cross-reactivity between penicillin and cephalosporins. Nebraska Medicine implemented a systemwide change in April 2022 that suppressed alerts for non–IgE-mediated penicillin allergies in the electronic medical record (EMR, Epic Systems) upon cephalosporin prescribing. We evaluated changes in perioperative antimicrobial surgical infection prophylaxis after this change. Methods: We conducted a quasi-experimental study of all patients undergoing procedures for which cefazolin is considered preferred per institutional guidance. Preintervention data were from April 1, 2021, to March 31, 2022, and postintervention data included patients from April 11, 2022, to October 31, 2022, after guidance was distributed to surgeons, operating room staff, and pharmacists. Patients were excluded if they were aged

In 2018, a clinical decision support (CDS) tool was implemented as part of a “daily checklist” for frontline pharmacists to review patients on antibiotics with procalcitonin (PCT) p = 0.0156). The LOS was similar in both groups (median 6.4 days vs. 7 days, p = 0.81). In conclusion, interventions driven by a CDS tool for pharmacist-driven antimicrobial stewardship in patients with a normal PCT resulted in fewer DOT and significantly higher rates of vancomycin discontinuation.

Going beyond author, title, subject and notes, there are many new (or newly-revitalized) fields and subfields in the MARC 21 format that support more structured data and could be beneficial to users if exposed in a discovery interface. In this article, we describe how the Orbis Cascade Alliance has implemented display, search and faceting for several of these fields and subfields in our Primo discovery interface. We discuss problems and challenges we encountered, both Primo-specific and those that would apply in any search interface.

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Intercountry adoption (ICA) is a relatively common practice. Since its contemporary conception during the Second World War, approximately one million children have been adopted internationally. Controversy surrounding ICA includes ideas about human rights and notions of child rescue in the context of major reform to prevent child sales and abduction under the Hague Convention on Intercountry Adoption. Social work, as a discipline, is a central player in ICA practices, and at least, one historian asserts that social work academic literature is scant on the topic of problematic practice and reforms. A review of the social work literature was conducted, and four thematic areas emerged in the 87 manuscripts reviewed: (a) social policy; (b) exploitation, social justice, ethics, and human rights; (c) clinical perspectives to include identity, child development, and family transition; and (d) child welfare practices. Results indicate a small but robust body of social work literature, and highlights are presented as well as analysis indicating methodical trends.

On the Code4Lib Journal, technology, and the universe of library cataloging and metadata.

The library metadata community is dealing with the challenge of implementing the conceptual model, Functional Requirements for Bibliographic Records (FRBR). In response, the Online Audiovisual Catalogers (OLAC) created a task force to study the issues related to creating and using FRBR-based work-level records for moving images. This article presents one part of the task force's work: it looks at the feasibility of creating provisional FRBR work-level records for moving images by extracting data from existing manifestation-level bibliographic records. Using a sample of 941 MARC records, a subgroup of the task force conducted a pilot project to look at five characteristics of moving image works. Here they discuss their methodology; analysis; selected results for two elements, original date (year) and director name; and conclude with some suggested changes to MARC coding and current cataloging policy.

Facet-based interfaces demonstrate some limitations of Library of Congress Subject Headings (LCSH), which were designed to deal with constraints that do not exist in the current computerized environment. This paper discusses some challenges for using LCSH for faceted browsing and navigation in library catalogs. Ideas are provided for improving results through system design, changes to LCSH practice, and LCSH structure.

