Yersinia Enterocolitica Sepsis in an Elderly Male With No Iron Overload: A Case Report From the Northeastern United States.

Yersinia enterocolitica (YE) is a facultative anaerobic gram-negative coccobacillus of the genus Yersinia (the most common ones are YE serogroups O:3; O:5,27; O:8; and O:9). Its incubation period is typically 1-14 days. The symptoms of YE infection include fever, abdominal pain (which may mimic appendicitis), and diarrhea (which may be bloody and can persist for several weeks). It is most commonly reported in infants and children due to cross-contamination of their feeds and pacifiers by people handling pork products, especially while cooking chitterlings. Necrotizing enterocolitis has been described in infants following YE infections. Adults who are immunocompromised or in an iron-overload state can develop sepsis with YE infection, which has a high fatality rate. Post-infectious sequelae like reactive arthritis and erythema nodosum can occur in certain HLA types. The diagnosis is made by isolating the organism from the body fluids, stool. The gastrointestinal (GI) pathogen panel by polymerase chain reaction (PCR) is helpful in making an early diagnosis. In this report, we discuss a case of an elderly male from a nursing facility who presented with abdominal pain, vomiting, GI bleeding, and sepsis. He required a brief ICU stay and pressor support. GI pathogen panel was instrumental in the early diagnosis of YE. This condition is not often reported in the Northeastern US. Using GI pathogen PCR testing will lead to the detection of more cases of YE in geographical regions where it was not considered prevalent.

Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics.

We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.

Differences in Access to and Use of Electronic Personal Health Information Between Rural and Urban Residents in the United States.

PURPOSE: The increase in use of health information technologies (HIT) presents new opportunities for patient engagement and self-management. Patients in rural areas stand to benefit especially from increased access to health care tools and electronic communication with providers. We assessed the adoption of 4 HIT tools over time by rural or urban residency. METHODS: Analyses were conducted using data from 7 iterations of the National Cancer Institute's Health Information National Trends Survey (HINTS; 2003-2014). Rural/urban residency was based on the USDA's 2003 Rural-Urban Continuum Codes. Outcomes of interest included managing personal health information online; whether providers maintain electronic health records (EHRs); e-mailing health care providers; and purchasing medicine online. Bivariate analyses and logistic regression were used to assess relationships between geography and outcomes, controlling for sociodemographic characteristics. FINDINGS: In total, 6,043 (17.6%, weighted) of the 33,749 respondents across the 7 administrations of HINTS lived in rural areas. Rural participants were less likely to report regular access to Internet (OR = 0.70, 95% CI = 0.61-0.80). Rural respondents were neither more nor less likely to report that their health care providers maintained EHRs than were urban respondents; however, they had decreased odds of managing personal health information online (OR = 0.59, 95% CI = 0.40-0.78) and e-mailing health care providers (OR = 0.62, 95% CI = 0.49-0.77). CONCLUSIONS: The digital divide between rural and urban residents extends to HIT. Additional investigation is needed to determine whether the decreased use of HIT may be due to lack of Internet connectivity or awareness of these tools.

The Health Information National Trends Survey (HINTS): A Resource for Consumer Engagement and Health Communication Research.

The contemporary healthcare system can help improve health literacy outcomes in two ways: first, by nurturing the skills and motivations needed for patients to be actively engaged in their own health and healthcare decisions; and, second, by creating a prepared and proactive healthcare system that adapts to patients' capacities and needs in efficacious ways. In 2001, the National Cancer Institute launched the Health Information National Trends Survey (HINTS) as a way for researchers and planners to understand how the public is interacting with a rapidly changing health information environment. Original iterations of the HINTS national probability sampling strategies took place on a biennial basis, but in subsequent years the protocol moved to a yearly administration. This yields a rich resource of cross-sectional, national surveillance data to evaluate for trends across and within vulnerable populations. Sixteen studies are presented from the published literature to illustrate how HINTS data were used to explore constructs of direct interest to health literacy researchers. Suggestions are given for how this ongoing public surveillance mechanism can be used: (a) to provide a sentinel view of how the public is interacting with information in the environment to address their health needs; (b) to generate research questions and hypotheses for further exploration using complementary methodologies; and

Common medications and prostate cancer mortality: a review.

