Yueju Li

EGFR Mutations Detected in Plasma Are Associated with Patient Outcomes in Erlotinib Plus Docetaxel-Treated Non-small Cell Lung Cancer

Purpose: Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility. Methods: An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system (DxS, Ltd) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib. Results: EGFR mutations were detected in 10 of 49 patients (20%). Six (12%) had single activating mutations in EGFR, associated with improved progression-free survival (median, 18.3 months), compared with all other patients (median, 3.9 months; p = 0.008), or those with wild-type EGFR (median, 4.0 months; p = 0.012). Four of 49 patients harbored a de novo T790M resistance mutation (median progression-free survival, 3.9 months). EGFR mutational status was associated with clinical response (45 assessable, p = 0.0001); in the six patients with activating mutations, all achieved complete (33%) or partial (67%) response. All CR patients had E19del detectable in both tumor and plasma. KRAS mutations were detected in two of 49 (4%) patients, both of whom had rapid progressive disease. Conclusions: Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib. The addition of docetaxel in this schedule did not diminish the efficacy of erlotinib against patients with EGFR activating mutations.

Reproducibility of macular thickness measurement among five OCT instruments: effects of image resolution, image registration, and eye tracking.

BACKGROUND AND OBJECTIVE To study the effect of image resolution, eye tracking, and image registration on central macular thickness reproducibility (rCMT) among spectral-domain and time-domain optical coherence tomography (SD-OCT and TD-OCT) instruments. PATIENTS AND METHODS Seventy-six eyes were imaged (44 normal, 32 maculopathy) either twice using four SD-OCT and one TD-OCT devices or three times using Spectralis SD-OCT (with and without eye tracking) (Heidelberg Engineering, Inc., Heidelberg, Germany). Cirrus images (Carl Zeiss Meditec, Dublin, CA) were further analyzed with three-point image registration. RESULTS All instruments had superior rCMT in normal versus pathologic eyes (P < .001). No difference in rCMT was noted among instruments in normal eyes (P = .92), but TD-OCT was superior to SD-OCT (P = .017) in pathologic eyes. Cirrus image registration improved rCMT for normal eyes (P = .04), with borderline improvement in pathologic eyes (P = .06). Spectralis eye tracking improved rCMT in normal (P = .01) and pathologic (P = .004) eyes. CONCLUSION Higher image resolution with SD-OCT may not improve rCMT, but image registration and eye tracking options may improve rCMT.

An evaluation of barriers to accrual in the era of legislation requiring insurance coverage of cancer clinical trial costs in California

PURPOSEClinical trials are essential to improve cancer therapy, but only 3% of newly diagnosed adult cancer patients enroll annually. We previously conducted a prospective analysis of factors affecting trial accrual at the UC Davis Cancer Center between 1997 and 2000. It was found that the accrual rate was 14% and that patients with private insurance were significantly less likely than patients with government insurance to enroll, suggesting that fear of insurance denial was a barrier. In 2002, a new California law (SB37) required insurers to reimburse routine costs of care for cancer trials. METHODSTo assess the impact of SB37 on accrual, we repeated our study using the same survey instrument. Oncologists seeing new patients at the UC Davis Cancer Center from August to November 2002 completed questionnaires that inquired about patient characteristics and eligibility, protocol availability, and patient willingness to participate. RESULTSPhysicians considered clinical trials for 55% (118/216) of patients, but trials were available for only 53% (62/118). Eligibility criteria were met by 82% (51/62). Of these, 69% (35/51) agreed to participate (vs 51% previously). No patient declined to participate because of insurance limitations (vs 8% previously). Furthermore, insurance type was no longer a significant factor in determining whether patients would enroll. This suggests that although the overall rate of accrual is only slightly increased after passage of SB37, patients may be more willing to enroll. Efforts to increase participation must include enhancing physician and patient awareness of SB37.