Purpose: With DCIS incidence on the rise, up to 30% of patients undergo mastectomy for Ductal carcinoma in situ (DCIS) (Nash and Hwang, in: Ann Surg Oncol 30(6):3206-3214, 2023). Local recurrence rates after mastectomy for DCIS are reportedly low, but risk factors for recurrence are not known (Kim et al., in: J Cancer Res Ther 16(6):1197-1202, 2020). We aim to define risk factors associated with ipsilateral breast cancer recurrence in patients undergoing mastectomy for DCIS., Methods: We aimed to identify risk factors that may contribute to recurrence of breast cancer following mastectomy for pure DCIS. We hypothesized that close or positive mastectomy margins, age at diagnosis, extent of breast disease and mutation carriers would be associated with increased risk of recurrence. We performed a retrospective chart review of patients who underwent unilateral or bilateral mastectomies for pure DCIS at a single academic tertiary referral center from 2013 to 2023., Results: There were 165 patients who met inclusion criteria with an average length of follow-up of 39.9 months. On final surgical pathology, the average span of DCIS was 33.7 mm (± 24.6 mm). Hormone receptor positive disease was identified in 80.6% of the patient cohort. For margin status, 23 patients (14%) had < 1 mm margins on final pathology and of those, 1 received adjuvant radiation therapy and 4 returned to the OR for re-excision. Only 1 (0.6%) patient had ipsilateral disease recurrence during the study period., Conclusion: Recurrence after mastectomy for pure DCIS is a rare event and in our study sample, only one recurrence occurred. Risk factors for recurrence appear unrelated to margin status, age, extent of DCIS, or pathogenic mutation (ElSherif et al., in Am J Surg 226(5):646-651, 2023)., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Given an orthographic transcription, forced alignment systems automatically determine boundaries between segments in speech, facilitating the use of large corpora. In the present paper, we introduce a neural network-based forced alignment system, the Mason-Alberta Phonetic Segmenter (MAPS). MAPS serves as a testbed for two possible improvements we pursue for forced alignment systems. The first is treating the acoustic model as a tagger, rather than a classifier, motivated by the common understanding that segments are not truly discrete and often overlap. The second is an interpolation technique to allow more precise boundaries than the typical 10 ms limit in modern systems. During testing, all system configurations we trained significantly outperformed the state-of-the-art Montreal Forced Aligner in the 10 ms boundary placement tolerance threshold. The greatest difference achieved was a 28.13 % relative performance increase. The Montreal Forced Aligner began to slightly outperform our models at around a 30 ms tolerance. We also reflect on the training process for acoustic modeling in forced alignment, highlighting how the output targets for these models do not match phoneticians' conception of similarity between phones and that reconciling this tension may require rethinking the task and output targets or how speech itself should be segmented., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

While known to influence visual lexical processing, the semantic information we associate with words has recently been found to influence auditory lexical processing as well. The present work explored the influence of semantic richness in auditory lexical decision. Study 1 recreated an experiment investigating semantic richness effects in concrete nouns (Goh et al., 2016). In Study 2, we expanded the stimulus set from 442 to 8,626 items, exploring the robustness of effects observed in Study 1 against a larger data set with increased diversity in both word class and other characteristics of interest. We also utilized generalized additive mixed models to investigate potential nonlinear effects. Results indicate that semantic richness effects become more nuanced and detectable when a wider set of items belonging to different parts of speech is examined. Findings are discussed in the context of models of spoken word recognition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: Unnecessary axillary surgery can potentially be avoided in patients with DCIS undergoing mastectomy. Current guidelines recommend upfront sentinel lymph node biopsy during the index operation due to the potential of upstaging to invasive cancer. This study reviews a single institution's experience with de-escalating axillary surgery using superparamagnetic iron oxide dye for axillary mapping in patients undergoing mastectomy for DCIS., Methods: This is a retrospective single-institution cross-sectional study. All medical records of patients who underwent mastectomy for a diagnosis of DCIS from August 2021 to January 2023 were reviewed and patients who had SPIO injected at the time of the index mastectomy were included in the study. Descriptive statistics of demographics, clinical information, pathology results, and interval sentinel lymph node biopsy were performed., Results: A total of 41 participants underwent 45 mastectomies for DCIS. The median age of the participants was 58 years (IQR = 17; range 25 to 76 years), and the majority of participants were female (97.8%). The most common indication for mastectomy was diffuse extent of disease (31.7%). On final pathology, 75.6% (34/45) of mastectomy specimens had DCIS without any type of invasion and 15.6% (7/45) had invasive cancer. Of the 7 cases with upgrade to invasive disease, 2 (28.6%) of them underwent interval sentinel lymph node biopsy. All sentinel lymph nodes biopsied were negative for cancer., Conclusion: The use of superparamagnetic iron oxide dye can prevent unnecessary axillary surgery in patients with DCIS undergoing mastectomy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study constitutes an investigation into the acoustic variability of intervocalic alveolar taps in a corpus of spontaneous speech from Madrid, Spain. Substantial variability was documented in this segment, with highly reduced variants constituting roughly half of all tokens during spectrographic inspection. In addition to qualitative documentation, the intensity difference between the tap and surrounding vowels was measured. Changes in this intensity difference were statistically modeled using Bayesian finite mixture models containing lexical and phonetic predictors. Model comparisons indicate predictive performance is improved when we assume two latent categories, interpreted as two pronunciation variants for the Spanish tap. In interpreting the model, predictors were more often related to categorical changes in which pronunciation variant was produced than to gradient intensity changes within each tap type. Variability in tap production was found according to lexical frequency, speech rate, and phonetic environment. These results underscore the importance of evaluating model fit to the data as well as what researchers modeling phonetic variability can gain in moving past linear models when they do not adequately fit the observed data., (© 2024 Acoustical Society of America.)

