AGI-134: a fully synthetic alpha-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

Background: Treatments that generate T cell-mediated immunity to a patient\u27s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) in situ leading to opsonization with pre-existing natural anti-alpha-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods: Various immunological effects of coating tumor cells with alpha-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (alpha1,3GT(-/-)) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel-Cox test, C5a data by Mann-Whitney test, and single tumor regression by repeated measures analysis. Results: In vitro, alpha-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8alpha+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in alpha1,3GT(-/-) mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. Conclusions: We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment

Efficacy of Intraoperative Recurrent Laryngeal Nerve Monitoring: A Single-Institutions’ Experience

Objective: To evaluate the efficacy of intraoperative nerve monitoring (IONM) during thyroidectomy in preventing recurrent laryngeal nerve (RLN) injury. Design: Retrospective cohort study. Setting: Academic institution. Patients: Consecutive sample of subjects undergoing thyroidectomy by experienced endocrine surgeons between 2006 and 2008 at a single institution. Intervention: Intraoperative RLN monitoring. Main outcome measure: RLN injury. Results: Between 2006 and 2008, 296 subjects underwent thyroid lobectomy or total thyroidectomy by the authors. One patient was excluded because of preoperative documentation of RLN injury. IONM was used in 253 (88%) cases, with a total of 403 nerves at risk of injury. Loss of RLN signal following surgical dissection occurred in 13 cases, prompting a change in surgical plan in one case. Post-operative laryngoscopy was performed in eight patients with hoarseness, documenting vocal cord paralysis in one patient who had clear intraoperative anatomic evidence of RLN injury. In no case did loss of RLN signal after dissection lead to nerve injury in the absence of anatomical evidence of injury as detected by the surgeon. Conclusions: IONM added cost and resulted in surgeon angst in cases of malfunction without a clear benefit in RLN identification and protection. Anatomic identification of the RLN should remain the gold standard in preventing RLN injury during thyroidectomy

Contemporary Analysis of Malignancies in Women of Child-Bearing Age: An NSQIP Analysis

Background: Recent evidence suggests that cancer incidence among pregnant women is increasing. The pattern of malignancies in pregnant women and how these compare to their nonpregnant counterparts has not been explored. Here we describe the differences in the proportion of resected malignancies in this population. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify women aged 18-49 who underwent an operation for malignancy from 2007-2012. Age-adjusted distribution of specific surgical interventions for malignancy based on ICD-9 codes were compared among pregnant and non-pregnant women using logistic regression analysis. Results: 42,732 subjects with malignancies surgically treated during child-bearing age were identified. 0.33% (n=143) were pregnant. The most common tumors requiring resection were breast (51%), thyroid (17%), and colorectal (9%). The distribution for most cancers was similar between groups. The age-adjusted proportion was significantly increased in breast, major salivary gland and oropharyngeal malignancies (p\u3c0.05). The proportion of resected colorectal cancers was significantly lower in pregnant women (p\u3c0.05; Table 1). Conclusion: This study serves as the first comprehensive and contemporary overview of malignancies resected in women of childbearing age. This study demonstrates that the proportion of resections among pregnant women was significantly greater in breast, major salivary gland and oropharyngeal cancers and lower for colorectal cancers. While these data might represent true differences in cancer incidence, further work is necessary to demonstrate if these are true differences in incidence versus differences in detection and treatment of the pregnant patient

Improving patient notification of solid abdominal viscera incidental findings with a standardized protocol

BACKGROUND: The increasing use of computed tomography (CT) scans in the evaluation of trauma patients has led to increased detection of incidental radiologic findings. Incidental findings (IFs) of the abdominal viscera are among the most commonly discovered lesions and can carry a risk of malignancy. Despite this, patient notification regarding these findings is often inadequate. METHODS: We identified patients who underwent abdominopelvic CTs as part of their trauma evaluation during a recent 1-year period (9/2011-8/2012). Patients with IFs of the kidneys, liver, adrenal glands, pancreas and/or ovaries had their charts reviewed for documentation of the lesion in their discharge paperwork or follow-up. A quality improvement project was initiated where patients with abdominal IFs were verbally informed of the finding, it was noted on their discharge summary and/or were referred to specialists for evaluation. Nine months after the implementation of the IF protocol, a second chart review was performed to determine if the rate of patient notification improved. RESULTS: Of 1,117 trauma patients undergoing abdominopelvic CT scans during the 21 month study period, 239 patients (21.4%) had 292 incidental abdominal findings. Renal lesions were the most common (146 patients, 13% of all patients) followed by hepatic (95/8.4%) and adrenal (38/3.4%) lesions. Pancreatic (10/0.9%) and ovarian lesions (3/0.3%) were uncommon. Post-IF protocol implementation patient notification regarding IFs improved by over 80% (32.4% vs. 17.7% pre-protocol, p = 0.02). CONCLUSION: IFs of the solid abdominal organs are common in trauma patients undergoing abdominopelvic CT scan. Patient notification regarding these lesions is often inadequate. A systematic approach to the documentation and evaluation of incidental radiologic findings can significantly improve the rate of patient notification

Does the Indication for Breast Surgery Impact Surgical Outcomes? A Contemporary Analysis of the ACS-NSQIP Database