Outcomes of Comprehensive Heart Care Programs in High-Risk Women

OBJECTIVE The purpose of this study was to improve the fund of knowledge, reduce cardiovascular disease (CVD) risk, and attain Healthy People 2010 objectives among women in model womens heart programs. METHODS A 6-month pre/post-longitudinal educational intervention of high-risk women (n = 1310) patients at six U.S. womens heart programs consisted of comprehensive heart health counseling and use of American Heart Association/American College of Cardiology (AHA/ACC) Evidence-Based Guidelines as enhancement to usual care delivered via five integrated components: education/awareness, screening/risk assessment, diagnostic testing/treatment, lifestyle modification/rehabilitation, and tracking/evaluation. Demographics, before and after knowledge surveys, clinical diagnoses, laboratory parameters, and Framingham risk scores were also determined. Changes in fund of knowledge, awareness, and risk reduction outcomes and Healthy People 2010 objectives were determined. RESULTS At 6 months, there were statistically significant improvements in fund of knowledge, risk awareness, and clinical outcomes. Participants attained or exceeded >90% of the Healthy People 2010 objectives. Proportions of participants showing increased knowledge and awareness of CVD as the leading killer of women, of all signs and symptoms of a heart attack, and calling 911 increased significantly (11.1%, 25.4%, and 34.6%, respectively). Health behavior counseling for physical activity, diet, and diabetes as CVD risk factors increased significantly (28.3%, 28.2%, and 12.5%, respectively). There was a statistical 4.1% increase in participants with systolic blood pressure (SBP) <140/90 mm Hg, a 4.7% decrease in participants with total cholesterol (TC) >240 mg/dL, a 4.5% decrease in participants with TC >200 mg/dL, a 5.9% decrease in participants with high-density lipoprotein cholesterol (HDL-C) <50 mg/dL, a 4.4% decrease in participants with HDL-C <40 mg/dL, and an 8.8% increase in diabetics with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. CONCLUSIONS CVD prevention built around a comprehensive heart care model program and AHA/ACC Evidence-Based Guidelines can be successful in improving knowledge and awareness, CVD risk factor reduction, and attainment of Healthy People 2010 objectives in high-risk women. Thus, these programs could have a dramatic and lasting impact on the health of women.

The effect of hand burns on quality of life in children.

There is limited data regarding the long-term outcomes for children with hand burns. The objective of this study was to prospectively document recovery after burn injury using a validated health outcomes burn questionnaire for infants, children, and adolescents. A single center prospective study was conducted on consecutive children aged 0 to 4 years and 5 to 18 years comparing outcomes between children with and without hand burns. Age specific American Burn Association/Shriners Hospitals for Children Burn Outcomes Questionnaires were administered at admission, first clinic after discharge, 3, 6, 12, 18, and 24 months after injury. One hundred eighty-one consecutive patients were enrolled in the study. Demographic, injury, and survey outcome data were available for 145 patients for at least 24 months after injury. Children with hand burns had significantly longer hospitalization, intensive care unit days, ventilator days, and TBSA burns. Initial Burn Outcomes Questionnaire scores for children with hand burns were significantly lower than controls and children with burns not involving the hand. For ages 0 to 4 years and 5 to 18 years, only the domain specific to upper extremity function was significantly decreased between the groups over the entire study period. Despite severe injury, children with hand burns have continued improvement in quality of life for at least 2 years after injury. The presence of a hand burn in the context of large TBSA burn is a marker of more severe acute illness and predicts increased resource utilization. Rehabilitative efforts after upper extremity injury should continue to target both physical function and the psychosocial impact of burn injury.

Detection by Immunofixation of M Proteins in Hypogammaglobulinemic Patients With Normal Serum Protein Electrophoresis Results

Serum protein electrophoresis (SPE) demonstrates a monoclonal protein as an M spike in the majority of patients with monoclonal gammopathies. However, in patients with an apparently normal SPE pattern or hypogammaglobulinemia, immunofixation electrophoresis (IFE) can reveal an M protein. We undertook this study to determine the yield of reflex IFE testing in patients with hypogammaglobulinemia and to identify any laboratory or biochemical parameters that would predict a positive IFE result. We evaluated 380 patients with hypogammaglobulinemia and a normal SPE pattern. Of 380, 37 (9.7%) had a positive IFE result in serum, urine, or both. Of the other laboratory values evaluated, a high alpha2-globulin level with an increased alpha2-globulin/alpha1-globulin ratio, a low hemoglobin level, and an elevated creatinine level predicted a positive IFE result. There was a 2-fold increase in the odds ratio for a positive IFE result when the alpha2-globulin/alpha1-globulin ratio was elevated. We recommend reflex IFE testing in patients with hypogammaglobulinemia with a normal SPE pattern if any of the following are present: elevated alpha2- globulin/alpha1-globulin ratio, low hemoglobin level, and elevated creatinine level.

Scope and Nature of Pain- and Analgesia-Related Content of the United States Medical Licensing Examination (USMLE)

Abstract Background “The ongoing opioid crisis lies at the intersection of two substantial public health challenges—reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications” [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE). Methods An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance. Results Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word “pain.” Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain. Conclusions This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Headache relief after anterior cervical discectomy: post hoc analysis of a randomized investigational device exemption trial: clinical article.

OBJECT The authors analyzed headache relief after anterior cervical discectomy. Headache may be relieved after anterior cervical discectomy, but the mechanism is unknown. If headaches were directly referred from upper cervical pathology, more headache relief would be expected from surgery performed at higher cervical levels. If spinal kinesthetics were the mechanism, then headache relief may differ between arthroplasty and fusion. Headache relief after anterior cervical discectomy was quantified by the operated disc level and by the method of operation (arthroplasty vs arthrodesis). METHODS The authors performed a post hoc analysis of an artificial disc trial. Data on headache pain were extracted from the Neck Disability Index (NDI) questionnaire. RESULTS A total of 260 patients underwent single-level arthroplasty or arthodesis. Preoperatively, 52% reported NDI headache scores of 3 or greater, compared with only 13%-17% postoperatively. The model-based mean NDI headache score at baseline was 2.5 (95% CI 2.3-2.7) and was reduced by 1.3 points after surgery (95% CI 1.2-1.4, p < 0.001). Higher cervical levels were associated with a greater degree of preoperative headache, but there was no association with headache relief. There was no significant difference in headache relief between arthroplasty and arthrodesis. CONCLUSIONS Most patients with symptomatic cervical spondylosis have headache as a preoperative symptom (88%). Anterior cervical discectomy with both arthroplasty and arthrodesis is associated with a durable decrease in headache. Headache relief is not related to the level of operation. The mechanism for headache reduction remains unclear.

