Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.

In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).

Composite mantle cell and primary cutaneous anaplastic large cell lymphoma: case report and review of the literature.

We describe the first reported occurrence of a composite cutaneous lymphoma involving a mantle cell lymphoma (MCL) and primary cutaneous anaplastic large cell lymphoma. The lesion occurred in a 76-year-old man with longstanding MCL who developed nodular skin lesions on his trunk and extremities. Biopsy revealed a CD30-positive lymphoma with pathological features characteristic of cutaneous anaplastic large cell lymphoma in the superficial dermis and a subjacent deposit of MCL in the deep dermis and subcutaneous adipose tissue. Immunophenotyping demonstrated T versus B lymphoid origin, respectively, for the 2 neoplasms, and fluorescence in situ hybridization demonstrated an 11;14 chromosomal translocation exclusively in the MCL. These results argue that the lymphomas represented clonally distinct neoplasms. Our case illustrates the extreme diversity associated with the cutaneous manifestations of lymphoid neoplasia and in particular of composite lymphomas, which present diagnostic challenges for clinicians and pathologists alike.

Human Papillomavirus-Related Ovarian Metastasis With Endocervical Adenocarcinoma: Report of 2 Cases and Review of Literature.

BACKGROUND: Most endocervical adenocarcinomas are associated with human papillomavirus (HPV) infection. Studies suggest that synchronous endocervical and ovarian tumors can contain identical HPV subtypes and that, in this setting, the ovarian tumors likely represent metastases from the endocervical adenocarcinoma rather than 2 independent primaries. However, there are still relatively few reports in the literature. RESULTS: We describe 2 patients with HPV-related endocervical adenocarcinoma or adenocarcinoma in situ who had metastatic ovarian tumors that simulated primary ovarian neoplasms. After total hysterectomy and bilateral salpingo-oophorectomy, patient 1, in her mid-40s, was diagnosed with endocervical adenocarcinoma in situ and patient 2, in her early 50s, was diagnosed with endocervical adenocarcinoma showing early focal stromal invasion. The ovarian tumors in both cases simulated independent borderline mucinous tumors without evidence of surface involvement or spread beyond the ovary. However, in both cases, the cervical and ovarian tumors showed diffuse, strong P16 staining and contained identical high-risk HPV subtypes (subtypes 16 and 18 in patient 1 and subtype 16 in patient 2). Patient 1 was treated with radiation therapy and remains recurrence free 5 years after diagnosis, and patient 2 has recently completed combined modality treatment with radiation therapy and cisplatin chemotherapy and remains recurrence free 10 months after diagnosis. CONCLUSIONS: A high index of suspicion and ancillary testing, including P16 immunostaining and molecular genetic testing for HPV, is required to properly diagnose and subclassify HPV-related endocervical adenocarcinoma metastatic to the ovary.

Exemestane for breast-cancer prevention in postmenopausal women.

BACKGROUND: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS: In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS: A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

Interprofessional care of people with multiple chronic conditions: An open-access resource for nursing educators.

Nurses, nurse practitioners, and other healthcare professionals must be prepared to care for the growing population of patients with multiple chronic conditions, to promote patient engagement, patient self-management, and for interprofessional collaboration. Interprofessional Care of Individuals with Multiple Chronic Conditions is an open-access eLearning course designed to prepare students with these skills. The course features multimedia presentations, interactive exercises, and an immersive "day in the life of a patient-centered medical home" in which learners make decisions, receive feedback, and experience consequences in the context of real-world video scenarios. Three hundred thirty-four nurse practitioner students participated in the educational program. To evaluate the program, we conducted a paired-samples t-test to compare scores on pre and posttest evaluation surveys. There was a significant difference in the scores for applying the Chronic Care Model t (df) = 15.99; p < 0.001, coaching for self-management t (df) = 11.04; p < 0.001 and interprofessional collaboration t (df) = 3.86; p < 0.00. The majority of students were satisfied or very satisfied with the modules. Students found the immersive video scenarios to be the best feature of the course. The course is available to assist students in gaining the ability to care for patients with chronic illnesses within interprofessional practice settings.

Predicting outcome in follicular lymphoma by using interactive gene pairs.

PURPOSE: Follicular lymphoma is a common lymphoma of adults. Although its course is often indolent, a substantial proportion of patients have a poor prognosis, often due to rapid progression or transformation to a more aggressive lymphoma. Currently available clinical prognostic scores, such as the follicular lymphoma international prognostic index, are not able to optimally predict transformation or poor outcome. EXPERIMENTAL DESIGN: Gene expression profiling was done on primary lymphoma biopsy samples. RESULTS: Using a statistically conservative approach, predictive interaction analysis, we have identified pairs of interacting genes that predict poor outcome, measured as death within 5 years of diagnosis. The best gene pair performs >1,000-fold better than any single gene or the follicular lymphoma international prognostic index in our data set. Many gene pairs achieve outcome prediction accuracies exceeding 85% in extensive cross-validation and noise sensitivity computational analyses. Many genes repeatedly appear in top-ranking pairs, suggesting that they reproducibly provide predictive capability. CONCLUSIONS: The evidence reported here may provide the basis for an expression-based, multi-gene test for predicting poor follicular lymphoma outcomes.

The reliability of lymphoma diagnosis in small tissue samples is heavily influenced by lymphoma subtype.

