Understand healthcare resource use (HCU) and costs for commercially insured patients with epilepsy in United States treated with brivaracetam (BRV) in the 12 months pre- and post-treatment initiation.

FDA's Pregnancy and Lactation Labeling Rule (PLLR) will replace pregnancy categories with new data requirements to aid decision-maker's assessment of pregnant/nursing mothers who require therapy. This descriptive study assessed the PsO population that may be impacted by new data. IMS PharMetrics claims were used to identify PsO patients with: ≥2 PsO diagnosis codes and continuous eligibility between 1/14–12/15, ≥1 PsO diagnosis or ≥1 PsO medication claim between 1/15–12/15 (measurement period). Age/gender at the start of the measurement period were used to allocate patients into the following cohorts: WoCBA (women 18–44 years), Women 45–65, Men 18–4, and Men 45–65. Outcomes including % biologic utilization and treatment changes [discontinuation (≥60–day gap with no additional biologic claims); switch (initiation of new biologic within 60 days); and re-initiation of the same or new biologic (after a gap ≥60 days)] were assessed in the measurement period. 75,019 PsO patients were allocated into the following cohorts: WoCBA (17%), Women 45–65 (33%), Men 18–44 (17%), and Men 45–65 (33%). Biologic utilization was lower among WoCBA (22%) and Women 45–65 (21%) and higher among Men 18–44 (29%) and Men 45–65 (27%). Across cohorts with biologic therapy, WoCBA had the highest proportion of treatment changes at 59% [Women 45–65 (53%), Men 18–44 (56%), Men 45–65 (47%)]. Re-initiating the same biologic (20%), discontinuation (18%), and switch (17%) were the leading causes of treatment changes among WoCBA. Despite the importance of disease control prior to and throughout pregnancy and the recent PLLR mandate, trends show lower rates of biologic use in WoCBA and women overall. This may be exacerbated by the high degree of treatment changes and can be an indicator of poor disease control. Further exploration is needed to better understand and examine whether treatment patterns among WoCBA patients can be optimized for improved outcomes.

Biologics are effective in managing rheumatoid arthritis (RA) but switching as early as 3 months into treatment due to primary non-response, or later due to lack of durability, is common. This analysis compared the cost per response (low disease activity [LDA]) between certolizumab pegol (CZP) and adalimumab (ADA) using EXXELERATE trial data from the US payer perspective. EXXELERATE (NCT01500278) was a phase IV, 104-week (Wk) randomized, head-to-head, superiority study comparing CZP+methotrexate (MTX) with ADA+MTX, for the treatment of moderate/severe RA. At Wk12 patients not achieving LDA, Disease Activity Score 28-joint erythrocyte sedimentation rate [DAS28-ESR] ≤3.2, or DAS28-ESR reduction from baseline ≥1.2, switched biologic treatment (CZP to ADA/ADA to CZP). Patients who switched treatment at Wk12 and/or withdrew at Wk24 due to non-response were classified as non-responders for subsequent timepoints. Downstream non-responder costs, including costs of patients that obtained a response after treatment switch, were attributed to the initial treatment used. Cost per response at Wk52 and Wk104 were calculated as: total cost among responders+non-responders divided by number of responders. Direct healthcare resource utilization use was estimated from EXXELERATE data; associated costs were derived from the RED BOOK™, Medicare fee schedule, Healthcare Cost and Utilization Project database, and published literature. 908 patients (454 per arm) were included in this analysis. LDA response rates were comparable between CZP and ADA at Wk52 (42% vs 39%) and Wk104 (36% vs 34%). Costs per LDA response for CZP vs ADA were $120,131 vs $133,974 (Wk52), and $237,607 vs $275,449 (Wk104), a difference of $13,843 and $37,842 respectively, primarily driven by drug cost. The EXXELERATE trial demonstrated the effective use of two sequential biologics in the same class to effectively control RA. CZP treatment was associated with lower one-year and two-year costs per LDA compared to ADA treatment.

