Monoclonal antibody (5G6.4) against ovarian carcinoma shows inhibition of in vitro colony formation

Monoclonal antibodies (MAbs) have the potential for diagnosis and therapy of cancer. 5G6.4 is a MAb of the IgG2a class which was produced by immunization of BALB/c mice with human ovarian carcinoma (Ov Ca) cells. To further characterize 5G6.4, its effect on cell growth was tested using a human Ov Ca cell line established in our laboratory. A clonogenic assay was set up in 48-well plates in a double agar system. The cells were plated and 5G6.4 was added at different concentrations. Control plates consisted of cells with media without MAb. Negative control plates were also prepared using the same concentrations of an isotype-matched antimelanoma MAb, 225.28s. Colony formation (CF) was reduced to 50% or less of control with increasing amounts of 5G6.4 up to 50 [mu]g/ml. Although CF was still depressed at concentrations above 50 [mu]g/ml, the inhibition did not follow a directly proportional line; instead, it followed a bell-shaped curve. Plates with the control MAb, 225.28s, did not show this response. Similar results were obtained with cells from malignant Ov Ca ascites in the same clonogenic assay. Our study suggests that in the evaluation of the in vitro effect of MAb on growth, the concentration of MAb is crucial and may not show a linear response and that 5G6.4 may have a direct therapeutic effect by blocking the growth of Ov Ca cells. 5G6.4 is presently under study for therapy in an animal model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26666/1/0000210.pd

Roadmap to a Comprehensive Clinical Data Warehouse for Precision Medicine Applications in Oncology

Leading institutions throughout the country have established Precision Medicine programs to support personalized treatment of patients. A cornerstone for these programs is the establishment of enterprise-wide Clinical Data Warehouses. Working shoulder-to-shoulder, a team of physicians, systems biologists, engineers, and scientists at Rutgers Cancer Institute of New Jersey have designed, developed, and implemented the Warehouse with information originating from data sources, including Electronic Medical Records, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology and Pathology archives, and Next Generation Sequencing services. Innovative solutions were implemented to detect and extract unstructured clinical information that was embedded in paper/text documents, including synoptic pathology reports. Supporting important precision medicine use cases, the growing Warehouse enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information of patient tumors individually or as part of large cohorts to identify changes and patterns that may influence treatment decisions and potential outcomes

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Monitoring Prevalence, Treatment, and Control Of Metabolic Conditions In New York City Adults Using 2013 Primary Care Electronic Health Records: A Surveillance Validation Study

Introduction: Electronic health records (EHRs) can potentially extend chronic disease surveillance, but few EHR-based initiatives tracking population-based metrics have been validated for accuracy. We designed a new EHR-based population health surveillance system for New York City (NYC) known as NYC Macroscope. This report is the third in a 3-part series describing the development and validation of that system. The first report describes governance and technical infrastructure underlying the NYC Macroscope. The second report describes validation methods and presents validation results for estimates of obesity, smoking, depression and influenza vaccination. In this third paper we present validation findings for metabolic indicators (hypertension, hyperlipidemia, diabetes). Methods:We compared EHR-based estimates to those from a gold standard surveillance source – the 2013-2014 NYC Health and Nutrition Examination Survey (NYC HANES) – overall and stratified by sex and age group, using the two one-sided test of equivalence and other validation criteria. Results: EHR-based hypertension prevalence estimates were highly concordant with NYC HANES estimates. Diabetes prevalence estimates were highly concordant when measuring diagnosed diabetes but less so when incorporating laboratory results. Hypercholesterolemia prevalence estimates were less concordant overall. Measures to assess treatment and control of the 3 metabolic conditions performed poorly. Discussion:While indicator performance was variable, findings here confirm that a carefully constructed EHR-based surveillance system can generate prevalence estimates comparable to those from gold-standard examination surveys for certain metabolic conditions such as hypertension and diabetes. Conclusions: Standardized EHR metrics have potential utility for surveillance at lower annual costs than surveys, especially as representativeness of contributing clinical practices to EHR-based surveillance systems increases

Comparison between nasopharyngeal swab and nasal wash, using culture and PCR, in the detection of potential respiratory pathogens