Using phonological neighborhood density has been a common method to quantify lexical competition. It is useful and convenient but has shortcomings that are worth reconsidering. The present study quantifies the effects of lexical competition during spoken word recognition using acoustic distance and acoustic absement rather than phonological neighborhood density. The indication of a word's lexical competition is given by what is termed to be its acoustic distinctiveness, which is taken as its average acoustic absement to all words in the lexicon. A variety of acoustic representations for items in the lexicon are analyzed. Statistical modeling shows that acoustic distinctiveness has a similar effect trend as that of phonological neighborhood density. Additionally, acoustic distinctiveness consistently increases model fitness more than phonological neighborhood density regardless of which kind of acoustic representation is used. However, acoustic distinctiveness does not seem to explain all of the same things as phonological neighborhood density. The different areas that these two predictors explain are discussed in addition to the potential theoretical implications of the usefulness of acoustic distinctiveness in the models. The present paper concludes with some reasons why a researcher may want to use acoustic distinctiveness over phonological neighborhood density in future experiments.

Background: Pregnant and postpartum women in high HIV prevalent regions are at increased HIV risk. Oral pre-exposure prophylaxis (PrEP) can decrease HIV incidence reducing infant HIV infections. Understanding healthcare worker (HCW) beliefs about PrEP prior to national roll-out is critical to supporting PrEP scale-up. Methods: We conducted 45 semi-structured interviews among a range of HCW cadres with and without PrEP provision experience purposively recruited from four clinics in Kenya to compare their views on prescribing PrEP during pregnancy and postpartum. Interviews were analysed using a conventional content analysis approach to identify key influences on PrEP acceptability and feasibility. Results: All HCWs perceived PrEP as an acceptable and feasible HIV prevention strategy for pregnant and postpartum women. They believed PrEP meets women's needs as an on-demand, female-controlled prevention strategy that empowers women to take control of their HIV risk. HCWs highlighted their role in PrEP delivery success while acknowledging how their knowledge gaps, concerns and perceived PrEP implementation challenges may hinder optimal PrEP delivery. Conclusion: HCWs supported PrEP provision to pregnant and postpartum women. However, counseling tools to address risk perceptions in this population and strategies to reduce HCW knowledge gaps, concerns and perceived implementation barriers are required.

Implementation research ethics can be particularly challenging when pregnant women have been excluded from earlier clinical stages of research given greater uncertainty about safety and efficacy in pregnancy. The evaluation of human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) during pregnancy offered an opportunity to understand important ethical considerations and social influences shaping women's decisions to participate in the evaluation of PrEP and investigational drugs during pregnancy. We conducted interviews with women ( n  = 51), focus groups with male partners (five focus group discussions [FGDs]), interviews with health providers ( n  = 45), four FGDs with pregnant/postpartum adolescents and four FGDs with young women. Data were analyzed using thematic content analysis, including ethical aspects of the data. Our study reveals that women navigate a complex network of social influences, expectations, support, and gender roles, not only with male partners, but also with clinicians, family, and friends when making decisions about PrEP or other drugs that lack complete safety data during pregnancy.

Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging., Background: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low., Methods: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen., Results: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm2; in US true-positive nodes, it was 6.8 mm2. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy., Conclusion: In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy., Competing Interests: The authors report no conflicts of interest, (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN , and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy., Experimental Design: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein-phosphoprotein changes, were analyzed., Results: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAF V600WT tumors responded to KRT-232 treatment alone while BRAF V600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors., Conclusions: KRT-232 is an effective therapy for the treatment of either BRAF WT or PAN WT (BRAF WT , NRAS WT ) TP53 WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAF V600 -mutant tumors., (©2020 American Association for Cancer Research.)