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2649 Background: Colorectal cancer (CRC) incidence and mortality are higher in African Americans (AAs), than in the general population. Whether or not there are any molecular particularities or preferential pathways in colon carcinogenesis in AAs need to be investigated at the genetic and epigenetic levels. We chose four prominent markers for epigenetic silencing including APC2. This new marker is a homologue of the adenomatous polyposis coli tumor suppressor which plays overlapping roles in wingless signaling and proliferation in CRC. In addition, we analyzed BRAF mutation, MSI status and MLH1 and MSH2 expression. Material and Methods: A total number of 223 cases of primary CRC were selected from Howard University and John Hopkins Hospitals. DNA was extracted from microdissected tumor and matched normal MSI were studies using five sets of primers (BAT25, BAT26, NR21, NR22 and NR24). P16, MLH1, APC, APC2 methylation and BRAF V600E mutation were determined by MSP and/or pyrosequencing. MLH1 and MSH2 expression was determined by immunohistochemistry. Demographic and clinical data were extracted from patients charts. Difference of MSI by dependent factors were assessed by computing OR (95%CI). Results: The mean (SD) age of cases was 66 (14) years and 42% were males. Fifty two percent (52%) of tumors were right sided, and 84% were moderately differentiated. The frequency of MSI was 20%. There was no statistically significant difference between age groups, gender, tumor location for MSI-H. The frequency of p16, MLH1, APC and APC2 methylation in the MSI-H group were 32%, 68%, 70% and 80%, respectively. Frequency of BRAF mutation was 23% among MSI-H group. MLH1 and MSH2 expression were 18% and 21% in MSI-H samples respectively. Conclusion: The MSI-H rate is higher (20%) than in the general population. At least 1/5 of MSI-H tumors (23%) are BRAF related. APC2, APC and MLH1 are frequent targets of epigenetic silencing and may be part of the colorectal cancer hypermethylome.

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% [7] of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil.

Background: Perianal mucinous adenocarcinoma is a rare variant of anal canal epithelioid tumors. Our objective in this report is to examine the clinical features, pathology, treatment, and outcome for patients with perianal mucinous adenocarcinoma.Methods: A retrospective review identified four patients with histologically proven perianal mucinous adenocarcinoma. The medical records of these patients were reviewed for presentation, therapy, and outcome.Results: Pain and bleeding were present in all cases. In three of four patients, chronic perirectal disease was present, including two abscesses and one fistula. All patients had extensive local disease at presentation. One patient presented with bilateral inguinal nodal metastases. Two patients received neoadjuvant chemotherapy and radiation, with a third patient receiving radiation alone. Two of these three patients underwent abdominoperineal resection. Three patients subsequently died (all of progression and/or recurrence) 2-48 months after diagnosis. The fourth patient (who was treated with chemotherapy and radiation followed by abdominoperineal resection) is alive and disease free at 12 months.Conclusions: Perianal mucinous adenocarcinoma is a rare disease with a poor prognosis, mostly due to its advanced nature at the time of diagnosis. Chemoradiation followed by surgery may improve outcome in selected individuals. (C) 1997 Wiley-Liss, Inc.