<p>Abstract</p> <p>Background</p> <p>Nasopharyngeal carriage of potential pathogens is important as it is both the major source of transmission and the prerequisite of invasive disease. New methods for detecting carriage could improve comfort, accuracy and laboratory utility. The aims of this study were to compare the sensitivities of a nasopharyngeal swab (NPS) and a nasal wash (NW) in detecting potential respiratory pathogens in healthy adults using microbiological culture and PCR.</p> <p>Results</p> <p>Healthy volunteers attended for nasal washing and brushing of the posterior nasopharynx. Conventional and real-time PCR were used to detect pneumococcus and meningococcus. Statistical differences between the two nasal sampling methods were determined using a nonparametric Mann-Whitney U test; differences between culture and PCR methods were determined using the McNemar test.</p> <p>Nasal washing was more comfortable for volunteers than swabbing (n = 24). In detection by culture, the NW was significantly more likely to detect pathogens than the NPS (<it>p </it>< 0.00001). Overall, there was a low carriage rate of pathogens in this sample; no significant difference was seen in the detection of bacteria between culture and PCR methods.</p> <p>Conclusions</p> <p>Nasal washing and PCR may provide effective alternatives to nasopharyngeal swabbing and classical microbiology, respectively.</p

Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study

BACKGROUND: While there is extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention. METHODS: We conducted a population-based case-control study to evaluate phytoestrogen intake from foods and supplements and epithelial ovarian cancer risk. Cases were identified in six counties in New Jersey through the New Jersey State Cancer Registry. Controls were identified by random digit dialing, CMS (Centers for Medicare and Medicaid Service) lists, and area sampling. A total of 205 cases and 390 controls were included in analyses. Unconditional logistic regression analyses were conducted to examine associations with total phytoestrogens, as well as isoflavones (daidzein, genistein, formononetin, and glycitein), lignans (matairesinol, lariciresinol, pinoresinol, secoisolariciresinol), and coumestrol. RESULTS: No statistically significant associations were found with any of the phytoestrogens under evaluation. However, there was a suggestion of an inverse association with total phytoestrogen consumption (from foods and supplements), with an odds ratio (OR) of 0.62 (95% CI: 0.38-1.00; p for trend: 0.04) for the highest vs. lowest tertile of consumption, after adjusting for reproductive covariates, age, race, education, BMI, and total energy. Further adjustment for smoking and physical activity attenuated risk estimates (OR: 0.66; 95% CI: 0.41-1.08). There was little evidence of an inverse association for isoflavones, lignans, or coumestrol. CONCLUSIONS: This study provided some suggestion that phytoestrogen consumption may decrease ovarian cancer risk, although results did not reach statistical significance

Clonal transitions and phenotypic evolution in Barrett esophagus

BACKGROUND & AIMS: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS: We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE

Lipid-specific IgMs induce antiviral responses in the CNS: implications for progressive multifocal leukoencephalopathy in multiple sclerosis

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS

Oral prehabilitation for patients with head and neck cancer:getting it right - the Restorative Dentistry-UK consensus on a multidisciplinary approach to oral and dental assessment and planning prior to cancer treatment

Historically, oral and dental issues for head and neck cancer patients were often not considered until after cancer treatment was complete. As a result, outcomes for oral rehabilitation were sometimes suboptimal. Inconsistencies in service delivery models and qualification, training and experience of staff delivering dental care often compounded this problem, making research and audit almost impossible. Collaborative working by consultants in restorative dentistry from all over the UK as part of a Restorative Dentistry-UK (RD UK) subgroup, renamed more recently as the RD-UK Head and Neck Cancer Clinical Excellence Network (CEN), has re-emphasised the importance of specialist restorative dentistry intervention at the outset of the head and neck cancer pathway to optimise outcomes of patient care. The CEN has driven several initiatives, reflecting Getting It Right First Time (GIRFT) principles aimed at reducing unwarranted variation. This improved consistency in approach and optimised collaborative working of the team now presents a better environment for multicentre audit and research. Ultimately, this should result in a continued improvement in patient and carer experience