Anaemia and type 2 diabetes: Implications from a retrospectively studied primary care case series

OBJECTIVES. To identify the prevalence of anaemia in Chinese type 2 diabetic patients managed in a primary care setting and to explore its associations with cardiovascular complications and kidney disease. DESIGN. Retrospective case series study. SETTING. General Out-patient Clinic of Hospital Authority, Hong Kong. PATIENTS. Chinese type 2 diabetic patients who had annual assessments between 1 January 2010 and 31 December 2011 were recruited. Their complete blood picture, serum creatinine, estimated glomerular filtration rate (calculated by Modification of Diet in Renal Disease method), haemoglobin A1c, and urine albumin-creatinine ratio were retrieved. Anaemia was defined as a haemoglobin level of <130 g/L in men and <120 g/L in women (World Health Organization criteria). Students t test and analysis of variance were used to analyse continuous variables and the Chi squared test for categorical data. Pearsons correlation coefficient and multivariate logistic regression were used to examine associations between haemoglobin level and different variables including age, gender, serum creatinine level, estimated glomerular filtration rate, and urine albumin-creatinine ratio. All statistical tests were two-sided, and a P value of <0.05 was considered significant. RESULTS. Among 6325 Chinese type 2 diabetic patients fulfilling the inclusion criteria, 1441 were found to have anaemia with a period prevalence of 22.8%. The prevalence of anaemia increased significantly with deterioration of renal function. Compared with diabetic patients with normal haemoglobin levels, anaemic diabetic patients had a higher co-morbidity rate for stroke, ischaemic heart disease, hypertension, and chronic kidney disease (P<0.001). Independent predictors for haemoglobin level among diabetic patients were age, gender, serum creatinine level, estimated glomerular filtration rate, haemoglobin A1c, and urine albumin-creatinine ratio (P<0.001). Multivariate analysis showed that male gender, old age, increased serum creatinine level, decreased estimated glomerular filtration rate, elevated urine albumin-creatinine ratio, and co-morbidity with stroke or ischaemic heart disease were associated with greater odds for the presence of anaemia. CONCLUSION. Anaemia is common among Chinese type 2 diabetic patients, particularly those with impaired renal function or established cardiovascular disease. Early detection of anaemia and prompt referral to specialist care for optimal treatment, if associated with severe renal impairment or high-risk proteinuria at the primary care settings, is recommended.

Synaptophysin-Ki67 double stain: a novel technique that improves interobserver agreement in the grading of well-differentiated gastrointestinal neuroendocrine tumors.

A common problem in the assessment of Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors is distinguishing tumor from non-tumor. This is because background stromal lymphocytes, entrapped non-neoplastic glands, and the delicate vascular network characteristic of neuroendocrine tumors frequently contain a subset of proliferating cells. Furthermore, in small biopsies, crush and cautery artifact can alter the morphologic appearance of tumor cells, making the Ki67 proliferative index more difficult to assess. To address these issues, we developed a synaptophysin-Ki67 double stain using a commercially available immunohistochemistry kit, allowing simultaneous visualization of tumor and proliferating nuclei. To test this method, three gastrointestinal pathologists individually graded 50 gastrointestinal neuroendocrine tumors first using synaptophysin-Ki67 double-stained slides and then, after a washout period, using Ki67-only stained slides (along with routine hematoxylin- and eosin-stained slides). Interobserver agreement on Ki67 proliferative index was moderate using the Ki67-only stained slides (intraclass correlation 0.51, 95% confidence interval: 0.35–0.66) and improved using the synaptophysin-Ki67 double stain (intraclass correlation 0.79, 95% confidence interval: 0.69–0.86). Similarly, interobserver agreement on tumor grade was fair with Ki67-only stained slides (κ=0.39, P<0.001) and improved with the double stain (κ=0.58, P<0.001). Analysis of individual pathologists’ scores revealed that fewer total number of tumor cells counted correlated with higher grade designation and appeared to contribute to grade discordance. In tumors cited as particularly challenging to assess by the pathologists, three of four tumors were grade discordant with the Ki67-only stain, whereas all four tumors were grade concordant with the synaptophysin-Ki67 stain. The synaptophysin-Ki67 double stain is the first technique to address specifically the histomorphologic challenges of evaluating Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors. Although further validation is needed, this study provides evidence that the synaptophysin-Ki67 double stain can improve interobserver agreement.