BACKGROUND: Hepatic insulin resistance has previously been demonstrated in chronic pancreatitis, and has been shown to be, ameliorated by pancreatic polypeptide administration. Insulin binding was investigated in chronic pancreatitis induced by infusion of oleic acid into the pancreatic duct of rats.METHODS: Acute pancreatitis was induced in 12 200 to 225 gr 8-week-old male Sprague-Dawley rats by intubation of the main bile duct at its junction with the duodenum through a small mid-line abdominal incision, and infusion of 99% oleic acid 0.015 mL/min for 4 minutes, with an additional 4 minutes dwell-time after infusion. Sham-operated animals served as controls, After 6 weeks, chronic pancreatitic and sham-operated animals received either intraperitoneal bovine pancreatic polypeptide or saline vehicle for 5 days, Intraduodenal glucose tolerance tests (GTT) were performed in fasted animals, after which tissues were procured. Insulin receptors were isolated from solubilized hepatocyte and rectus abdominus membranes and competitive-binding studies were performed by incubation with I-125-insulin. Dissociation coefficients (K-d) and maximum binding capacities (B-max) for high-affinity receptors were derived from Scatchard analyses.RESULTS: B-max and K-d in muscle were not altered in animals with chronic pancreatitis. In liver, B-max was significantly less in rats with chronic pancreatitis given saline than in sham-operated rats given saline (17.0 +/- 6.3 versus 47.6 +/- 13.1 fmol/mg protein; data are mean +/- SEM), Pancreatic polypeptide administration increased hepatic B-max in rats with chronic pancreatitis (to 47.2 +/- 9.8 fmol/mg protein), but had no significant effect in sham-operated rats. Receptor affinity was not significantly different in rats with chronic pancreatitis or rats who underwent sham operations and was unaltered by the administration of pancreatic polypeptide. The integrated plasma glucose response during the GTT was reduced by pancreatic polypeptide administration in rats with chronic pancreatitis (29.5 +/- 15.0 mg/dL per minute versus 69.0 +/- 21.8 in chronic pancreatitis without pancreatic polypeptide), but was not significantly altered in sham-operated animals.CONCLUSION: Diminished expression of high-affinity receptors on the hepatocyte membrane may contribute to hepatic insulin resistance in chronic pancreatitis. In this model, pancreatic polypeptide improved glucose tolerance and increased receptor capacity to the level observed in livers from nonpancreatitic animals.

The histopathologic characteristics of primary plaques and recurrent carotid disease were studied in 32 patients. These data were related to symptoms, recurrence interval (6 to 176 months), arteriographic anatomy, and in situ operative findings. A striking predilection was noted for recurrent lesions to be located in the internal carotid artery near the origin, but still within the confines, of the original endarterectomy site and suture line. Although recurrence was frequently associated with a long primary arteriotomy, evidence of technical faults or periarterial fibrosis was rare. Early recurrent lesions (recurrence interval <36 months, n = 13) had significantly more smooth muscle cells and proteoglycans (p<0.001) than late recurrent lesions (recurrence interval >36 months, n = 19). As previously reported, features of atherosclerosis (abundant collagen, calcium deposits, and foam cells) were more pronounced in late recurrences (p<0.001). However, the histopathologic differentiation between early and late recurrent carotid disease was indistinct. A continuum was noted whereby characteristics of late recurrent lesions increased in proportion to recurrence interval. All recurrent lesions were easily distinguished from primary plaques in that recurrences had a less orderly arrangement of all elements and lacked the classic topographic features of advanced atherosclerosis. An important feature that differentiated primary and recurrent lesions was the presence of surface and intraplaque thrombus in 90% of recurrent lesions (p<0.001). In early recurrent disease, luminal surface thrombus was striking; this was frequently platelet-rich and showed organization devoid of neovascularity. Intraplaque thrombus was more common in late recurrent disease, consisted almost entirely of fibrin, and was often contiguous with luminal surface thrombus. No discernible relationships were noted between thrombus associated with recurrent lesions and the presence or absence of symptoms, treatment with antiplatelet agents, and hypertension. This finding suggests that thrombus was a continuous and intrinsic component of recurrent disease rather than a secondary, complicating feature. Recurrent carotid disease is a progressive lesion that stems from ongoing thrombogenesis occurring at the endarterectomy site. Organized thrombus and smooth muscle cell proliferation comprise the bulk of the lesion, which undergoes atherosclerotic change with time. (J VASC SURG 1986;3:10-23.)

It is well established that small clinically undetected thyroid carcinomas can produce extensive lymphatic metastases. However, occult papillary carcinoma of the thyroid presenting as a large blood-borne metastasis and occult papillary carcinoma of the thyroid leading to death are both uncommon. The authors report two unusual cases of clinically occult carcinoma of the thyroid. The first case is a 2.4 mm microscopic carcinoma presenting as a large solitary pulmonary metastasis, and is one of the smallest reported primary papillary thyroid carcinomas presenting as a distant hematogenous metastasis. The second case represents a lethal carcinoma with extensive metastases not diagnosed until autopsy. These two cases effectively illustrate that the absence of a clinically detectable thyroid abnormality does not exclude the possibility of extensive hematogenous and lymphatic metastases from a minute or undetected carcinoma of the thyroid.