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A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.

PURPOSE: To develop an innovative machine learning (ML) model that predicts personalized risk of primary ovarian insufficiency (POI) after chemotherapy for reproductive-aged women. Currently, individualized prediction of a patient’s risk of POI is challenging. METHODS: Authors of published studies examining POI after gonadotoxic therapy were contacted, and six authors shared their de-identified data (N = 435). A composite outcome for POI was determined for each patient and validated by 3 authors. The primary dataset was partitioned into training and test sets; random forest binary classifiers were trained, and mean prediction scores were computed. Institutional data collected from a cross-sectional survey of cancer survivors (N = 117) was used as another independent validation set. RESULTS: Our model predicted individualized risk of POI with an accuracy of 88% (area under the ROC 0.87, 95% CI: 0.77–0.96; p

Interleukin-12 (IL-12) is a pro-inflammatory cytokine involved in the generation of an inflammatory tumor microenvironment and is critical in eliciting a productive anti-tumor immune response. It has been investigated as an anti-cancer therapeutic using various delivery routes, but intratumoral injection of plasmid IL-12 (tavokinogene telseplasmid; TAVO) followed by electroporation is a gene therapy approach that results in more sustained production of IL-12 locally with minimal systemic immune-related toxicity. Here we show that TAVO not only provides protection in the treated triple-negative breast cancer (TNBC) lesion, but also induces a systemic, abscopal effect. Single cell RNAsequencing (scRNAseq) of infiltrating immune cells shows a significant increase in both CD4 and CD8 T cells as well as dendritic cells within the treated lesions, while simultaneously decreasing a granulocytic myeloid derived suppressor population. scRNAseq allows for a detailed look into not only the overall pathway enrichment caused by TAVO treatment, but also the specific receptor-ligand interactions occurring between cell types. A combination of these analyses revealed an enrichment in the IFN-gamma induced PDL1 pathway by TAVO, typified by an increase in the interaction between PDL1 on dendritic cells and PD1 on CD8 T cells. Further, dramatic enrichment of the CXCL9/10/11/CXCR3 axis was observed, consistent with previous studies in melanoma. Analysis of paired TCR alpha and beta chains on T cells additionally demonstrated a dramatic shift in tumor infiltrating T cell (TIL) clonality and frequency. In sum, these preclinical studies identify a signature of increased antigen presentation, T cell infiltration and expansion, and a decrease in the number of granulocytes but also a particular enhancement of the PDL1 immunosuppressive pathway following TAVO treatment. Using this signature, we focus on an in-depth analysis of 2 patients from a single arm, prospective clinical trial of TAVO monotherapy (OMS-I140) in pre-treated advanced TNBC that went on to receive anti-PD-1 as their immediate next therapy with clinical anti-tumor response. Together these data support the combination of TAVO with PD1/PDL1 inhibitors while also identifying other key pathways that may enhance responsiveness in TNBC patients for whom treatment options remain limited. Citation Format: Erika J Crosby, Hiroshi Nagata, Melinda L Telli, Chaitanya R Acharya, Irene Wapnir, Kaitlin Zablotsky, Erica Browning, Reneta Hermiz, Lauren Svenson, Donna Bannavong, Kellie Malloy, David A Canton, Chris G Twitty, Takuya Osada, Herbert Kim Lyerly. Intratumoral delivery of tavokinogene telseplasmid (plasmid IL-12) and electroporation induces an immune signature that predicts successful combination in patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-22.

In this investigation, we have developed a new semiconductive Polymeric Transparent Matrix (PTM) as a substitute to the glass substrate used in a conventional optoelectronic device. Initially, we have synthesized Poly(methyl methacrylate) (PMMA) and series of its copolymers with Styrene in different weight percent (wt.%) ratio via solution polymerization process. The obtained polymers were characterized using various techniques to understand the effect of introducing different proportions of Styrene comonomers on PMMA backbone. The optimum composition of PTM was chosen based on copolymer’s mechanical properties, optical transparency, and ultraviolet (UV) shielding properties. Then, a series of nanocomposites consisting of optimized PTM and various wt.% of Multiwalled Carbon Nanotubes (MWCNT) as a conductive filler were fabricated to increase the conductivity of PTM. A steep increase (109 fold) in bulk electrical conductivity was observed in case of 0.25 wt% MWCNT loaded optimized composite matrix, along with the retention of a good amount of optical transparency (88% at 550 nm) and 100% UV-C shielding. This optimized nanocomposite has also shown amelioration in mechanical properties as a result of uniform dispersion of MWCNT. These remarkable attributes favor the use of this optimized semiconducting PTM as a potential transparent substrate for next-generation organic optoelectronic devices.

IL26 is a unique amphipathic member of the IL10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. Although IL26 has almost no described role in cancer, our in vivo screen of inflammatory and cytokine pathway genes revealed IL26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4+ T cells within clinical TNBC specimens. IL26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required neutrophils. IL26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL26 vaccine to stimulate antibody production and suppress IL26-enhanced engraftment in vivo, suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL26-mediated inflammatory stimulation. Significance: These findings identify IL26 as a unique, clinically relevant, inflammatory amplifier that enhances TNBC engraftment and dissemination in association with neutrophils, which has potential as a therapeutic target.

Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs. METHODS: Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed. RESULTS: The mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways. CONCLUSION: Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04081272. FUNDING: The Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Radiopharmaceuticals are increasingly used for the treatment of various cancers with novel radionuclides, compounds, tracer molecules, and administration techniques. The goal of radiation therapy, including therapy with radiopharmaceuticals, is to optimise the relationship between tumour control probability and potential complications in normal organs and tissues. Essential to this optimisation is the ability to quantify the radiation doses delivered to both tumours and normal tissues. This publication provides an overview of therapeutic procedures and a framework for calculating radiation doses for various treatment approaches. In radiopharmaceutical therapy, the absorbed dose to an organ or tissue is governed by radiopharmaceutical uptake, retention in and clearance from the various organs and tissues of the body, together with radionuclide physical half-life. Biokinetic parameters are determined by direct measurements made using techniques that vary in complexity. For treatment planning, absorbed dose calculations are usually performed prior to therapy using a trace-labelled diagnostic administration, or retrospective dosimetry may be performed on the basis of the activity already administered following each therapeutic administration. Uncertainty analyses provide additional information about sources of bias and random variation and their magnitudes; these analyses show the reliability and quality of absorbed dose calculations. Effective dose can provide an approximate measure of lifetime risk of detriment attributable to the stochastic effects of radiation exposure, principally cancer, but effective dose does not predict future cancer incidence for an individual and does not apply to short-term deterministic effects associated with radiopharmaceutical therapy. Accident prevention in radiation therapy should be an integral part of the design of facilities, equipment, and administration procedures. Minimisation of staff exposures includes consideration of equipment design, proper shielding and handling of sources, and personal protective equipment and tools, as well as education and training to promote awareness and engagement in radiological protection. The decision to hold or release a patient after radiopharmaceutical therapy should account for potential radiation dose to members of the public and carers that may result from residual radioactivity in the patient. In these situations, specific radiological protection guidance should be provided to patients and carers.

Background The chromium-51-labeled posttransfusion recovery (PTR) study has been the gold-standard test for assessing red blood cell (RBC) quality. Despite guiding RBC storage development for decades, it has several potential sources for error. Methods Four healthy adult volunteers each donated an autologous, leukoreduced RBC unit, aliquots were radiolabeled with technetium-99m after 1 and 6 weeks of storage, and then infused. Subjects were imaged by single-photon-emission computed tomography immediately and 4 hours after infusion. Additionally, from subjects described in a previously published study, adenosine triphosphate levels in transfusates infused into 52 healthy volunteers randomized to a single autologous, leukoreduced, RBC transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage were correlated with PTR and laboratory parameters of hemolysis. Results Evidence from one subject imaged after infusion of technetium-99m-labeled RBCs suggests that, in some individuals, RBCs may be temporarily sequestered in the liver and spleen immediately following transfusion and then subsequently released back into circulation; this could be one source of error leading to PTR results that may not accurately predict the true quantity of RBCs cleared by intra- and/or extravascular hemolysis. Indeed, adenosine triphosphate levels in the transfusates correlated more robustly with measures of extravascular hemolysis in vivo (e.g., serum iron, indirect bilirubin, non-transferrin-bound iron) than with PTR results or measures of intravascular hemolysis (e.g., plasma free hemoglobin). Conclusions Sources of measurement error are inherent in the chromium-51 PTR method. Transfusion of an entire unlabeled RBC unit, followed by quantifying extravascular hemolysis markers, may more accurately measure true posttransfusion RBC recovery.

ObjectiveTo determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD.MethodsWe combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro.ResultsMultiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01).ConclusionsThe composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.

Aim: To do a research study on Medicolegal Autopsies conducted at Government Medical College Mortuary, Ongole, Andhra Pradesh from 1st January 2020 to 31st December 2020. Materials & Methodology: This study was conducted at Government Medical College, Ongole from 1st January to 31st December 2020. A total of 534 medicolegal cases were brought to mortuary for the sake of medicolegal autopsy during the study period. Result: In the research study, it is evident from the statistics that maximum number of medicolegal autopsies were conducted in the decreasing order in the following deaths - Road Traffic Accidents < Poisoning < Hanging < Homicidal Deaths < Deaths due to hit by Train < Drowning < Burns < Fall from Height < Snake Bite. Medicolegal autopsies were done more in males compared to females in almost all types of deaths. Likewise maximum number of autopsies were conducted in the active age group of 18 to 36 years

Purpose: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed. Patients and Methods: Using mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single-arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma datasets. Results: Single-cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T-cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pretreatment and posttreatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T-cell infiltration following treatment. One patient, previously unresponsive to anti–PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti–PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response. Conclusions: These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.

Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.

Purpose: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. Experimental Design: Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination. Results: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. Conclusions: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).

Seckel syndrome, first defined by Seckel in 1960, is a rare (incidence 1:10,000) genetically heterogeneous autosomal recessive disorder presenting at birth. Seckel described the disease on the basis of two cases he had studied in Chicago as well as 13 cases on nanocephalic dwarfs reported in the literature over a 200-year period. It is Characterized by dwarfism prenatally resulting in low birth weight, abnormally small head with a “bird‑headed” like appearance (beaked nose, receding forehead, prominent eyes, and micrognathia) and mental retardation. Other facial features include abnormally large eyes and narrow face. This syndrome has an autosomal recessive pattern of inheritance. A case of Seckel syndrome that was reported is described in this article.

Even though the global incidence of tuberculosis (TB) has been showing a declining trend every year, it is still a significant public health problem in India. On the other hand, cancer has also been the reason for considerable mortality and morbidity across this population. The incidence of TB has been reportedly increasing in patients with both pulmonary and non-pulmonary cancers. Incidence of pulmonary TB in head and neck malignancy is around 3.1% to 6.6%. We present a case history of 50 years old with locally advanced recurrent head and neck malignancy with active pulmonary Koch’s. The decision was to provide him supportive care and treating the infection was pragmatic in spite of expected delay in anti-cancer treatment. It is extremely important to come up with a proper protocol for the need of prophylactic treatment, detection and the concurrent treatment of both cancer and TB.

