Biomarkers of systemic inflammation provide additional prognostic stratification in cancers of unknown primary.

BACKGROUND: Biomarkers of systemic inflammation have been shown to predict outcomes in patients with cancer of unknown primary (CUP). We sought to validate these findings in patients with confirmed CUP (cCUP) and explore their role alongside existing clinicopathological prognostic categories. PATIENTS AND METHODS: CUP oncologist from across the United Kingdom were invited to include patients with cCUP referred to their local CUP multidisciplinary team. Patient demographics, clinical, pathological and outcome data were recorded and analysed. RESULTS: Data were available for 548 patients from four CUP services. 23% (n = 124) of patients met clinicopathological criteria for favourable-risk cCUP. On multivariate analysis c-reactive protein (CRP) (p < 0.001) and the Scottish Inflammatory Prognostic Score (SIPS: combining albumin and neutrophil count) (p < 0.001) were independently predictive of survival. CRP and SIPS effectively stratified survival in patients with both favourable-risk and poor-risk cCUP based on clinicopathological features. CONCLUSIONS: Biomarkers of systemic inflammation are reliable prognostic factors in patients with cCUP, regardless of clinicopathological subgroup. We recommend that CRP or SIPS are incorporated into routine clinical assessments of patients with cCUP as a tool to aid investigation and/or treatment decision-making across all groups. Established clinicopathological factors can then be used to inform management pathways and specific systemic anticancer therapy selection.

Integrating electronic geriatric assessment and frailty screening for adults with acute myeloid leukemia to drive personalized treatment decisions.

PURPOSE: Evidenced based guidelines for patients with Acute Myeloid Leukemia (AML) acknowledge increasing importance of frailty assessment when deciding on treatment, yet comprehensive geriatric assessment (GA) results are not easily incorporated into clinic workflows and the electronic health record. This study assessed the feasibility of electronic GA use in a real-world environment. METHODS: Patients with AML, ≥ 60 years and at a treatment decision-making point were recruited at three academic institutions. An electronic GA (eGA) was completed by patients prior to starting treatment. Results were immediately available on a dashboard. Data on feasibility, useability and acceptability of the intervention were collected immediately after the clinical visit. Patients completed follow up surveys at 3 months and chart reviews were done to capture treatment and toxicities. RESULTS: 77 patients were enrolled with a median age of 71 years (range=61-88). The eGA results were 25 fit (31.0 %), 22 (32.0 %) intermediate, and 23 (31.0 %) frail. There was 62.7 % (n = 47) provider concordance with the eGA result and 27 (36.0 %) post visit reports indicated that the eGA results influenced the treatment decision. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. CONCLUSION: Patients easily completed an eGA prior to starting treatment. Results were reviewed by the physician and considered in the decision for optimal treatment. One third of physician reports indicated the results were used to inform the treatment decision. Feasibility of completing the eGA in the clinic without workflow disruption and utility of the results was demonstrated.

Goals, preferences, and concerns of patients with acute myeloid leukemia at time of treatment decision.

INTRODUCTION: Current cancer value-based models require documentation of patient goals of care and an evidence-based treatment course commensurate with patient goals. This feasibility study assessed the utility of an electronic tablet-based questionnaire to elicit patient goals, preferences, and concerns at a treatment decision making time point in patients with acute myeloid leukemia. MATERIALS AND METHODS: Seventy-seven patients were recruited from three institutions prior to seeing the physician for treatment decision-making visit. Questionnaires included demographics, patient beliefs, and decision-making preferences. Analyses included standard descriptive statistics appropriate for the level of measurement. RESULTS: Median age was 71 (range = 61-88), 64.9% female, 87.0% white, and 48.6% college educated. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. All but one patient completed the survey prior to starting treatment (98.7%). Providers reviewed the survey results prior to seeing the patient 97.4% of the time. When asked their goals of care, 57 (74.0%) patients agreed with the statement "my cancer is curable" and 75 (97.4%) agreed that the treatment goal was to get rid of all cancer. Seventy-seven (100%) agreed the goal of care is to feel better and 76 (98.7%) agreed the goal of care is live longer. Forty-one (53.9%) indicated they wanted to make treatment decisions together with the provider. The top two concerns were understanding treatment options (n = 24; 31.2%) and making the right decision (n = 22; 28.6%). DISCUSSION: This pilot demonstrated the feasibility of using technology for decision-making at the point of care. Eliciting patient goals of care, treatment outcomes expectations, decision-making preferences, and top concerns may provide clinicians with information to inform the treatment discussion. A simple electronic tool may provide valuable insight into patient understanding of disease to better tailor patient-provider discussion and treatment decision-making.