PURPOSE: Most prostate cancer patients also have comorbidities that are treated with both prescription and nonprescription medications; furthermore, many use dietary supplements. We assess their association with prognosis after prostate cancer diagnosis, and we discuss methodological challenges and clinical implications. METHODS: We reviewed high-quality observational studies investigating the association of commonly used medications and supplements with prostate cancer-specific mortality. RESULTS: There is preliminary evidence that statins and metformin use may be associated with lower risk of cancer-specific mortality after prostate cancer diagnosis; conversely, high calcium and multivitamin supplementation may be associated with increased risk. Evidence is inconclusive for nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (aspirin), insulin, antihypertensives such as angiotensin-converting enzyme inhibitors and beta-blockers, digoxin, and warfarin. Common limitations of the internal validity of studies examined include unmeasured confounding and confounding by indication, competing risks, and time-related biases such as immortal time bias. The majority of studies focused on Caucasian men with specific comorbidities, while heterogeneity among patients and tumors was mostly not assessed. CONCLUSIONS: Commonly prescribed medications and over-the-counter supplements may influence prognosis among prostate cancer patients. Further well-designed pharmacoepidemiologic studies and randomized controlled trials of selected medications in appropriate patient groups are necessary before these drugs can bear new indications for prostate cancer treatment. We discuss considerations when deciding about use of these drugs in clinical practice at the present time.

The Value of Systematic Reviews in Estimating the Cost and Barriers to Translation in Tissue Engineering.

Little quantitative data exist concerning barriers that impede translation from bench to bedside. We systematically reviewed synthetic or biosynthetic polymer nerve scaffolds for peripheral nerve repair to study a defined research area that is beyond the discovery phase and has potential for clinical application. Using electronic and manual search methods, we identified published English language articles, where scaffolds were tested in preclinical animal models. A systematic review of these 416 reports estimated all costs related to the use of animals, surgery, and evaluation methods. The research studied 17 different nerves in eight animal species, with use of 65 evaluation methods at an estimated cost of $61,264,910 for the preclinical studies. A total of 127 surveys were sent to authors, of whom 12 could not be accessed electronically and 45 (39%) responded. Major causes for failure to translate included lack of a commercial partner, insufficient financial resources, a research program not involved in translation, and lack of expertise in regulatory affairs. This review emphasizes the urgent need for standardization of preclinical models and the need to establish better collaboration between laboratory investigators, clinicians, and the companies involved in commercialization. It identifies important areas for education of future investigators in the process of translation from discovery to improved health such as those funded by the National Institutes of Health Clinical and Translational Science Awards.

The role of Internet resources in clinical oncology: promises and challenges.

The Internet is a valuable tool that continues to revolutionize many aspects of our lives; however, the ability to disseminate diverse data across populations and nations presents both opportunities and challenges. Online resources are increasingly used in health care, providing wider access to information for patients, researchers, and clinicians. At the turn of the millennium, the National Cancer Institute (NCI) predicted that Internet-based technologies would create a revolution in communication for oncology professionals and patients with cancer. Herein, findings from the NCI's Health Information National Trends Survey are reviewed to give insight into how Internet trends related to oncology patients are evolving. Future trends are discussed, including examples of 'connected health' in oncology; the spread of mobile and ubiquitous access points to Internet-hosted information; the diffusion of devices, sensors, and apps; the spread of personal data sharing; and an evolution in how networks can support person-centred and family-centred care.

The association of copy number variation and percent mammographic density.

BACKGROUND: Percent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer. Inherited factors are hypothesized to explain between 30 and 60% of the variance in this trait. However, previously identified common genetic variants account for less than 6% of the variance in PD, leaving much of the genetic contribution to this trait unexplained. We performed the first study to examine whether germline copy number variation (CNV) are associated with PD. Two genome-wide association studies (GWAS) of percent density conducted on the Illumina 660W-Quad were used to identify and replicate the association between candidate CNVs and PD: the Minnesota Breast Cancer Family Study (MBCFS) and controls from the Mayo Venous Thromboembolism (Mayo VTE) Case-Control Study, with 585 and 328 women, respectively. Linear models were utilized to examine the association of each probe with PD, adjusted for age, menopausal status and BMI. Segmentation was subsequently performed on the probe-level test statistics to identify candidate CNV regions that were associated with PD. RESULTS: Sixty-one probes from five chromosomal regions [3q26.1 (2 regions), 8q24.22, 11p15.3, and 17q22] were significantly associated with PD in MBCFS (p-values <0.0001). A CNV at 3q26.1 showed the greatest evidence for association with PD; a region without any known SNPs. Conversely, the CNV at 17q22 was largely due to the association between SNPs and PD in the region. SNPs in the 8q24.22 region have been shown to be associated with risk of many cancers; however, SNPs in this region were not responsible for the observed CNV association. While we were unable to replicate the associations with PD, two of the five CNVs (3q26.1 and 11p15.3) were also observed in the Mayo VTE controls. CONCLUSIONS: CNVs may help to explain some of the variability in PD that is currently unexplained by SNPs. While we were able to replicate the existence of two CNVs across the two GWAS studies, we were unable to replicate the associations with PD. Even so, the proximity of the identified CNV regions to loci known to be associated with breast cancer risk suggests further investigation and potentially shared genetic mechanisms underlying the PD and breast cancer association.

Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients.

Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P=6 × 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P=0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.

Clinical Course and Prognosis of Non-Secretory Multiple Myeloma.

OBJECTIVE: To determine the prognosis of patients with non-secretory myeloma. Methods: We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow up testing (non-secretory myeloma). The overall survival (OS) of patients with non-secretory myeloma was compared with 7075 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis. RESULTS: One hundred and twenty four patients met criteria for non-secretory multiple myeloma. The median follow-up was 102 months (range, 1-204 months). The median progression free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 99.2 versus 43.8 months (prior to 2001) versus 99.2 months (2001-2012), P<0.001. OS was superior in patients with a normal baseline FLC ratio (n=10) compared to patients with an abnormal ratio (n=19), medians not reached in both groups. Prior to 2001, OS was similar in non-secretory myeloma (n=86) and secretory myeloma (n=4011), median 3.6 versus 3.5 years, respectively, P=0.63. However, among patients diagnosed between 2001-2012, OS was superior in non-secretory myeloma (n=36) compared to secretory myeloma (n=2942), median 8.3 versus 5.4 years, respectively, P=0.03. CONCLUSIONS: Non-secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non-secretory myeloma, and appears superior to secretory myeloma. This article is protected by copyright. All rights reserved.

Clinical course and prognosis of non-secretory multiple myeloma.

OBJECTIVE: To determine the prognosis of patients with non-secretory myeloma. METHODS: We studied 124 patients diagnosed with multiple myeloma who had no monoclonal protein detected on serum and urine immunofixation at diagnosis and on all subsequent follow-up testing (non-secretory myeloma). The overall survival (OS) of patients with non-secretory myeloma was compared with 6953 patients with typical myeloma seen during the same time period in whom a monoclonal protein was detected at the time of diagnosis. RESULTS: One hundred and twenty-four patients met criteria for non-secretory multiple myeloma. The median follow-up was 102 months (range, 1-204 months). The median progression-free survival with initial therapy was 28.6 months, and the median OS was 49.3 months. There was a significant improvement in OS since 2001; median survival 43.8 months (prior to 2001) vs. 99.2 months (2001-2012), P < 0.001. OS was superior in patients with a normal baseline FLC ratio (n = 10) compared to patients with an abnormal ratio (n = 19), medians not reached in both groups. Prior to 2001, OS was similar in non-secretory myeloma (n = 86) and secretory myeloma (n = 4011), median 3.6 vs. 3.5 yr, respectively, P = 0.63. However, among patients diagnosed between 2001 and 2012, OS was superior in non-secretory myeloma (n = 36) compared to secretory myeloma (n = 2942), median 8.3 vs. 5.4 yr, respectively, P = 0.03. CONCLUSIONS: Non-secretory myeloma is an uncommon subtype of multiple myeloma. In the last decade, there has been an improvement in the survival of non-secretory myeloma and appears superior to secretory myeloma.

Rituximab for non-Hodgkin's lymphoma: a story of rapid success in translation.

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Responsiveness of cytogenetically discrete human myeloma cell lines to lenalidomide: lack of correlation with cereblon and interferon regulatory factor 4 expression levels.

The introduction of novel immunomodulatory drugs (IMiDs) has dramatically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib-based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). We examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its downstream target interferon regulatory factor-4 (IRF4), which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that lenalidomide response did not correlate with specific cytogenetic translocations. There were distinct groups of lenalidomide-responsive and non-responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC-1 (IC50 = 2.6 µm vs. 0.005 µm, P < 0.0001), but did not have an effect on the IC50 of the non-responsive DP-6 HMCL (P > 0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN and IRF4 expression. Our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. While CRBN and IRF4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment.

Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma.

We previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first-degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.

Increased prevalence of light chain monoclonal gammopathy of undetermined significance (LC-MGUS) in first-degree relatives of individuals with multiple myeloma.

Previously, we reported increased risk of heavy-chain (HC) monoclonal gammopathy of undetermined significance (MGUS) among first-degree (1°) relatives of multiple myeloma (MM) or HC-MGUS probands. This study investigated whether there was comparable risk for light-chain (LC) MGUS among 911 relatives of the same HC-MGUS/MM probands versus a reference population of 21 463. Seventeen 1° relatives had LC-MGUS (adjusted prevalence = 1·7%, 95% CI = 0·9­2·6%). There was increased risk of LC-MGUS in relatives of MM probands (RR = 3·4, 95% CI = 2·0­5·5). We saw no increased risk in relatives of HC-MGUS probands. We conclude that the prevalence of LC-MGUS is significantly higher among 1° relatives of MM probands compared to the reference population.

Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics.

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics.

Routine incorporation of FISH into multiple myeloma (MM) diagnostic testing has led to a better appreciation of the heterogeneity of genetic abnormalities associated with this disease. We studied a group of 484 patients with newly diagnosed symptomatic MM to better understand the prevalence of the various abnormalities and the prognostic significance of the overlapping abnormalities. A translocation involving the IgH locus and 1 of the 5 recurrent partner chromosomes was seen in 161 (33%) patients, and 275 (57%) had trisomy of at least 1 odd-numbered chromosome. High-risk FISH, defined as the presence of t(4;14), t(14;16), t(14;20), or loss of P53, was seen in 115 (24%) patients; the median overall survival for this group was 3.9 years, compared with "not reached" for standard-risk patients (P < .001). Among the patients with high-risk FISH, 49 patients who also had at least 1 trisomy had a median overall survival that was not reached, compared with 3 years for high-risk patients without a concurrent trisomy (P = .01). Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers.

Linking expression of FOXM1, CEP55 and HELLS to tumorigenesis in oropharyngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: To investigate the relationship between the expression of FOXM1, CEP55, and HELLS in oropharyngeal squamous cell carcinoma to human papillomavirus (HPV), smoking, and tumor stage. STUDY DESIGN: Retrospective cohort study. METHODS: Transcriptome data were analyzed from matched tumor-normal samples taken from patients with oropharyngeal squamous cell carcinoma. Data were previously generated using deep-sequencing techniques (mRNA-Seq). Transcript levels of all three genes were validated using the NanoString nCounter system in a larger group of patients. Analyses were conducted to assess possible associations between expression levels and HPV infection status, smoking status, or tumor staging. RESULTS: FOXM1, CEP55, and HELLS were all overexpressed in oropharyngeal squamous cell carcinoma tissue when compared to normal tissue. Significant trends were found between expression levels of FOXM1, CEP55, and HELLS and tumor staging. Tumors staged 3 or greater showed significantly higher levels of expression compared with those staged 1. No significant association or trend was found between expression of any genes of interest and etiologic subgroupings (i.e., HPV, smoking). CONCLUSIONS: FOXM1, CEP55, and HELLS were all overexpressed in oropharyngeal squamous cell carcinoma. Gene expression is related to tumor stage. The significant association between the expression of these genes and advanced tumor stage suggest that they may play a role in tumorigenesis.