// Qing Cheng 1, 4 , Xuechan Li 4 , Chaitanya R. Acharya 1 , Terry Hyslop 2, 4 , Julie Ann Sosa 1, 3, 4 1 Department of Surgery, Duke University Medical Center, Durham, NC 27710 USA 2 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710 USA 3 Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA 4 Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA Correspondence to: Julie Ann Sosa, email: julie.sosa@dm.duke.edu Qing Cheng, email: q.cheng@dm.duke.edu Keywords: papillary thyroid cancer, disease progression, genomic alterations, clinical and pathologic factors, risk index model Received: September 02, 2016 Accepted: January 24, 2017 Published: February 06, 2017 ABSTRACT Although the majority of papillary thyroid cancer (PTC) is indolent, a subset of PTC behaves aggressively despite the best available treatment. A major clinical challenge is to reliably distinguish early on between those patients who need aggressive treatment from those who do not. Using a large cohort of PTC samples obtained from The Cancer Genome Atlas (TCGA), we analyzed the association between disease progression and multiple forms of genomic data, such as transcriptome, somatic mutations, and somatic copy number alterations, and found that genes related to FOXM1 signaling pathway were significantly associated with PTC progression. Integrative genomic modeling was performed, controlling for demographic and clinical characteristics, which included patient age, gender, TNM stages, histological subtypes, and history of other malignancy, using a leave-one-out elastic net model and 10-fold cross validation. For each subject, the model from the remaining subjects was used to determine the risk index, defined as a linear combination of the clinical and genomic variables from the elastic net model, and the stability of the risk index distribution was assessed through 2,000 bootstrap resampling. We developed a novel approach to combine genomic alterations and patient-related clinical factors that delineates the subset of patients who have more aggressive disease from those whose tumors are indolent and likely will require less aggressive treatment and surveillance ( p = 4.62 × 10 –10 , log-rank test). Our results suggest that risk index modeling that combines genomic alterations with current staging systems provides an opportunity for more effective anticipation of disease prognosis and therefore enhanced precision management of PTC.

The HER2-specific monoclonal antibody (mAb), trastuzumab, has been the mainstay of therapy for HER2(+) breast cancer (BC) for approximately 20 years. However, its therapeutic mechanism of action (MOA) remains unclear, with antitumor responses to trastuzumab remaining heterogeneous and metastatic HER2(+) BC remaining incurable. Consequently, understanding its MOA could enable rational strategies to enhance its efficacy. Using both murine and human versions of trastuzumab, we found its antitumor activity dependent on Fcγ receptor stimulation of tumor-associated macrophages (TAMs) and antibody-dependent cellular phagocytosis (ADCP), but not cellular cytotoxicity (ADCC). Trastuzumab also stimulated TAM activation and expansion, but did not require adaptive immunity, natural killer cells, and/or neutrophils. Moreover, inhibition of the innate immune ADCP checkpoint, CD47, significantly enhanced trastuzumab-mediated ADCP and TAM expansion and activation, resulting in the emergence of a unique hyperphagocytic macrophage population, improved antitumor responses, and prolonged survival. In addition, we found that tumor-associated CD47 expression was inversely associated with survival in HER2(+) BC patients and that human HER2(+) BC xenografts treated with trastuzumab plus CD47 inhibition underwent complete tumor regression. Collectively, our study identifies trastuzumab-mediated ADCP as an important antitumor MOA that may be clinically enabled by CD47 blockade to augment therapeutic efficacy.

Combined heart-kidney transplantation (CHKT) is a therapy for a carefully selected subgroup of patients with concomitant heart and kidney failure. Discerning whether there is reversible or irreversible kidney disease is crucial to selection for CHKT versus heart transplant alone to optimize therapeutic value and organ allocation. Methods for determining extent of kidney disease include estimating glomerular filtration rate, creatinine clearance, kidney ultrasonography, and kidney biopsy. Additionally, the use of extracorporeal membrane oxygenation (ECMO) in the setting of CHKT only recently emerged as feasible. We present a case of a 69-year-old man with cardiogenic shock who was placed on venoarterial-ECMO (VA-ECMO) following orthotopic heart transplant (OHT) due to severe mediastinal bleeding and remained on VA-ECMO during kidney transplant. To our knowledge, this is the second report of a patient undergoing kidney transplant while on VA-ECMO following OHT.

Radioactive iodine has been, in various forms, the mainstay of Nuclear Medicine. Iodine-123 is the most widely used iodine isotope for single photon imaging. Iodine-125 continues to be used in diverse applications from in vitro radioassay to in vivo estimation of various pathophysiologic correlates. Iodine-131 (131I), useful for imaging as well as therapy, has contributed more than any other radionuclide to the growth and sustenance of Nuclear Medicine. Positron emission tomography (PET) is an indispensable tool in current clinical practice, spurred by the rapid and increasing availability of radiopharmaceuticals for in vivo imaging. Most clinical PET imaging utilizes fluorine-18; there is a need for positron emitters with longer half-lives, suitable for imaging larger molecules of interest. Iodine-124 (124I) has approximately 23 % positron emission; its 4-day half-life lends itself to sequential imaging, and its dosimetry is comparable to iodine-131. Iodine can be easily attached to a variety of molecules without alteration of physico-chemical or biologic properties. PET with 124I-labeled molecules enables longitudinal in vivo assessment of their distribution; such pharmacokinetic and biodistribution information has considerable utility in oncologic and non-oncologic applications. We will provide a clinical perspective on the physical and chemical characteristics of 124I, as the iodide, as well as radiolabeled to a wide variety of molecules of interest. Radioiodination is accomplished based on the chemical and biologic nature of the ligand to be studied, and issues of relevance will be highlighted. We will conclude by describing the current and potential future clinical applications of 124I-based tracers used for molecular imaging in diagnosis and therapy.