A specific pathologic diagnosis is important in malignant lymphoma because the diverse disease subtypes require tailored approaches to clinical management. Reliance on small samples obtained with cutting needles has been advocated as a less invasive alternative to using larger, excised samples. Although published studies have demonstrated the safety and apparent sufficiency of this approach in informing clinical care, none have systematically determined the accuracy of pathologic lymphoma subtyping based on very small samples. We used a tissue microarray representing 67 cases of malignant lymphoma and 17 samples of nonneoplastic lymphoid tissue to model lymphoma diagnosis in small samples. Overall, 73.8% of the cases were diagnosed with a level of confidence deemed sufficient for directing clinical management; 85.9% of these diagnoses were accurate. Small cell lymphomas with highly distinctive immunophenotypes, including small lymphocytic, mantle cell, and T-lymphoblastic lymphoma, were recognized most consistently and accurately in the small samples. In contrast, follicular lymphoma and marginal zone lymphoma were especially difficult. Our results indicate that the reliability of lymphoma diagnoses based on small samples is heavily influenced by lymphoma subtype.

First fatal case of systemic suppurative/necrotizing granulomatous disease following etanercept therapy for psoriasis.

Tumour necrosis factor (TNF) plays an important role in the formation and maintenance of granulomas, whereas TNF inhibition leads to downregulation of adhesion molecules and decrease in circulating inflammatory cytokines. TNF inhibitor therapy has been associated with reactivation of infections with diminished granuloma formation and development of sarcoidosis-like granulomas in different organs, with no known reports of mortality. We describe the first fatal case of systemic suppurative granulomatous disease in a 41-year-old man following etanercept therapy for severe cutaneous psoriasis and deforming psoriatic arthritis. We describe the clinical course with macroscopic and microscopic findings at autopsy and a review of the relevant literature. Practicing physicians should be aware of the first fatality associated with systemic suppurative granulomatous disease following etanercept therapy.

Nursing Education Transformation: Promising Practices in Academic Progression.

BACKGROUND: Health care has changed over the past decade; yet, nursing education has not kept pace with social and scientific advances. The Institute of Medicine report, The Future of Nursing: Leading Change, Advancing Health, called for a more highly educated nursing work-force and an improved nursing education system. Since the release of that report, the Future of Nursing: Campaign for Action, supported by the Robert Wood Johnson Foundation, AARP, and the AARP Foundation, has worked with nursing education leaders to better understand existing and evolving nursing education structures. METHOD: Through a consensus-building process, four overarching promising practice models, with an emphasis on seamless academic progression, emerged to advance the goals of education transformation. RESULTS: Key nurse educators and other stakeholders refined those models through a series of meetings, collaborative partnerships, and focused projects that were held across the United States. CONCLUSION: This article summarizes that process and provides a description of the models, challenges, common themes, recommendations, and progress to date.

Herpes simplex virus lymphadenitis: the elusive doppelganger in immunocompromised patients.

Herpes simplex virus has protean manifestations and is an important cause of morbidity in the immunocompromised host. We report a case of recurrent lymphadenopathy and rash in a patient with chronic lymphocytic leukemia. The elusive clinical diagnosis eventually required core biopsy of a lymph node with immunohistochemistry and confirmation by polymerase chain reaction. This case illustrates the challenging clinical and laboratory diagnosis of herpes simplex virus lymphadenitis and the need to maintain a high index of suspicion for infection when treating an immunocompromised patient with unusual and/or persistent symptoms.

A comparison of rural versus urban trauma care.

OBJECTIVE: We compared the survival of trauma patients in urban versus rural settings after the implementation of a novel rural non-trauma center alternative care model called the Model Rural Trauma Project (MRTP). MATERIALS AND METHODS: We conducted an observational cohort study of all trauma patients brought to eight rural northern California hospitals and two southern California urban trauma centers over a one-year period (1995-1996). Trauma patients with an injury severity score (ISS) of >10 were included in the study. We used logistic regression to assess disparities in odds of survival while controlling for Trauma and Injury Severity Score (TRISS) parameters. RESULTS: A total of 1,122 trauma patients met criteria for this study, with 336 (30%) from the rural setting. The urban population was more seriously injured with a higher median ISS (17 urban and 14 rural) and a lower Glasgow Coma Scale (GCS) (GCS 14 urban and 15 rural). Patients in urban trauma centers were more likely to suffer penetrating trauma (25% urban versus 9% rural). After correcting for differences in patient population, the mortality associated with being treated in a rural hospital (OR 0.73; 95% CI 0.39 to 1.39) was not significantly different than an urban trauma center. CONCLUSION: This study demonstrates that rural and urban trauma patients are inherently different. The rural system utilized in this study, with low volume and high blunt trauma rates, can effectively care for its population of trauma patients with an enhanced, committed trauma system, which allows for expeditious movement of patients toward definitive care.

Differential expression of cell-cycle regulatory proteins defines distinct classes of follicular lymphoma.

Follicular lymphoma, a relatively common neoplasm of mature B lymphocytes, generally pursues an indolent clinical course. The disease is biologically heterogeneous, however, and aggressive instances associated with short survival are relatively common. Because defects in the regulation of apoptotic cell death are fundamental in follicular lymphoma pathogenesis, we hypothesized that deregulated expression of components of the Rb signaling pathway may promote cell proliferation, thereby complementing antecedent antiapoptotic mutations and producing more aggressive disease. We determined the differential expression of key cell-cycle regulatory proteins in lymphoma cells by incorporating formalin-fixed, paraffin-embedded samples from the initial, diagnostic biopsies from 127 cases of follicular lymphoma into tissue microarrays, histologic sections of which were stained by immunohistochemistry for p53, pRb, p16(INK4a), and cyclin D3. The results were ascertained by visual inspection and then correlated with histopathological and clinical parameters, including overall survival. Our findings show that increased abundance of p53 or p16(INK4a) is associated with reduced overall survival and conventional pathological markers of tumor aggressiveness including high histologic grade. Therefore, subjective quantification of cell-cycle regulatory proteins by immunohistochemistry can identify biologically and clinically distinct subsets of follicular lymphoma cases.