New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity was characterized in breast cancer (BC) and pancreatic cancer (PC) patient-derived organoids. Baseline heterogeneity was analyzed for each patient, demonstrating that single-cell techniques, such as OMI, are required to capture the complete picture of heterogeneity present in a sample. Treatment-induced changes in heterogeneity were also analyzed, further demonstrating that these measurements greatly complement current techniques that only gauge average cellular response. Finally, OMI of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response for the first time. Organoids were treated with the same drugs as the patient's prescribed regimen, and OMI measurements of heterogeneity were compared to patient outcome. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual patients, and to develop new effective therapies that address cellular heterogeneity in cancer., (Copyright © 2020 Sharick, Walsh, Sprackling, Pasch, Pham, Esbona, Choudhary, Garcia-Valera, Burkard, McGregor, Matkowskyj, Parikh, Meszoely, Kelley, Tsai, Deming and Skala.)

Multiple measures of vowel overlap have been proposed that use F1, F2, and duration to calculate the degree of overlap between vowel categories. The present study assesses four of these measures: the spectral overlap assessment metric [SOAM; Wassink (2006). J. Acoust. Soc. Am. 119(4), 2334-2350], the a posteriori probability (APP)-based metric [Morrison (2008). J. Acoust. Soc. Am. 123(1), 37-40], the vowel overlap analysis with convex hulls method [VOACH; Haynes and Taylor, (2014). J. Acoust. Soc. Am. 136(2), 883-891], and the Pillai score as first used for vowel overlap by Hay, Warren, and Drager [(2006). J. Phonetics 34(4), 458-484]. Summaries of the measures are presented, and theoretical critiques of them are performed, concluding that the APP-based metric and Pillai score are theoretically preferable to SOAM and VOACH. The measures are empirically assessed using accuracy and precision criteria with Monte Carlo simulations. The Pillai score demonstrates the best overall performance in these tests. The potential applications of vowel overlap measures to research scenarios are discussed, including comparisons of vowel productions between different social groups, as well as acoustic investigations into vowel formant trajectories.

The Massive Auditory Lexical Decision (MALD) database is an end-to-end, freely available auditory and production data set for speech and psycholinguistic research, providing time-aligned stimulus recordings for 26,793 words and 9592 pseudowords, and response data for 227,179 auditory lexical decisions from 231 unique monolingual English listeners. In addition to the experimental data, we provide many precompiled listener- and item-level descriptor variables. This data set makes it easy to explore responses, build and test theories, and compare a wide range of models. We present summary statistics and analyses.

Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types., (©2018 American Association for Cancer Research.)

To optimize scale-up of pre-exposure prophylaxis (PrEP) for pregnant women at risk of HIV in high HIV burden settings, implementation strategies must be developed that account for perceptions of PrEP in this unique population. Semistructured focus group discussions were conducted with 68 HIV-uninfected Kenyan pregnant and postpartum women without prior PrEP knowledge or experience. A qualitative descriptive analysis was performed, using a constant comparison approach, to identify key themes related to the values and rationale impacting potential PrEP use in pregnancy. Median age was 19.5 years and participants were either pregnant or had 1-2 children. Almost all (96%) were married or had a steady partner. Women felt pregnancy was a time of high HIV risk because they desired sex less frequently, which may lead their partners to have outside partnerships. This made PrEP an attractive HIV prevention option for themselves and their infants. Although women believed male partner behaviors influenced their HIV risk, many women perceived that male partners would react negatively, including becoming physically violent, if they discovered that women used PrEP. Clinicians were identified as potential facilitators of PrEP use who could explain PrEP to male partners on behalf of pregnant women. Women said that community-level stigma against HIV and potential for conflating PrEP with antiretroviral therapy (ART) would necessitate that PrEP use be discreet. Our results indicate the importance of addressing risk perception of women, concerns of male partners, HIV stigma, and benefits of PrEP for HIV prevention as programs are developed for pregnant women.

Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF V600mut melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single-cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin-expressing melanoma cells. Melanoma cell subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100β+ melanoma cells. This quantitative single-cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The exclusion of pregnant women from health research remains a significant challenge globally. In settings where cultural traditions and gender norms support a more restricted decision-making role for women in general, little is known about the attitudes of male partners toward the inclusion of women in research during pregnancy. Understanding the expectations of both men and women in such cultural settings offers an opportunity to engage and address local ethical concerns to improve women's access to research during pregnancy and enhance intervention development. In this paper, we present a qualitative research ethics case study, drawn from the Partners Demonstration Project of pre-exposure prophylaxis (PrEP) in Kenya, regarding the role of male partners in decision-making to continue PrEP during pregnancy. PrEP is an effective HIV prevention tool; however, since pregnant women were excluded from early PrEP clinical trials, safety and efficacy data during pregnancy are limited. Given continued high rates of HIV infection for women, some pregnant women are now being provided with PrEP or are involved in PrEP research. Men and women in our study were equally concerned about the health risks of PrEP to the fetus and depended on healthcare provider guidance to understand these risks. Because the demonstration project enrolled couples, an implicit social expectation for many women's continuation of PrEP during pregnancy was consultation with male partners. Some women reported that consenting to participate was exclusively a woman's decision; however, many reported that they deferred to their male partner's opinion and support during the decision-making process. Most male partners believed women should not participate in research studies without their partner's permission, while a few men believed participation was ultimately a woman's decision. We suggest that relational autonomy can support a middle ground for informed consent that promotes women's autonomy while accommodating partner engagement.

Background: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma., Methods: After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156)., Results: Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival., Discussion: In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

Treatment of advanced BRAF V600 -mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c + immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations. Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell-inflamed, stromal adaptations, many of which are tumor cell-driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248-65. ©2017 AACR. See related commentary by Haq, p. 1216 This article is highlighted in the In This Issue feature, p. 1201 ., (©2017 American Association for Cancer Research.)

Objectives: The perceptions, motivations, and beliefs of HIV-uninfected women about pre-exposure prophylaxis (PrEP) use during pregnancy can influence its uptake and adherence. This study elicited the views of HIV-uninfected women with personal experience taking PrEP during pregnancy., Design: Qualitative interviews were conducted with HIV-uninfected women who had personal experience taking PrEP while pregnant., Methods: Semistructured interviews were conducted with 21 HIV-uninfected Kenyan women in HIV-serodiscordant couples enrolled in an open-label PrEP demonstration project who became pregnant while using PrEP and continued PrEP through their pregnancy. Interviews were audio-recorded and transcribed into English. A qualitative descriptive analysis was performed, using a constant comparison approach to identify key themes related to PrEP use in pregnancy., Results: Desire to remain HIV uninfected and have an HIV-free infant were strong motivators influencing continued use of PrEP during pregnancy. Supporting HIV-infected partners and childbearing within an HIV-serodiscordant relationship were also motivators. Women had challenges distinguishing normal pregnancy symptoms from PrEP side effects and were concerned that observed side effects could be signs of danger for the infant related to PrEP exposure. Health care providers were important conduits of knowledge about PrEP, and continuity of PrEP providers throughout pregnancy facilitated adherence., Conclusions: HIV-uninfected women in HIV-serodiscordant couples were motivated to use PrEP during pregnancy to remain HIV uninfected and to have an HIV-free child but had concerns about side effects. Health care providers will be important for PrEP messaging and adherence support in this unique population.

Breast conserving surgery is the preferred treatment for women diagnosed with early stage invasive breast cancer. To ensure successful breast conserving surgeries, efficient tumour margin resection is required for minimizing tumour recurrence. Currently surgeons rely on touch preparation cytology or frozen section analysis to assess tumour margin status intraoperatively. These techniques have suboptimal accuracy and are time-consuming. Tumour margin status is eventually confirmed using postoperative histopathology that takes several days. Thus, there is a need for a real-time, accurate, automated guidance tool that can be used during tumour resection intraoperatively to assure complete tumour removal in a single procedure. In this paper, we evaluate feasibility of a 3-dimensional scanner that relies on Raman Spectroscopy to assess the entire margins of a resected specimen within clinically feasible time. We initially tested this device on a phantom sample that simulated positive tumour margins. This device first scans the margins of the sample and then depicts the margin status in relation to an automatically reconstructed image of the phantom sample. The device was further investigated on breast tissues excised from prophylactic mastectomy specimens. Our findings demonstrate immense potential of this device for automated breast tumour margin assessment to minimise repeat invasive surgeries.

Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations., (Copyright © 2017. Published by Elsevier B.V.)

We use recent research to provide an explanation of how animals might detect earthquakes before they occur. While the intrinsic value of such warnings is immense, we show that the complexity of the process may result in inconsistent responses of animals to the possible precursor signal. Using the results of our research, we describe a logical but complex sequence of geophysical events triggered by precursor earthquake crustal movements that ultimately result in a sound signal detectable by animals. The sound heard by animals occurs only when metal or other surfaces (glass) respond to vibrations produced by electric currents induced by distortions of the earth's electric fields caused by the crustal movements. A combination of existing measurement systems combined with more careful monitoring of animal response could nevertheless be of value, particularly in remote locations., Competing Interests: The authors declare no conflict of interest.

Purpose: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity. Experimental Design: The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ -null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and PI3Kγ null versus PI3Kγ WT mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice. Results: Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of PI3Kγ in the host. The antitumor effect of PI3Kγ loss in host, but not tumor, was partially reversed by CD8 + T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone. Conclusions: PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. Clin Cancer Res; 23(13); 3371-84. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear., Methods: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis., Results: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group., Conclusions: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

Background: Orphans and vulnerable children (OVCs) represent a significant population worldwide, enduring poor health and living conditions. Evidence-based interventions are needed. However, without parents, ethical concerns about including OVCs in research persist. The aim of our study was to better understand the ethical challenges facing researchers who work with OVCs., Methods: We conducted semi-structured interviews with 12 international pediatric researchers working with OVCs in seven countries. We used descriptive content analysis to characterize the ethical rationale for inclusion and associated challenges., Results: Researchers believed research was justified as a necessary means for informing evidence-based interventions to benefit OVCs directly or as a population. Ethical challenges included difficulty identifying OVCs given variation among children living without parents; difficulty identifying guardians among a range of caregivers; concerns about meaningfulness of guardian consent; difficulty assessing risk; and responding to children's many needs., Conclusions: A range of caregivers bear responsibility to protect OVC's interests in place of parents in research but are often not prepared to do so. This places greater burden on researchers to assess risks and respond to children's needs. Findings suggest that we should improve support and rethink the roles of guardians, researchers and older children in research participation and protection., (© The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.

Therapies targeting the mitogen-activated protein kinase signaling pathway can induce profound tumor regression in patients with advanced BRAF-mutated melanoma. Most patients develop resistance after several months of treatment, which is typically followed by rapid disease progression and death. BRAF- and mitogen-activated protein kinase kinase (MEK)-targeted therapies were initially thought to exert their therapeutic effects through direct inhibition of signaling within the tumor cell, resulting in cell death. Recent evidence suggests that BRAF-targeted therapy also augments the host immune response to melanoma. This is characterized by enhanced expression of melanoma differentiation antigens, reduced levels of immunosuppressive cytokines in the micro environment, and a CD8 T-cell response and T-cell-mediated cytotoxicity. These changes are noted within days of starting therapy, correlate with tumor response, reverse with resistance, and occur in metastatic and advanced, operable disease. Enhanced PDL-1 expression by melanoma cells and increased markers of immune exhaustion, including PD-1 and TIM-1, have been identified, suggesting that the immune response is down-modulated before resistance occurs. These findings indicate that BRAF- and MEK-targeted therapies have multiple, complex, and interrelated mechanisms of action and validate the investigation of combination treatment strategies with targeted therapy and immune checkpoint inhibitors, as well as other therapies that modulate the immune microenvironment. They also lend support for clinical trials investigating preoperative and adjuvant BRAF-targeted therapy for high-risk, BRAF-mutated melanoma. Together, these studies will enhance our understanding of the mechanism of action of BRAF-targeted therapies and may identify additional opportunities to improve the outcome of patients with advanced melanoma.

Purpose: Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression., Experimental Design: We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models., Results: We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody., Conclusions: These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment., (©2015 American Association for Cancer Research.)

Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

Background: We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance., Study Design: Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains., Results: Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition., Conclusions: Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies., (Copyright © 2015. Published by Elsevier Inc.)