Background. There is limited data about whether perioperative outcomes differ based on the indication for breast surgery. Herein we aim to assess if breast surgery for prophylaxis, compared to that for malignancy, impacts surgical outcomes. Methods. All women who underwent simple or subcutaneous mastectomy were identified from the 2007-2012 ACS-NSQIP database. Patients were identified by their ICD-9 codes and categorized into two groups. Group 1 consisted of patients diagnosed with breast cancer or carcinoma in situ; group 2 consisted of patients diagnosed with a genetic predisposition to malignant neoplasm of the breast (i.e., BRCA mutation). Demographic and preoperative variables were compared between groups and outcome variables. Outcome variables were analyzed using age- and operative time-adjusted logistic regression models. Results. 30,803 patients were identified. Group 1 consisted of 30,644 (99.5%) patients diagnosed with malignancy; group 2 consisted of 159 (0.5%) who underwent prophylactic surgery. In univariate analyses, those undergoing prophylactic surgery were significantly younger (p \u3c 0.01). There were no other preoperative differences between groups. When adjusted, the prophylactic group demonstrated a greater risk of DVT (p = 0.03). There were no differences in mortality, superficial/deep/organ space infections, UTI, wound dehiscence, or MI. Conclusion. In this analysis of a national cohort of breast surgery patients, those undergoing prophylactic surgery due to a genetic predisposition had a greater risk of perioperative DVT, compared to those who underwent surgery for a diagnosis of malignancy. This data may allow for improved perioperative management of patients to prevent DVT development and their devastating consequences

Somatic molecular analysis augments cytologic evaluation of pancreatic cyst fluids as a diagnostic tool

Objective: Better tools are needed for early diagnosis and classification of pancreatic cystic lesions (PCL) to trigger intervention before neoplastic precursor lesions progress to adenocarcinoma. We evaluated the capacity of molecular analysis to improve the accuracy of cytologic diagnosis for PCL with an emphasis on non-diagnostic/negative specimens. Design: In a span of 7 years, at a tertiary care hospital, 318 PCL endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) were evaluated by cytologic examination and molecular analysis. Mucinous PCL were identified based on a clinical algorithm and 46 surgical resections were used to verify this approach. The mutation allele frequency (MAF) of commonly altered genes (BRAF, CDKN2A, CTNNB1, GNAS, RAS, PIK3CA, PTEN, SMAD4, TP53 and VHL) was evaluated for their ability to identify and grade mucinous PCL. Results: Cytology showed a diagnostic sensitivity of 43.5% for mucinous PCL due in part to the impact of non-diagnostic (28.8%) and negative (50.5%) specimens. Incorporating an algorithmic approach or molecular analysis markedly increased the accuracy of cytologic evaluation. Detection of mucinous PCL by molecular analysis was 93.3% based on the detection of KRAS and/or GNAS gene mutations (p = 0.0001). Additional genes provided a marginal improvement in sensitivity but were associated with cyst type (e.g. VHL) and grade (e.g. SMAD4). In the surgical cohort, molecular analysis and the proposed algorithm showed comparable sensitivity (88.9% vs. 100%). Conclusions: Incorporating somatic molecular analysis in the cytologic evaluation of EUS-FNA increases diagnostic accuracy for detection, classification and grading of PCL. This approach has the potential to improve patient management

Judgment of the Humanness of an Interlocutor Is in the Eye of the Beholder

Despite tremendous advances in artificial language synthesis, no machine has so far succeeded in deceiving a human. Most research focused on analyzing the behavior of “good” machine. We here choose an opposite strategy, by analyzing the behavior of “bad” humans, i.e., humans perceived as machine. The Loebner Prize in Artificial Intelligence features humans and artificial agents trying to convince judges on their humanness via computer-mediated communication. Using this setting as a model, we investigated here whether the linguistic behavior of human subjects perceived as non-human would enable us to identify some of the core parameters involved in the judgment of an agents' humanness. We analyzed descriptive and semantic aspects of dialogues in which subjects succeeded or failed to convince judges of their humanness. Using cognitive and emotional dimensions in a global behavioral characterization, we demonstrate important differences in the patterns of behavioral expressiveness of the judges whether they perceived their interlocutor as being human or machine. Furthermore, the indicators of interest displayed by the judges were predictive of the final judgment of humanness. Thus, we show that the judgment of an interlocutor's humanness during a social interaction depends not only on his behavior, but also on the judge himself. Our results thus demonstrate that the judgment of humanness is in the eye of the beholder

Validation of Walk Score® for Estimating Neighborhood Walkability: An Analysis of Four US Metropolitan Areas

Neighborhood walkability can influence physical activity. We evaluated the validity of Walk Score® for assessing neighborhood walkability based on GIS (objective) indicators of neighborhood walkability with addresses from four US metropolitan areas with several street network buffer distances (i.e., 400-, 800-, and 1,600-meters). Address data come from the YMCA-Harvard After School Food and Fitness Project, an obesity prevention intervention involving children aged 5–11 years and their families participating in YMCA-administered, after-school programs located in four geographically diverse metropolitan areas in the US (n = 733). GIS data were used to measure multiple objective indicators of neighborhood walkability. Walk Scores were also obtained for the participant’s residential addresses. Spearman correlations between Walk Scores and the GIS neighborhood walkability indicators were calculated as well as Spearman correlations accounting for spatial autocorrelation. There were many significant moderate correlations between Walk Scores and the GIS neighborhood walkability indicators such as density of retail destinations and intersection density (p < 0.05). The magnitude varied by the GIS indicator of neighborhood walkability. Correlations generally became stronger with a larger spatial scale, and there were some geographic differences. Walk Score® is free and publicly available for public health researchers and practitioners. Results from our study suggest that Walk Score® is a valid measure of estimating certain aspects of neighborhood walkability, particularly at the 1600-meter buffer. As such, our study confirms and extends the generalizability of previous findings demonstrating that Walk Score is a valid measure of estimating neighborhood walkability in multiple geographic locations and at multiple spatial scales

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10$^{−8}$) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the estimated heritability. We implicate ~250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility