Express and Implied Terms.

Contract terms can be express or implied. But what does that mean? I argue that the distinction can be illuminated by reference to the philosophy of language. Express terms are best understood by reference to the truth-conditional content of the parties' agreement; implied terms are derived from express terms by a process of reasoning, albeit one aimed at establishing the parties' commitments.

Ethnic hair care products may increase false positives in hair drug testing.

The question of why different races appear more susceptible to hair contamination by external drugs remains controversial. This research studied susceptibility of head hair to external cocaine and methamphetamine when hair products have been applied. Three different chemical classes of ethnic hair products were applied to Caucasian, Asian, and African hair. Some products increased the methamphetamine and cocaine concentrations in all hair types. A unique finding of this research is that certain ethnic hair products can replace moisture as a diffusion medium, thereby increasing the susceptibility to contamination over 100-fold compared to petroleum-based products.

Cardiac safety results from a phase II, open-label, multicenter, pilot study of two docetaxel-based regimens plus bevacizumab for the adjuvant treatment of subjects with node-positive or high-risk node-negative breast cancer.

PURPOSE: Adding antiangiogenic therapy to standard chemotherapy has improved response rates and progression-free survival in metastatic breast cancer (BC) patients. This phase II study evaluated cardiac safety of bevacizumab with/without trastuzumab with two docetaxel-based regimens in early BC. METHODS: 127 women with non-metastatic node-positive or high-risk node-negative BC were enrolled. Women with human epidermal growth factor receptor 2 (HER2)-negative BC (n = 93) received docetaxel/doxorubicin/cyclophosphamide (TAC) + bevacizumab, while women with HER2-positive disease (n = 34) received docetaxel/carboplatin/trastuzumab (TCH) + bevacizumab, every 3 weeks for six cycles. Maintenance therapy with bevacizumab alone or bevacizumab plus trastuzumab, respectively, was given every 3 weeks for 52 weeks. The primary objective was to evaluate cardiac safety, as measured by the incidence of ≥ grade 3 clinical congestive heart failure (CHF); the secondary objective was assessment of safety and toxicity. RESULTS: At least one cardiac adverse event (AE; CHF, cardiomyopathy, or left ventricular dysfunction) was reported in 26.1% of TAC (n = 92) and 17.6% of TCH subjects (n = 34); there were no cardiac deaths. ≥ Grade 3 clinical CHF was observed in 4.3% in the TAC plus bevacizumab stratum and 0% in the TCH plus bevacizumab stratum. A ≥ grade 3 treatment-emergent AE (any kind) related to study treatment was observed in 59.8% in the TAC with bevacizumab and 52.9% in the TCH plus bevacizumab stratum. CONCLUSION: Adding bevacizumab to a docetaxel-based regimen with trastuzumab did not appear to increase cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00446030, registered March 8, 2007.

Clonality assessment of cutaneous B-cell lymphoid proliferations: a comparison of flow cytometry immunophenotyping, molecular studies, and immunohistochemistry/in situ hybridization and review of the literature.

Cutaneous lymphoid infiltrates are diagnostically challenging. Although ancillary techniques to assess clonality can help distinguish between reactive lymphoid hyperplasia and lymphoma, one of the most widely used techniques in hematopathology, flow cytometry immunophenotyping (FCI), has not been routinely applied to skin specimens. We performed FCI on 73 skin specimens from 67 patients clinically suspected of having a cutaneous B-cell lymphoma (CBCL) and compared the results with those obtained from immunoglobulin heavy chain (IGH) gene molecular studies (58 cases, primarily by polymerase chain reaction) and either immunohistochemistry (IHC) or in situ hybridization to evaluate for light chain restriction (22 and 2 cases, respectively). Sufficient quantity of CD45 (leukocyte common antigen)-positive cells and staining quality were achieved in 88% of cases by FCI, and clonality was detected in 68% of CBCLs versus molecular studies showing sufficient DNA quality in 74% and only 39% clonality detection, and interpretable/contributory IHC results in 84% of cases with 55% clonality detection. Clonality was documented more frequently in secondary rather than primary CBCLs by all 3 techniques. Therefore, FCI is feasible and appears to be more reliable than molecular studies or IHC/in situ hybridization for detecting clonality in CBCLs and can provide additional prognostically and therapeutically relevant information. The exception is cases with plasmacytic differentiation such as marginal zone lymphoma for which IHC might be a superior tool. We have also shown that a large subset of primary cutaneous follicle center lymphomas express CD10 and/or BCL2 by FCI. Recent advances in FCI beg the question of applicability to cutaneous T-cell and NK-cell lymphomas.

Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue.

BACKGROUND: As Chronic Fatigue Syndrome (CFS) has been known to follow Epstein-Bar virus (EBV) and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS) patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM). We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively. METHODS: Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-ß in duplicate plasma samples available in bio-bank from 9 PI-CFS subjects and 12 recovered controls at 24 months post-infection. RESULTS: Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls. CONCLUSION: These results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS.

Design and analytic validation of BCR-ABL1 quantitative reverse transcription polymerase chain reaction assay for monitoring minimal residual disease.

CONTEXT: Monitoring minimal residual disease by quantitative reverse transcription polymerase chain reaction has proven clinically useful, but as yet there are no Food and Drug Administration-approved tests. Guidelines have been published that provide important information on validation of such tests; however, no practical examples have previously been published. OBJECTIVE: To provide an example of the design and validation of a quantitative reverse transcription polymerase chain reaction test. DESIGN: To describe the approach used by an individual laboratory for development and validation of a laboratory-developed quantitative reverse transcription polymerase chain reaction test for BCR-ABL1 fusion transcripts. RESULTS: Elements of design and analytic validation of a laboratory-developed quantitative molecular test are discussed using quantitative detection of BCR-ABL1 fusion transcripts as an example. CONCLUSIONS: Validation of laboratory-developed quantitative molecular tests requires careful planning and execution to adequately address all required analytic performance parameters. How these are addressed depends on the potential for technical errors and confidence required for a given test result. We demonstrate how one laboratory validated and clinically implemented a quantitative BCR-ABL1 assay that can be used for the management of patients with chronic myelogenous leukemia.

Palliative medicine consultation impacts DNR designation and length of stay for terminal medical MICU patients.

OBJECTIVE: The purpose of this study was to assess the impact of a palliative medicine consultation on medical intensive care unit (MICU) and hospital length of stay, Do Not Resuscitate (DNR) designation, and location of death for MICU patients who died during hospitalization. METHOD: A comparison of two retrospective cohorts in a 17-bed MICU in a tertiary care university-affiliated hospital was conducted. Patients admitted to the MICU between January 1, 2003 and June 30, 2004 (N = 515) were compared to MICU patients who had had a palliative medicine consultation between January 1, 2005 and June 1, 2009 (N = 693). To control for disease severity, only patients in both cohorts who died during their hospitalization were considered for this study. RESULTS: Palliative medicine consultation reduced time until death during the entire hospitalization (log-rank test, p < 0.01). Time from MICU admission until death was also reduced (log-rank test, p < 0.01), further demonstrating the impact of the palliative care consultation on the duration of dying for hospitalized patients. The intervention group contained a significantly higher percentage of patients with a DNR designation at death than did the control group (86% vs. 68%, χ2 test, p < 0.0001). SIGNIFICANCE OF RESULTS: Palliative medicine consultation is associated with an increased rate of DNR designation and reduced time until death. Patients in the intervention group were also more likely to die outside the MICU as compared to controls in the usual care group.

Study of vitreous potassium correlation with time since death in the postmortem range from 2 to 110 hours using capillary ion analysis.

The time-dependent postmortem increase of potassium concentration in the eye fluids has been studied since the 1960s. However, important discrepancies on the reproducibility of the phenomenon have hampered the use of this parameter in real cases. In recent years, a new analytical approach based on capillary ion analysis (CIA) has been reported. In the present work, the correlation between vitreous potassium and postmortem interval (PMI) has been re-evaluated by using CIA in a group of 164 cases with PMIs ranging from 2 to 110 hours. The correlation of the two parameters was described by the following regression equation: y = 0.1733x + 2.3008 (x = PMI; y = K(+) concentration); correlation coefficient = 0.962. The re-calculation of PMIs on the basis of this equation provided calculated PMIs with an average error of 5.54 hours (SD = 4.16). However, the percent PMI calculation error decreased with the increase of PMI, becoming acceptable for practical application above 24 hours since death.

Validation of multiplex ligation-dependent probe amplification for confirmation of array comparative genomic hybridization.

The American College of Medical Genetics recommends that each laboratory should confirm abnormal or ambiguous results detected by array comparative genomic hybridization (aCGH). At present, the gold standard method for aCGH confirmation is fluorescent in situ hybridization (FISH). However, FISH is not well suited for small tandem duplications or very small deletions that are detectable by oligonucleotide arrays. Therefore, we developed and validated multiplex ligation-dependent probe amplification (MLPA) for aCGH confirmation. The method performance validation showed linearity through the expected analytical measurement range (0.05 to 2 genome equivalents). The interassay normalized coefficient of variation averaged 3.7% across 12 control and target probes. This low imprecision allowed detection of 20% mosaicism with exceptional confidence (P<0.006). Comparison with a combined gold standard of phenotype, aCGH, karyotype, and/ or FISH showed 100% concordance for 218 samples using an X/Y chromosome-specific probe set (95% confidence interval, 98.3%-100.0%). Patient-specific probe sets also showed 100% concordance to the gold standard for 18 genomic targets. In conclusion, we have developed and validated an MLPA assay using a novel approach to accommodate the fact that positive controls would not be available at the time of testing. We initially validated the MLPA method using X/Y chromosome-specific probes and well-characterized samples and then validated new probe sets by comparision with reference populations. We have successfully incorporated aCGH confirmation using custom-designed MLPA into our normal workflow, and used it for confirmation of all abnormal or ambiguous results.

Are physicians ethically obligated to address hospice as an alternative to "usual" treatment of advancing end-stage disease?

Hospice care is ideally suited to meet the psychosocial and spiritual needs of dying patients, providing the opportunity to settle financial, property, and inheritance issues; to mend lacerations in important lifetime relationships, including forgiving and asking forgiveness; and to assure a degree of autonomous control over the environment and the social and spiritual processes that attend one's death. Physicians are not only imprecise in prognosticating a patient's time to die, they tend to be over-optimistic in their predictions. A "no" answer to the question, "Would I be surprised if this patient died in the next year?" is a reasonable starting-point for discussing hospice care as a potential treatment plan, now or in the future. Physicians have a duty to present palliative care in hospice as an alternative to the recurrent hospital interventions that are typical in the last six to 12 months of life tor patients who are failing and have declining prospects for one-year survival.

Methylated arginine derivatives in children and adolescents with chronic kidney disease.

Asymmetric dimethylarginine (ADMA), a methylated L: -arginine (Arg) derivative is associated with endothelial dysfunction, vasoconstriction, and hypertension in animals and humans. We examined the relationship between these derivatives, estimated glomerular filtration rate (eGFR), and awake (AW) and asleep (AS) blood pressure (BP) load in children and adolescents (n = 28) with stage 2-3 chronic kidney disease (CKD) and in matched intra-familial controls (n = 10). Plasma L: -Arg, ADMA, and symmetric dimethylarginine (SDMA) levels were measured by high-performance liquid chromatography-tandem mass spectrometry. Subjects wore a 24-hr ambulatory BP monitor with BP load >95th percentile. ADMA, SDMA/ADMA ratio and SDMA were 38-200% higher in CKD patients while L: -Arg/ADMA and L: -Arg/SDMA ratios and the L: -Arg level were 11-64% lower. The eGFR explained 42-60% of L: -Arg/SDMA, SDMA/ADMA, and SDMA variability (n = 38). Using linear regression, SDMA and SDMA/ADMA separately explained 15-38% of AW and AS systolic (S) BP and diastolic (D) BP load variability (p < 0.001-0.022). Using multivariate stepwise regression with eGFR held constant, SDMA/ADMA was a significant independent variable for AW DBP load (p = 0.03). In conclusion, BP load and a disproportionate elevation of SDMA are seen in children and adolescents with stage 2-3 (mild-moderate) CKD. SDMA is a strong marker for reduced eGFR and serves as a moderate but significant indicator of 24-hr BP load variability.

Measurement of arginine derivatives in pediatric patients with chronic kidney disease using high-performance liquid chromatography-tandem mass spectrometry.

