Publications

Vulvar Intraepithelial Neoplasia (VIN) is the precursor lesion of Vulvar Squamous Cell Carcinoma (VSCC), and the differentiated type (dVIN) is more frequently observed in relation to VSCC. In contrast to usual-type VIN (uVIN), which is related to infection by human papillomavirus (HPV), a germline mutation in the p53 gene is thought to be associated with ~90% of dVIN cases. To date, no infectious agent has been identified in association with dVIN, and studies investigating this possibility have been hindered by the difficulty in accurately diagnosing dVIN from small biopsies. Here, we used immunostaining for p16ink4a), a biomarker for HPV infection, to study 14 uVIN high-grade VIN and 14 dVIN cases, and to select 10 dVIN cases to broadly screen for all kn(own viruses using a pan-viral microarray platform (ViroChip). All of the uVIN tissue samples, including 8 warty and 6 basaloid cases, showed positivity with the p16(ink4a) immunostain. The staining pattern was full-thickness for all except two cases in which positive staining was localized in the lower 1/3 of the epidermis. In contrast, immunostaining for p16(ink4a) was negative in all dVIN cases. ViroChip analysis of 10 pure dVIN samples confirmed the absence of human papillomavirus subtypes or any other virus with the exception of a single sample that showed a weak microarray signature to a porcine herpesvirus. Follow-up PCR testing of the sample was negative for herpesvirus, and in-depth metagenomic next-generation sequencing revealed only sequences corresponding to non-pathogenic viral flora and bacterial contamination. In this study, we demonstrated lack of a virus association in 10 dVIN cases. Alternative pathways for carcinogenesis such as the p53 mutation should be considered for investigation of potential treatment options in dVIN.

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

BACKGROUND

A community-based non-profit hospice provider implemented "TeleCaring" as a quality improvement intervention to identify and take action on patient or caregiver needs or concerns, such as uncontrolled symptoms or prescription problems.

MEASURES

We assessed the rate of acceptance of the intervention, intensity of the intervention, escalations of calls from Specialists to Nurses, and the effect of the intervention on utilization of clinical services, clinical miles traveled, and family satisfaction with care.

INTERVENTION

TeleCaring consisted of daily proactive phone calls to patients and caregivers by Specialists and Nurses.

OUTCOMES

Eighty-eight percent of new home hospice patients accepted TeleCaring when offered. A total of 5.3% of calls by Specialists were escalated to Nurses. TeleCaring participants had lower utilization of clinical services compared with non-participants. Family satisfaction increased and clinical miles decreased across the organization after the implementation of TeleCaring.

CONCLUSIONS/LESSONS LEARNED

TeleCaring is a viable method to proactively identify home hospice patient or caregiver needs and adjust clinical services accordingly.

There are wide disparities in breast cancer-specific survival by patient sociodemographic characteristics. Women of lower income, for instance, have higher relapse and death rates from breast cancer. One possible contributing factor for this disparity is low use of adjuvant endocrine therapy-an extremely efficacious therapy in women with early stage, hormone receptor positive breast cancer, the most common subtype of breast cancer. Alone, adjuvant endocrine therapy decreases breast cancer recurrence by 50% and death by 30%. Data suggest that low use of adjuvant endocrine therapy is a potentially important and modifiable risk factor for poor outcome in low-income breast cancer patients.

BACKGROUND

Myocardial perfusion scintigraphy (MPS) is used widely to assess cardiovascular risk in patients with chest pain. The utility of carotid intima-media thickness (CIMT) and endothelial function as assessed by reactive hyperemia-peripheral arterial tonometry index (RHI) in risk stratifying patients with angina-like symptoms needs to be defined. We investigated whether the addition of CIMT and RHI to Framingham Cardiovascular Risk Score (FCVRS) and MPS improves comprehensive cardiovascular risk prediction in patients presenting with angina-like symptoms.

METHODS

We enrolled 343 consecutive patients with angina-like symptoms suspected of having stable angina. MPS, CIMT, and RHI were performed and patients were followed for cardiovascular events for a median of 5.3 years (range 4.4-6.2). Patients were stratified by FCVRS and MPS.

RESULTS

During the follow-up, 57 patients (16.6%) had cardiovascular events. Among patients without perfusion defect, low RHI was significantly associated with cardiovascular events in the intermediate and high FCVRS groups (hazard ratio (HR) [95% confidence interval (CI)] of RHI ≤ 2.11 was 6.99 [1.34-128] in the intermediate FCVRS group and 6.08 [1.08-114] in the high FCVRS group). Furthermore, although MPS did not predict, only RHI predicted hard cardiovascular events (cardiovascular death, myocardial infarction, and stroke) independent from FCVRS, and adding RHI to FCVRS improved net reclassification index (20.9%, 95% CI 0.8-41.1, p = 0.04). Especially, RHI was significantly associated with hard cardiovascular events in the high FCVRS group (HR [95% CI] of RHI ≤ 1.93 was 5.66 [1.54-36.4], p = 0.007).

CONCLUSIONS

Peripheral endothelial function may improve discrimination in identifying at-risk patients for future cardiovascular events when added to FCVRS-MPS-based risk stratification.