Background Mantle-cell lymphoma (MCL) is sensitive to radiotherapy, and the CD20 antigen is relatively highly expressed in MCL. Therefore, radioimmunotherapy using radiolabeled anti-CD20 monoclonal antibodies has the potential to treat MCL. The objective of this study was to investigate the efficacy, pharmacokinetics, and safety of tositumomab (TST) and iodine-131 tositumomab (I-131 TST) followed by 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated MCL ( ClinicalTrials.gov NCT00022945 ). Patients and Methods In this phase 2 open-label study, patients received dosimetric (day 0: 450 mg TST, then 35 mg I-131 TST [5 mCi]) and therapeutic (between days 7 and 14: 450 mg TST, then an individualized dose of I-131 TST [65-75 cGy]) TST/I-131 TST, with CHOP treatment commencing approximately 13 weeks after the therapeutic dose. The primary end point was the MCL response rate to treatment; secondary end points included confirmed complete response rate and total body residence time. Results Twenty-six patients were enrolled, and 25 were included in the intent-to-treat population. The overall unconfirmed response rate was 84%, and the confirmed complete response rate was 44%. The median progression free-survival was 27.6 months. The median total body residence time was 94.5 hours. No new or unexpected safety signals were identified. Conclusion Patients with previously untreated MCL who received radioimmunotherapy with TST/I-131 TST followed by CHOP had a high response rate and a long duration of response, indicating that radioimmunotherapy is a therapeutic option in this patient population.

Despite promising advances, overcoming immune suppression and driving productive immune responses in the tumor microenvironment remains a significant challenge. Using a spontaneous breast cancer model, we found that vaccination targeting HER2d16, a highly expressed driver of oncogenicity and HER2-therapeutic resistance, elicited significant anti-tumor responses. In contrast, vaccines targeting a non-driver tumor-specific antigen (GFP) or unique non-driver tumor neoepitopes had no impact on tumor occurrence or progression. While vaccine-induced HER2-specific CD8+ T cells were essential for responses, tumors treated therapeutically with a vaccine alone ultimately progressed. However, long-term tumor control and complete tumor regression was only achieved when vaccine was combined with immune-checkpoint blockade (anti-PD1). Single cell RNAsequencing of tumor-infiltrating T cells (TILs) revealed that while vaccination expanded CD8 T cells within the tumor, only the combination of vaccine with anti-PD1 therapy induced a tumor rejection activation signature that was identified in the expanded T cell clones. We go on to use the single cell data to clone and reexpress the TCRs from expanded TILs from vaccinated mice and show that they are HER2-reactive. This data conclusively demonstrates the efficacy of this vaccination strategy in expanding tumor rejection T cells and supports its further evaluation in an ongoing Phase II trial (NCT03632941). The workflow used to identify and clone expanded, tumor specific T cells has broad potential applications across tumor types and treatment platforms. Citation Format: Erika J. Crosby, Chaitanya Acharya, Christopher Rabiola, William J. Muller, Lewis A. Chodosh, Gloria Broadwater, Jonathan Shepherd, Daniel Hollern, Xiaping He, Charles M. Perou, Benjamin K. Ashby, Benjamin G. Vincent, Michael A. Morse, Herbert K. Lyerly, Zachary C. Hartman. Stimulation and expansion of oncogene-reactive tumor infiltrating T cells through combined Ad-HER2Δ16 vaccination and anti-PD1 enable anti-tumor responses against established HER2 BC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 904.

TPS249 Background: Human kallikrein-2 (hk2) is a member of the kallikrein family, is produced by prostatic epithelium, has 80% DNA sequence homology with PSA, is both circulating and bound to prostatic tissue, and is highly expressed even in high grade tumors. hK2 holds the promise of serving as a new therapeutic target for radiopharmaceuticals in prostate cancer. h11B6 is a humanized antibody directed to an epitope found on the catalytically active form of hK2, which is permanently internalized after binding. This is a first-in-human trial of [111In]-DOTA-h11B6 to determine the radio-immunotherapeutic potential of targeting hK2 with nanomolar affinity. The trial will determine the most favorable antibody mass as well as assess tumor targeting. Methods: To determine the optimal antibody mass, two cohorts of patients will be studied. All patients will receive 2 mg of [111In]-labeled h11B6. The first cohort consists of escalating amounts of antibody mass in 2-6 patients: 2, 10 and 20 mg total antibody respectively. Patients will undergo serial whole-body images for up to a week, along with assessments of serum clearance kinetics and normal organ residence time. The lowest mass amount of antibody that demonstrates favorable biodistribution and evidence of radioactivity accumulation in tumor will be used for the second cohort. Up to 6 patients will be studied in the second cohort, which will focus on assessment of antibody tumor targeting. Following this optimization and targeting imaging trial, a phase 1 dose-escalation radioimmunotherapy trial may be performed. Clinical trial information: NCT04116164.

Cardiovascular diseases are the major cause of mortality rate in India with more than 50 % of the patients coming from a rural background. IoT plays a crucial role in developing point of care devices which cater to the healthcare demands of the rising rural populace.ECG monitoring system plays a key role as a diagnostic tool for cardiac abnormalities. Thus it becomes important to develop a portable point of care (POC) device at an affordable price so as to monitor the patients’ cardiac health without interfering in their daily schedule.We developed an end to end health care workflow comprising three important modules. Firstly, a Bluetooth Low Energy (BLE) enabled portable 5-lead ECG monitor system with small form factor. Next, a smart phone based android application, which receives, plots and analyzes the data sent from ECG device. Finally, a remote server where the patient data and analysis reports are stored for future reference of a professional medical practitioner.The device was tested using real time data from a rural hospital and further the obtained ECG signatures were compared with standard GE and SIEMENS ECG machines. The results were validated by a cardiologist of a super specialty hospital.

1706 Objectives: 90Y-radioembolization treatment planning includes determination of the lung shunt fraction (LSF) to maintain mean lung dose to below 25-30 Gy. The estimated mean lung dose constrains the total amount of administered activity and hence the ability to treat tumor to higher dose levels. The device package inserts recommend use of 1000 g lung mass in the calculation of lung dose. Errors in lung mass and lung shunt fraction contributes to the overall errors in lung doses. Here we investigated the accuracy and 95% prediction interval (95%PI) of 5 common methods for calculating the lung mass. The bias can be corrected, if errors are normally distributed, rendering the 95%PI as the more relevant metric. As secondary objective, we investigated the mean errors in lung mass and lung dose that stems from using a fixed 1000 g lung mass for all patients. Relative errors in lung mass estimation are directly proportional to the errors in lung dose. Methods: An IRB-approved retrospective study was conducted on 52 consecutive HCC patients assessed for 90Y-radioembolization with TheraSphere from 2015-2016. As part of routine workup, all patients underwent a diagnostic contrast CT (cCT) of the chest and abdomen prior to the 99mTc-MAA SPECT and non-contrast CT (ncCT) of the liver and chest region. Of these 52 patients, 12 had complete lungs in the SPECT/ncCT field of view (FOV) while 40 had a varying range of lung in the SPECT/ncCT FOV. The gold-standard estimate of true lung mass was defined as the mean of the masses estimated from the cCT and the ncCT using an HU-based volume&density calculation. Linear regression was derived from the complete lung scan data to estimate true lung mass from a lung mass estimated using the cCT HU-based volume&density Methods: This regression was then used on all 52 patients to calculate the true lung mass from the cCT HU-based volume&density mass estimation. The 5 common methods of lung mass calculation investigated were: 1) ncCT HU-based volume&density, 2) ncCT volume & fixed 0.3 g/ml density, 3) fixed mass of 1000 g, 4) gender-based fixed mass of 1000 g for men and 800 g for women, and 5) weight-scaled gender-based fixed mass. A Bland-Altman analysis was performed to estimate the mean relative error and 95%PI of these 5 methods compared to the true lung mass. Results: The mean relative error [95%PI] for lung mass was -9% [±21%] and -11% [±23%] with the ncCT HU-based volumed the errors changed to -23% [±24%] and -14% [±33%], respectively, when partial lung was scanned. In all 52 cases, the fixed mass based methods (1000 g, gender-based, weight-scaled-gender) had large mean errors (26%, 20%, 37%) and very wide 95%PI (±44%, ±41%, ±54%). The errors were not normally distributed in the 1000 g and gender-based fixed mass methods. The 95%PI after bias corrections for all patients were 26%, 31%, and 54% for ncCT HU-based volume&density, ncCT volume&fixed-density, and weight-scaled-gender fixed mass methods. On average, the fixed lung mass of 1000 g overestimated the true lung mass by 23% [±44%] resulting in a corresponding underestimation of the lung dose. Conclusion: Use of the default fixed lung mass of 1000 g severely overestimates the true lung mass. Errors in both ncCT-based methods were lowest compared to fixed mass methods but HU-based volume&density had the narrowest 95%PI. Over all patients, lung mass errors in 95%PI after bias correction with the ncCT HU-based volume&density and volume&fixed-density methods were 26% and 31%. We recommend scanning the maximum lung volume allowed in 99mTc-MAA SPECT/CT and using the bias-corrected ncCT HU-based volume&density method to estimate lung mass when calculating mean lung dose for 90Y-radioembolization treatment planning. Investigations on incorporation of additional errors from LSF estimation on the final mean lung dose is currently underway.

Background: Upper-body subcutaneous adipose tissue, measured by neck circumference (NC), has been positively associated with hypertension (HT). This study was conducted with the objective to correlate and evaluate NC with HT and to define critical cut-off point for screening HT in adult population of central India. Methods: This cross sectional study was carried out in the urban filed practice area of Government Medical College Nagpur. All patients attending OPD during study period, aged >30 years after applying exclusion criteria were included in study. Sample size was calculated to be 182. The socioeconomic details were assessed using questionnaire. Anthropometric measurements and blood pressure were recorded using standard guidelines. Data was analysed using Epi Info 7 and SPSS. Unpaired t test, Pearsons correlation and finally ROC analysis was done. Results: Out of total 206 individuals, 107 were male; majority being aged >50 years. The mean value of NC was 36.43±3.23 cm and 34.84±4.07 cm in hypertensive and non-hypertensives respectively and was seen significantly associated with HT (p=0.02). Positive correlation was seen between SBP and NC in male r=0.27 and in females r=0.26 (p=0.001).On applying ROC, AUC for male and female was 0.652 (p=0.007) and 0.68 (p = 0.002) respectively and the best cutoff for male was 36.5cm and female was 33.5cm with sensitivity of 74% and 72.71% respectively. Conclusions: NC is positively correlated with hypertension. NC >36.5cm for males and >33.5cm for females was the best cut-off levels for screening for HT. NC could be a potential, inexpensive, easy screening tool for screening HT.