A Study Design to Harmonize Patient-Reported Outcomes Across Data Sets.

PURPOSE: Using patient-reported outcomes (PROs) provides important insights from the patient's perspective and can be valuable to monitor and manage treatment-related adverse events during cancer treatment. Additionally, the digital administration of PROs (electronic PROs [ePROs]) provides real-time updates to clinical care teams on treatment-related symptoms in-between clinic visits. However, given the variability in the methodology and timing of the data collection, using and harmonizing these data across different systems remains challenging. Identifying data elements to capture and operating procedures for harmonization across ePRO tools will expedite efforts to generate relevant and robust data on use of ePRO data in clinical care. METHODS: Friends of Cancer Research assembled a consortium of project partners from key health care sectors to align on a framework for ePRO data capture across ePRO tools and assessment of the impact of ePRO data capture on patient outcomes. RESULTS: We identified challenges and opportunities to align ePRO data capture across ePRO tools and aligned on key data elements for assessing the impact of ePRO data capture on patient care and outcomes. Ultimately, we proposed a study protocol to leverage ePRO data for symptom and adverse event management to measure real-world effectiveness of ePRO tool implementation on patient care and outcomes. CONCLUSION: This work provides considerations for harmonizing ePRO data sets and a common framework to align across multiple ePRO tools to assess the value of ePROs for improving patient outcomes. Future efforts to interpret evidence and evaluate the impact of ePRO tools on patient outcomes will be aided by improved alignment across studies.

Circulating Tumour DNA in Melanoma-Clinic Ready?

PURPOSE OF REVIEW: Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma. RECENT FINDINGS: In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic.

Delivering an iterative Communication Partner Training programme to multidisciplinary healthcare professionals: A pilot implementation study and process evaluation.

BACKGROUND: Despite evidence that Communication Partner Training (CPT) can enable health professionals to communicate more effectively with people with aphasia (PWA), an evidence-practice gap exists. To address this, a tailored implementation intervention was developed and trialled to improve health professionals' implementation of communication strategies in a subacute setting. AIMS: To explore the outcomes and perceived feasibility, acceptability and potential effectiveness of an iterative CPT implementation intervention on multidisciplinary healthcare professionals' communication with PWA. METHODS & PROCEDURES: The CPT implementation intervention was delivered to two groups of healthcare professionals (n = 6 and 7) approximately 6 months apart. The intervention underwent two iterations targeting emerging barriers to implementation success, with Group 2 receiving a modified version of the Group 1 intervention. A concurrent qualitative process evaluation was conducted to understand key factors determining implementation outcomes. Quantitative outcomes were recorded at baseline and 3-month follow-up, including the Measure of Skill in Supported Communication (MSC), a customized behavioural determinants survey mapped to the Theoretical Domains Framework (TDF) and the Organizational Readiness for Change survey. Focus groups and semi-structured interviews were conducted with health professional participants and the speech-language therapist trainer to explore perceptions of feasibility, acceptability and potential effectiveness. Content analysis was used to analyse the qualitative data, with categories and themes generated. OUTCOMES & RESULTS: The Group 2 implementation intervention was adapted based on feedback and reflections from Group 1 participants to incorporate more time for practice interactions and discussion during training, individual follow-up sessions and provision of accessible resources to aid communication attempts. There were greater improvements seen in the Group 2 outcomes on both the MSC and the TDF survey, suggesting that the iterative tailoring of the intervention was successful in addressing the barriers to change and led to improved implementation. The difference between the group's outcomes may also partly be explained by the impact of organizational readiness, which decreased during Group 1's implementation period. Despite similar themes emerging from the stakeholder perspectives in both groups (training factors, implementation facilitators, implementation barriers, and changes in knowledge and practice), these diverted in ways which served to explain the different implementation outcomes. CONCLUSIONS & IMPLICATIONS: An iteratively adapted CPT implementation intervention targeting healthcare professionals' use of supported communication strategies was feasible and acceptable for most participants. The implementation intervention was potentially effective in changing participants' communication with PWA, particularly for Group 2. Future CPT implementation efforts should continue to incorporate stakeholder input and tailor strategies to the organizational context, and measure whether outcomes are sustained in the long term. What this paper adds What is already known on the subject CPT is a complex intervention that can improve communication access and outcomes for PWA. However, there are barriers to both delivering CPT programmes to staff, and for staff in modifying their communication behaviours. Despite increasing efforts to improve CPT implementation, it remains largely unclear whether CPT implementation interventions are effective in improving interactions between staff and patients, and what elements of an implementation intervention result in changed behaviour. What this study adds to existing knowledge This study showed that adopting an iterative, barriers-focused approach to implementation facilitated practice change for one of the groups that participated in the programme. Incorporating stakeholder feedback in an ongoing way led to improvements in feasibility, acceptability and potential effectiveness, with several of the main barriers being effectively addressed by the intervention. Some key mechanisms of change were identified. What are the potential or actual clinical implications of this work It is necessary to develop active, targeted implementation strategies to support healthcare professionals to modify their communication, monitor implementation barriers as they arise and modify behaviour-change strategies accordingly. In a similar context, it is suggested that CPT implementation interventions should incorporate the use of audit feedback, physical resources and educational lectures paired with interactions with PWA in order to bring about change, with ongoing support and facilitation.

Secure Base Provision: A New Approach to Examining Links Between Maternal Caregiving and Infant Attachment.

This observational study addressed a critical gap in the understanding of the precursors of infant attachment by examining whether a new conceptualization of maternal caregiving behavior, secure base provision (SBP), explained variance in attachment above and beyond variance explained by sensitivity. Participants included 83 low-socioeconomic status (SES), 4.5-month-old infants (56% male) and their mothers. Infant-mother dyads completed laboratory tasks at 4.5 months and three 30-min home visits between 7 and 9 months, then returned to the laboratory at 12 months for an attachment assessment. Maternal sensitivity did not significantly predict infant attachment security. SBP significantly predicted infant attachment, over and above sensitivity, with an effect size eight times larger than that of sensitivity in meta-analytic findings for low-SES families.

Mechanosensor transient receptor potential vanilloid member 4 (TRPV4) regulates mouse cholangiocyte secretion and bile formation.

Mechanosensitive signaling has emerged as a mechanism for the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving increases in [Ca2+]i and activation of Ca2+-activated Cl- channels. However, the initiating steps translating shear force to increases in intracellular calcium concentration ([Ca2+]i) are unknown. Transient receptor potential vanilloid member 4 (TRPV4), a nonselective cation channel present in the apical membrane of cholangiocytes, has been proposed as a potential mechanosensor. The aim of the present studies was to determine the potential role of TRPV4 in initiating mechanosensitive signaling in response to fluid-flow in cholangiocytes. TRPV4 expression was confirmed in both small and large mouse cholangiocytes. Exposure of cells to either fluid flow or specific TRPV4 pharmacological agonists rapidly increased both [Ca2+]i and membrane cation currents. Both flow- and agonist-stimulated currents displayed identical biophysical properties and were inhibited in the presence of TRPV4 antagonists or in cells after transfection with TRPV4 small interfering RNA. Transfection of mouse cholangiocytes with a TRPV4-enhanced green fluorescent protein construct increased the expression of TRPV4 and the magnitude of flow-stimulated currents. A specific TRPV4 agonist significantly increased the biliary concentration of ATP and bile flow in live mice when administered intravenously and increased ATP release from cholangiocyte monolayers when applied exogenously. The findings are consistent with a model in which activation of cholangiocyte TRPV4 translates shear force into an acute rise in membrane cation permeability, [Ca2+]i, ATP release, and bile flow. Understanding the role of mechanosensitive transport pathways may provide novel insights to modulate bile flow for the treatment of cholestatic liver disorders.NEW & NOTEWORTHY These studies functionally characterize TRPV4 as a mechanosensitive channel in mouse cholangiocytes. By mediating a rapid rise in intracellular Ca2+, necessary for Ca2+-dependent secretion, TRPV4 represents a mechanosensor responsible for translating fluid flow into intracellular signaling and biliary secretion. Furthermore, intravenous infusion of a specific TRPV4 agonist increases bile flow in live mice. Understanding the role of TRPV4 in mechanosensitive transport pathways may provide novel insights to modulate bile flow during cholestasis.

Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors.

Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer.Experimental Design: Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data were used to compare IGF1R/InsR activation in estrogen receptor-positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.Results: Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin-deficient ER+ ILC compared with IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture.Conclusions: We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin-deficient breast cancers. Clin Cancer Res; 24(20); 5165-77. ©2018 AACR.

Enhanced reactive oxygen species through direct copper sulfide nanoparticle-doxorubicin complexation.

CuS-based nanostructures loading the chemotherapeutic agent doxorubicin (DOX) exerted excellent cancer photothermal chemotherapy under multi-external stimuli. The DOX loading was generally designed through electrostatic interaction or chemical linkers. However, the interaction between DOX molecules and CuS nanoparticles has not been investigated. In this work, we use PEGylated hollow copper sulfide nanoparticles (HCuSNPs) to directly load DOX through the DOX/Cu2+ chelation process. Distinctively, the synthesized PEG-HCuSNPs-DOX release the DOX/Cu2+ complexes into surrounding environment, which generate significant reactive oxygen species (ROS) in a controlled manner by near-infrared laser. The CuS nanoparticle-mediated photothermal ablation facilitates the ROS-induced cancer cell killing effect. Our current work reveals a DOX/Cu2+-mediated ROS-enhanced cell-killing effect in addition to conventional photothermal chemotherapy through the direct CuS nanoparticle-DOX complexation.

Obstetric Transport.

Obstetric transport is a specialized medical transport for maternal, fetal, and neonatal concerns. Perinatal regionalization of care provides a broader geographic availability of obstetric services with defined levels of maternal and neonatal care so that women can be transported to centers with increased resources and capabilities to reduce morbidity and mortality. The Emergency Medical Treatment and Active Labor Act provides regulatory guidance for care of laboring women who require transfer to a higher level of care. The Situation, Background, Assessment, and Recommendation communication can identify key pieces of medical information with recommendations given for mutual expectations of next steps.

Direct Dry-Grinding Synthesis of Monodisperse Lipophilic CuS Nanoparticles.

Copper sulfide nanoparticles, effective absorbers of near-infrared light, are recently attracting broad interest as a photothermal coupling agent for cancer therapy. Lipophilic copper sulfide nanoparticles are preferred for high performance biomedical applications due to high tissue affinity. Synthesis of lipophilic copper sulfide nanoparticles requires complicated multi-step processes under severe conditions. Here, we describe a new synthetic process, developed by direct dry-grinding of copper(II) acetylacetonate with sulfur under ambient environment at low temperature. The formed CuS nanoparticles are of uniform size, ~10 nm in diameter, and are monodispersed in chloroform. Each covellite CuS nanocrystal surface is modified with oleylamine through hydrogen bonding between sulfur atoms and amine groups of oleylamine. The nanoparticles demonstrate near-infrared light absorption for photothermal applications. The synthetic methodology described here is more convenient and less extreme than previous methods, and should thus greatly facilitate the preparation of photothermal lipophilic copper sulfide nanomaterials for cancer therapy.

Maternal-fetal transfer of anti-N-methyl-D-aspartate receptor antibodies.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a neuroautoimmune disease commonly associated with ovarian teratomas. It is characterized by neuropsychiatric symptoms, seizures, and autonomic instability. Few cases are described in pregnancy, and little is known about potential fetal effects. CASE: Anti-NMDA receptor encephalitis was diagnosed at 24 weeks of gestation. No improvement occurred with intravenous immunoglobulin, methylprednisolone, and plasmapheresis. Imaging was unremarkable. Cesarean delivery with concurrent bilateral oophorectomy resulted in prompt maternal improvement. Antibody titers were positive in cord blood. CONCLUSION: Anti-N-methyl-D-aspartate receptor encephalitis in pregnancy can lead to NMDA receptor antibodies in the fetal circulation. Pregnancy interruption through early delivery with or without oophorectomy may accelerate maternal recovery.

One-pot formation of multifunctional Pt-conducting polymer intercalated nanostructures.

A novel multifunctional Pt nanoparticle@PPy nanofiber intercalated structure (Pt NP@PPy NF) has been synthesized facilely in one-pot. Pt NPs, with size and facet control, were nicely assembled and embedded into the polymer nanofiber network. Polyvinylpyrrolidone (PVP) was used during the synthesis process which would assist the self-assembly of the metal nanoparticles and polymer backbones into the intercalated structure. Space-confined distribution of the Pt NPs was achieved within the large dimension PPy nanofiber network, which could enhance the interfacial electron transfer process as well as diminish the catalyst deformation. The as-formed Pt NPs have a cluster-like structure and are mainly composed of 3.5 nm primary Pt particles with (100) surface atoms. Enhanced electrocatalytic properties were shown by the Pt NP@PPy NF intercalated structure, with sufficiently high enzyme-less glucose biosensitivity and a long linear range from 1-30 mM (R = 0.9995). High electrochemical cycling stability, chloride (Cl(-)) tolerance and good selectivity are also obtained for the Pt NP@PPy NF structure, as the electrode showed no obvious response to the common interfering agents, such as ascorbic acid (AA), uric acid (UA), and 4-acetamidophenol (AP). Furthermore, the Pt NP@PPy NF showed excellent catalytic activity for the methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR), which displayed sufficient CO tolerance, and higher activity compared to the commercial Pt/C catalyst. This intrinsically multifunctional Pt NP@PPy NF with well-controlled Pt facets thus could serve as an advanced electrocatalyst for biosensing and fuel cell applications, surpassing the performance of many existing materials.

Phage-Like Streptococcus pyogenes Chromosomal Islands (SpyCI) and Mutator Phenotypes: Control by Growth State and Rescue by a SpyCI-Encoded Promoter.

We recently showed that a prophage-like Streptococcus pyogenes chromosomal island (SpyCI) controls DNA mismatch repair and other repair functions in M1 genome strain SF370 by dynamic excision and reintegration into the 5' end of mutL in response to growth, causing the cell to alternate between a wild type and mutator phenotype. Nine of the 16 completed S. pyogenes genomes contain related SpyCI integrated into the identical attachment site in mutL, and in this study we examined a number of these strains to determine whether they also had a mutator phenotype as in SF370. With the exception of M5 genome strain Manfredo, all demonstrated a mutator phenotype as compared to SpyCI-free strain NZ131. The integrase gene (int) in the SpyCIM5 contains a deletion that rendered it inactive, and this deletion predicts that Manfredo would have a pronounced mutator phenotype. Remarkably, this was found not to be the case, but rather a cryptic promoter within the int ORF was identified that ensured constitutive expression of mutL and the downstream genes encoded on the same mRNA, providing a striking example of rescue of gene function following decay of a mobile genetic element. The frequent occurrence of SpyCI in the group A streptococci may facilitate bacterial survival by conferring an inducible mutator phenotype that promotes adaptation in the face of environmental challenges or host immunity.

Detection of creatine kinase macroenzymes.

BACKGROUND: It is vital to detect macroenzymes in patients' plasma or serum since their presence may lead to spurious elevation of enzyme activity, thereby causing diagnostic confusion. Our service for macroenzyme detection has been made available to laboratories throughout the UK. This report describes our laboratory's experience with macro-creatine kinase (CK) detection over a 10-year period. METHODS: In each sample received, the presence of macro-CK was looked for by both polyethylene glycol percent precipitable activity (%PPA) and isoenzyme electrophoresis (IsoEP). The accumulated findings over 10 years were reviewed. RESULTS: Out of a total number of 255 requests received from throughout the UK, 30 patients (11.8%) were found to be positive for macro-CK (28 type 1 and 2 type 2). Among those found to be positive, the total CK elevation was relatively modest and the %PPA positively correlated with macro-CK by IsoEP and densitometry (Spearman r(s) = 0.631). The upper reference limit for %PPA of CK could be increased from 37% to 45% after assessment by both an International Federation of Clinical Chemistry-approved calculation and by receiver operating characteristic curve analysis. CONCLUSIONS: Adoption of this change would allow for a more cost-effective investigation protocol. More than 80% of those positive for macro-CK type 1 (immunoglobulin bound) were female, which conforms to findings in many autoimmune processes.

ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification.

Although many genes are known to be critical for early hematopoiesis in the embryo, it remains unclear whether distinct regulatory pathways exist to control hematopoietic specification versus hematopoietic stem cell (HSC) emergence and function. Due to their interaction with key regulators of hematopoietic commitment, particular interest has focused on the role of the ETS family of transcription factors; of these, ERG is predicted to play an important role in the initiation of hematopoiesis, yet we do not know if or when ERG is required. Using in vitro and in vivo models of hematopoiesis and HSC development, we provide strong evidence that ERG is at the center of a distinct regulatory program that is not required for hematopoietic specification or differentiation but is critical for HSC maintenance during embryonic development. We show that, from the fetal period, ERG acts as a direct upstream regulator of Gata2 and Runx1 gene activity. Without ERG, physiological HSC maintenance fails, leading to the rapid exhaustion of definitive hematopoiesis.

Soft tissue sarcoma with metastasis to the stomach: a case report.

Soft tissue sarcomas are unusual malignancies comprising 1% of cancer diagnoses in the United States. Undifferentiated pleomorphic sarcoma accounts for approximately 5% of sarcomas occurring in adults. The most common site of metastasis is the lung, with other sites being bone, the brain, and the liver. Metastasis to the gastrointestinal tract has rarely been documented. We present an unusual case of high-grade pleomorphic sarcoma with metastasis to the stomach, complicated by upper gastrointestinal bleeding.

Unusual case of dysphagia in a male.

Plummer Vinson Syndrome, a triad of dysphagia, esophageal web, and iron-deficiency anemia, is a rarely reported diagnosis in current literature. The exact etiology of the syndrome remains controversial, but it has been linked to complicated nutritional deficiencies, autoimmune disorders, and hereditary factors, and has a remarkably high female to male ratio. This paper describes an atypical case presentation in a 53-year-old male with a remote history of peptic ulcer disease surgery.

Genome sequence of a nephritogenic and highly transformable M49 strain of Streptococcus pyogenes.

The 1,815,783-bp genome of a serotype M49 strain of Streptococcus pyogenes (group A streptococcus [GAS]), strain NZ131, has been determined. This GAS strain (FCT type 3; emm pattern E), originally isolated from a case of acute post-streptococcal glomerulonephritis, is unusually competent for electrotransformation and has been used extensively as a model organism for both basic genetic and pathogenesis investigations. As with the previously sequenced S. pyogenes genomes, three unique prophages are a major source of genetic diversity. Two clustered regularly interspaced short palindromic repeat (CRISPR) regions were present in the genome, providing genetic information on previous prophage encounters. A unique cluster of genes was found in the pathogenicity island-like emm region that included a novel Nudix hydrolase, and, further, this cluster appears to be specific for serotype M49 and M82 strains. Nudix hydrolases eliminate potentially hazardous materials or prevent the unbalanced accumulation of normal metabolites; in bacteria, these enzymes may play a role in host cell invasion. Since M49 S. pyogenes strains have been known to be associated with skin infections, the Nudix hydrolase and its associated genes may have a role in facilitating survival in an environment that is more variable and unpredictable than the uniform warmth and moisture of the throat. The genome of NZ131 continues to shed light upon the evolutionary history of this human pathogen. Apparent horizontal transfer of genetic material has led to the existence of highly variable virulence-associated regions that are marked by multiple rearrangements and genetic diversification while other regions, even those associated with virulence, vary little between genomes. The genome regions that encode surface gene products that will interact with host targets or aid in immune avoidance are the ones that display the most sequence diversity. Thus, while natural selection favors stability in much of the genome, it favors diversity in these regions.