As many as 40 % of breast cancer patients undergoing axillary lymph node dissection (ALND) and radiotherapy develop lymphedema. We report our experience performing lymphatic–venous anastomosis using the lymphatic microsurgical preventive healing approach (LYMPHA) at the time of ALND. This technique was described by Boccardo, Campisi in 2009. LYMPHA was offered to node-positive women with breast cancer requiring ALND. Afferent lymphatic vessels, identified by injection of blue dye in the ipsilateral arm, were sutured into a branch of the axillary vein distal to a competent valve. Follow-up was with pre- and postoperative lymphoscintigraphy, arm measurements, and (L-Dex®) bioimpedance spectroscopy. Over 26 months, 37 women underwent attempted LYMPHA, with successful completion in 27. Unsuccessful attempts were due to lack of a suitable vein (n = 3) and lymphatic (n = 5) or extensive axillary disease (n = 1). There were no LYMPHA-related complications. Mean follow-up time was 6 months (range 3–24 months). Among completed patients, 10 (37 %) had a body mass index of ≥30 kg/m2 (mean 27.9 ± 6.8 kg/m2, range 17.4–47.6 kg/m2), and 17 (63 %) received axillary radiotherapy. Excluding two patients with preoperative lymphedema and those with less than 3-month follow-up, the lymphedema rate was 3 (12.5 %) of 24 in successfully completed and 4 (50 %) of 8 in unsuccessfully treated patients. Our transient lymphedema rate in this high-risk cohort of patients was 12.5 %. Early data show that LYMPHA is feasible, safe, and effective for the primary prevention of breast cancer-related lymphedema.

Intestinal Malrotation in adults is twisting of the intestines that lead to mal positioning of the bowels and malfixation of the mesentery, blocking the digestive tract and preventing the proper passage of food. Midgut malrotation is a congenital anomaly in the embryological development of the foetal intestinal rotation. It has been estimated that it affects approximately 1 in 500 l ive births . [ 1 ] Symptomatic malrotation is estimated to occur in 1 in 6000 live births . [ 2 ] Traditionally, intestinal malrotation has been considered primarily a disease of infancy with infrequent occurrence beyond the first year of life. Adult midgut malrotation is very rare and its incidence has been reported to be between 0. 0001% and 0. 19% . [ 3 , 4 ] Most adult diagnoses of midgut malrotation are made in asymptomatic patients; either on imaging investigations for unrelated conditions or at operations for other pathology. However, there are a small proportion of affected adults who may present with acu te or chronic symptoms of intestinal obstruction or intermittent and recurrent abdominal pain. The true diagnosis in this age group is fraught with immense difficulty, especially because the typical presentation is with non - specific symptoms and the fact t hat adult Surgeons usually have low index of suspicion and may not consider the diagnosis a possibility in the initial evaluation of adult patients with abdominal pain. We report a rare case of an 36 year old patient presented as acute intestinal obstruct ion due to midgut malrotation

Introduction: Upper body obesity has been attributed to increased cardiovascular risk in various studies. Measuring the Neck Circumference (NC) is an easy and inexpensive method to determine the upper body obesity. Aim: To correlate NC with Waist to Hip ratio (W:H ratio) and to find critical cut off points for NC for the screening cardiovascular risk among adults. Materials and Methods: A community based cross-sectional study was conducted among apparently healthy adults in field practice area of a tertiary care hospital in Maharashtra, India. A predesigned and pretested questionnaire was used and following the standard guidelines Waist Circumference (WC), Hip Circumference (HC) and NC were measured. Necessary permissions were sought before the start of the study. Indian standard cut off for W:H ratio was used to classify the cardiovascular risk among the study subjects. Statistical analysis: Epi info 7.1 and Statistical Package for the Social Sciences (SPSS) version 20.00 was used for analysis. Chi square test (For proportions), independent t-test (For mean), Pearson’s correlation coefficient and Receiver Operating Characteristic (ROC) analysis was done. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were calculated. Results: Total of 300 study subjects were recruited in the present study . There were equal number of males (n=150) and females (n=150) with the average age of the study population as 44.70±20.24 years. The Pearson’s correlation coefficient between NC and W:H ratio was 0.42 and 0.33 among males and females respectively. Based on receiver operating curve analysis for NC, cut off of 32.5 cm among females and 35.5 cm among males was defined as best critical cut off to screen the adults for cardiovascular risk. Conclusion: A significant association was observed between NC and W:H ratio (p

Context: Chronic diseases such as diabetes, hypertension, and respiratory diseases are affecting the younger age groups occurring across the world. Raised blood pressure in children is increasing at an alarming rate. Aims: The aim was to study the prevalence of hypertension and prehypertension among children of schools in rural health training center area of a tertiary care hospital in Nagpur, Maharashtra, and to find any association between generalized obesity and central obesity with hypertension/prehypertension. Settings and Design: A cross-sectional study was conducted in the schools under the administrative cover of Indira Gandhi Government Medical College, Nagpur. Materials and Methods: Schoolchildren who had completed 10 years and not more than 13 years, whose parents gave consent, who gave assent, and apparently healthy were included in the study. The demographic particulars such as age and gender were collected using the case record form. Anthropometric measurements and blood pressure were measured using the standard guidelines. Statistical Analysis Used: Qualitative variables expressed in terms of percentages and quantitative in terms of mean and standard deviation. Chi-square test for trend and Student's t-test were used. Results: The prevalence of hypertension and prehypertension was 3.57% and 6.25%, respectively. We found a significant association between hypertension/prehypertension with waist-to-hip ratio of the children (P < 0.05). Conclusions: We found a higher prevalence of hypertension and prehypertension among the schoolchildren in rural areas, and we found a significant association between central obesity and hypertension/prehypertension.

Objective To evaluate whether the rate of ectopic pregnancy differs between fresh and frozen embryo transfers. Design Systematic review and meta-analysis. Setting Centers for reproductive care. Materials and methods An electronic literature search in MEDLINE through PubMed was performed through December 2013. We included clinical trials comparing outcomes of in vitro fertilization (IVF) cycles between fresh and frozen embryo transfers. Main outcome measures Ectopic pregnancy rates from fresh versus frozen IVF cycles. Results A meta-analysis revealed no significant difference between ectopic pregnancy rates in fresh versus frozen embryo transfer. Similarly, there was no difference between ectopic pregnancy rates in natural-cycle frozen embryo transfer versus programmed cycles. Conclusions Differences in the hormonal milieu of the uterine environment between fresh and frozen embryo transfer stimulation do not appear to affect the ectopic pregnancy rate. More directed studies are needed before a definite recommendation can be made as to which is safer for prevention of ectopic pregnancy– fresh or frozen embryo transfer.

Detection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques. Clin Cancer Res; 20(23); 5888–97. ©2014 AACR.

De Novo minimal change disease in the renal allograft is an infrequently reported cause of glomerulopathy. The paucity of reported cases in the medical literature and strict clinical-pathological criteria for diagnosis has made this entity an infrequently encountered disease process. We describe a case of MCD sixteen months post-transplant that has initially responded well to corticosteroid therapy.

1073 Background: The prognostic and predictive value of tumor infiltrating lymphocytes for ICB has been recognized in a variety of tumor types, including TNBC. Nonetheless, our understanding of the mechanistic aspects of T cell activation remains incomplete. We hypothesize that a specific effector phenotype of T cell cytolytic activity (ECA) is a consistent feature of epithelial tumors, possibly varying by tumor types with a range of inflammatory features. Methods: We evaluated 6,311 purified CD3+ single cells from human primary TNBC and computed sample set enrichment scores of a set of previously published immune metagenes. Following unsupervised clustering of the enrichment scores of the entire single cell population, two subgroups of cells with highest and lowest average enrichment score of T cell cytolytic activity formed a basis for detecting functional gene expression modules. Spectral decomposition and Jackstraw analysis estimated eight modules with overlapping sets of genes. Each gene expression module was then used to train a Random Forest classifier of ECA phenotype. Results: We discovered that our module-derived classifiers were prognostic not only in TNBC samples obtained from both TCGA (N = 150) and METABRIC (N = 320) datasets but also in 14 other tumor types encompassing 6,000 samples. For example, patient samples from TCGA dataset predicted to be in group ECA ‘High’ have better progression-free survival (p-value: 0.0098l; HR: 0.30) and better overall survival (p-value: 0.0066; HR: 0.17). In both breast datasets, gene within the classifier are relatively under-expressed in ER+ tumors as opposed to HER2+ and TNBC (p-value < 2.2e-16). In a dataset of normal, pure DCIS and mixed DCIS (GSE26304;N = 114), the same genes were relatively under-expressed in DCIS samples relative to invasive tumors (p-value < 2.2e-16). Additionally, in a pre-therapy tumor dataset of fifty-one advanced melanoma patients treated with Nivolumab, who previously either progressed on ipilimumab or were ipilimumab-naïve, our module-derived classifier was able to classify responders and non-responders with 77% accuracy (p-value = 0.02) and was associated with progression-free survival (p-value = 0.03; HR: 0.28). Conclusions: Our study highlights one important application of single-cell genomics in our understanding of immune microenvironment and potentially identify new immunotherapy targets.

Background: Tuberculosis is major public health problem especially in the low and middle income countries like India. We conducted a study to assess the knowledge, attitude and practice related to tuberculosis among the patients attending our tertiary care institute. Methods: A cross sectional study was conducted in a tertiary care hospital on the patients attending OPD of tertiary care hospital in Maharashtra. The patients with debilitating illness or bed bound patients and those diagnosed and cured of tuberculosis or were on treatment of tuberculosis were excluded from the study. A pretested and designed questionnaire was used to assess the knowledge, attitude and practice about the cause, clinical features and treatment of tuberculosis. Results: The mean age of the study subjects was 43.34±11.23 years with male: female ratio of 1.45. About 16.67% of the subjects stated that cause of TB is bacteria, 51.33% reported that cough was the most common symptom, 58.67% believed that it spreads from person to person and among the people who said it spreads 58.67% said that it can be preventable. Conclusions: About 1/5 th of the study subjects expressed the cause of TB is bacteria or germs, and more than ½ believed that TB spreads from person to person. About 2/3 rd of the patients felt that TB was a very serious disease; more than ½ of them expressed fear if they were diagnosed with TB but more than ½ of them also expressed rejection if they have a TB patient as a closed one.

BACKGROUND Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed. METHODS A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m2 loading, 250 mg/m2 maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUVmax) for those treated initially with everolimus was −24% (2% to −54%), and with cetuximab was −5% (−23 to 36%). The Ktrans measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population. Cancer 2014;120:77–85. © 2013 American Cancer Society.

This paper presents the load-settlement response of a surface footing placed over buried flexible pipe through model plate load tests. Experiments are conducted in a rectangular box after placing a model footing on the surface of sand placed at two different relative densities. Combination of tests were performed, such as, (1) model footing placed over sand compacted at low relative density (RD=50%) and model buried flexible pipe (PVC pipe) placed at 0.5 B and 1.0 B depth, and (2) model footing placed over sand compacted at high relative density (RD=88%) and model buried flexible pipe (PVC pipe) placed at 0.5 B & 1.0 B depth; where B = diameter of the model footing. The results of the model plate load test provide useful interpretation about the combined behavior of buried flexible pipe–soil system in terms of load-settlement response. The influence on the bearing capacity of sand in different relative densities and that caused by the presence of a buried flexible pipe beneath the footing is also ...

Objective To clearly define the proportions of benign vs malignant histologic findings in resected renal masses through an in-depth review of the contemporary medical data to assist in preoperative risk assessment. Materials and Methods PubMed and select oncology congresses were searched for publications that identify the histologic classification of resected renal masses in a representative sample from the contemporary data: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit 2003-2011. Results We identified 26 representative studies meeting the inclusion criteria and incorporating 27,272 patients. The frequency of benign tumors ranged from 7% to 33%, with most studies within a few percentage points of the mean (14.5% ± 5.2%, median 13.9%). Clear cell renal cell carcinoma occurred in 46% to 83% of patients, with a mean of 68.3% (median 61.3; SD = 11.9%). An inverse relationship between tumor size and benign pathologic features was identified in 14 of 19 (74%) studies that examined an association between tumor size and pathologic characteristics. A statistically significant correlation between clear cell renal cell carcinoma and tumor size was identified in 13 of 19 studies (63%). The accuracy of preoperative cross-sectional imaging was low in the 2 studies examining computed tomography (17%). Conclusion Benign renal tumors represent ∼15% of detected surgically resected renal masses and are more prevalent among small clinical T1a lesions. Noninvasive preoperative differentiation between more and less aggressive renal masses would be an important clinical advance that could allow clinicians greater diagnostic confidence and guide patient management through improved risk stratification.

Purpose A clinical study to characterize renal masses with positron emission tomography/computed tomography (PET/CT) was undertaken. Patients and Methods This was an open-label multicenter study of iodine-124 (124I) -girentuximab PET/CT in patients with renal masses who were scheduled for resection. PET/CT and contrast-enhanced CT (CECT) of the abdomen were performed 2 to 6 days after intravenous 124I-girentuximab administration and before resection of the renal mass(es). Images were interpreted centrally by three blinded readers for each imaging modality. Tumor histology was determined by a blinded central pathologist. The primary end points—average sensitivity and specificity for clear cell renal cell carcinoma (ccRCC)—were compared between the two modalities. Agreement between and within readers was assessed. Results 124I-girentuximab was well tolerated. In all, 195 patients had complete data sets (histopathologic diagnosis and PET/CT and CECT results) available. The average sensitivity was 86.2% (95% CI, 75.3% to 97.1%) for PET/CT and 75.5% (95% CI, 62.6% to 88.4%) for CECT (P = .023). The average specificity was 85.9% (95% CI, 69.4% to 99.9%) for PET/CT and 46.8% (95% CI, 18.8% to 74.7%) for CECT (P = .005). Inter-reader agreement was high (κ range, 0.87 to 0.92 for PET/CT; 0.67 to 0.76 for CECT), as was intrareader agreement (range, 87% to 100% for PET/CT; 73.7% to 91.3% for CECT). Conclusion This study represents (to the best of our knowledge) the first clinical validation of a molecular imaging biomarker for malignancy. 124I-girentuximab PET/CT can accurately and noninvasively identify ccRCC, with potential utility for designing best management approaches for patients with renal masses.

BACKGROUND. Some countries have limited the maximum allowable storage duration for red cells to 5 weeks before transfusion. In the US, red blood cells can be stored for up to 6 weeks, but randomized trials have not assessed the effects of this final week of storage on clinical outcomes. METHODS. Sixty healthy adult volunteers were randomized to a single standard, autologous, leukoreduced, packed red cell transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage (n = 10 per group). 51-Chromium posttransfusion red cell recovery studies were performed and laboratory parameters measured before and at defined times after transfusion. RESULTS. Extravascular hemolysis after transfusion progressively increased with increasing storage time (P < 0.001 for linear trend in the AUC of serum indirect bilirubin and iron levels). Longer storage duration was associated with decreasing posttransfusion red cell recovery (P = 0.002), decreasing elevations in hematocrit (P = 0.02), and increasing serum ferritin (P < 0.0001). After 6 weeks of refrigerated storage, transfusion was followed by increases in AUC for serum iron (P < 0.01), transferrin saturation (P < 0.001), and nontransferrin-bound iron (P < 0.001) as compared with transfusion after 1 to 5 weeks of storage. CONCLUSIONS. After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin, and produced circulating nontransferrin-bound iron. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal. REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02087514","term_id":"NCT02087514"}}NCT02087514. FUNDING. NIH grant HL115557 and UL1 TR000040.

Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of a ideal cellular target(s), available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability and most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in the context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles are discussed from the perspective of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analyses of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co‐occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P

To determine whether IVF clinics are compliant with American Society for Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology (SART) (ASRM/SART) guidelines and assess the multiple pregnancy outcomes according to the number of embryos transferred.Retrospective cohort study.Not applicable.Data from 59,689 fresh first autologous IVF cycles from the 2011-2012 SART registry.None.Percentage of compliant cycles, multiple pregnancy rate (PR).Between 2011 and 2012, a total of 59,689 fresh first autologous cycles were analyzed. Among cleavage-stage ET cycles, the noncompliance rate ranged from 10%-27.4% depending on the age group. The multiple PR was significantly increased in noncompliant cycles involving patients35 years (38.1% vs. 28.7%) and 35-37 years (35.4% vs. 24.5%) compared with compliant cycles. Among blastocyst-stage ET cycles, the highest rate of noncompliance was seen in patients35 years old (71%), which resulted in a statistically higher multiple PR (48.3% vs. 2.8%) compared with compliant cycles. Far fewer cycles were noncompliant in patients 35-40 years of age. In a subanalysis of compliant cycles, transferring two blastocyst embryos in patients 35-37 years and 38-40 years resulted in a higher live birth rate compared with the transfer of one embryo (50.4% vs. 40.9% and 42.1% vs. 30.0%, respectively) but the multiple PR was also significantly higher (40.5% vs. 1.7% and 34.0% vs. 2.0%, respectively).Most first fresh autologous IVF cycles performed from 2011-2012 were compliant with ASRM/SART guidelines, except those that involved a blastocyst ET in patients35 years. Despite compliance, cycles that involved the transfer of1 embryo resulted in a high multiple PR, whereas noncompliant cycles resulted in an even more remarkable multiple PR for both cleavage and blastocyst-stage embryos. Clinics need to be more compliant with ET limits and ASRM/SART need to consider revising their guidelines to limit the number of blastocyst transfer to one in patients ≤40 years of age undergoing their first IVF cycle. Furthermore, decreasing the number of cleavage-stage embryos transferred in patients ≤40 years of age should also be considered.