BACKGROUND: The arginine derivatives asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) interfere with endothelial nitric oxide synthesis. Plasma ADMA and SDMA have been shown to be risk factors for cardiovascular disease and/or kidney function deterioration in a variety of patient populations. METHODS: We developed a method to quantitatively measure arginine, ADMA, and SDMA using HPLC-tandem mass spectrometry. 13C6-L-Arginine was used as the internal standard, while the derivatives were separated on a silica column in less than 14 min. Plasma levels of ADMA, SDMA, and arginine were measured in children with stage II or III chronic kidney disease (CKD) and age- and gender-matched siblings. RESULTS: The chromatography exhibited no observable ion suppression in the patient specimens tested. There was no apparent carryover for any of the analytes. The assay was linear over 0.32-2.29, 0.23-4.43, and 1.00-303.89 micromol/L for ADMA, SDMA, and arginine, respectively. Plasma ADMA, SDMA, and arginine (mean+/-SD) were 1.10+/-0.35, 2.06+/-1.11, and 57.93+/-22.10 mumol/L for children with CKD, and 0.78+/-0.16, 0.71+/-0.23, and 65.29+/-21.30 micromol/L for the healthy siblings. CONCLUSIONS: The method exhibited no observable ion suppression in the patient specimens tested and has an acceptably short analytical cycle time. Children with CKD had higher levels of ADMA and SDMA than the healthy siblings.

Can axillary dissection be avoided in patients with sentinel lymph node metastasis?

BACKGROUND: Who should undergo a completion dissection following identification of a +sentinel lymph node (SLN) is controversial. METHODS: The records of 1,133 patients who underwent SLN mapping were reviewed. The association between patient, tumor, and treatment characteristics and the presence of +SLNs and +nonSLNs was analyzed using two-way tables of frequency counts and Pearson chi2 test. Possible predictors of +SLNs and +nonSLNs were analyzed using simple and multiple logistic regression. RESULTS: One thousand one hundred forty-eight SLN procedures were performed. 367 procedures (32%) yielded +SLNs. For patients with a +SLN, on multiple logistic regression analysis LVSI, increasing numbers of +SLNs, decreasing numbers of negative SLNs, and increasing size of the largest SLN metastasis were statistically significantly associated with increased likelihood of nonSLN involvement. No subgroup was identified that did not have a significant rate of nonSLN involvement on completion axillary dissection, except those who had a large number of negative SLNs (> or =3) and small size of the largest SLN metastasis (<10 mm). CONCLUSIONS: A definitive answer to the question of who needs a completion axillary dissection awaits the results of ongoing trials. In the interim, our data does not support eliminating dissection for any subgroup of patients with +SLNs.

Sentinel lymph node positivity of patients with ductal carcinoma in situ or microinvasive breast cancer.

PURPOSE: The purpose of this study was to determine the rates of sentinel lymph node (SLN) positivity in patients with a final diagnosis of ductal carcinoma in situ (DCIS) or microinvasive breast cancer (MIC). METHODS: One hundred thirty patients underwent SLN mapping from 1998 to 2003 for DCIS or MIC. RESULTS: One hundred nine patients with DCIS and 21 with MIC underwent SLN mapping. One patient with bilateral DCIS underwent 2 SLN procedures; therefore, the results of 131 SLN procedures are included. On hematoxylin and eosin (H&E) staining, 4 of 110 patients (3.6%) with DCIS had positive SLNs. Four additional patients had positive SLNs by IHC staining only (3.6%). Two of 8 patients underwent completion axillary dissection, and neither had additional involved nodes on completion axillary dissection. One of the 21 patients with MIC had positive SLNs by hematoxylin and eosin (H&E) (4.8%), and another had an involved SLN by IHC staining (4.8%). The patient with the positive SLN by H&E had 1 additional node on completion axillary dissection. CONCLUSION: Rates of SLN positivity for patients with DCIS are modest, even in a high-risk population, and there is continuing uncertainty about its clinical importance.

Evaluation of an immunoassay of whole blood sirolimus in pediatric transplant patients in comparison with high-performance liquid chromatography/tandem mass spectrometry.

BACKGROUND: Sirolimus is widely used as an immunosuppressant, along with calcineurin inhibitors. Because of its variable pharmacokinetics and narrow therapeutic range, therapeutic drug monitoring of sirolimus is critical to optimize its therapeutic effect and to minimize toxicity. Although liquid chromatography/tandem mass spectrometry is considered the method of choice, the technical and financial challenges of this method are obstacles to its use. A microparticle enzyme immunoassay on the Abbott IMx has recently been reintroduced to the clinical diagnostic market. METHODS: We evaluated this immunoassay using high-performance liquid chromatography/tandem mass spectrometry as the reference method. Precision and carryover were evaluated using an expanded CLSI EP10-A2 protocol. Linearity was studied by serial dilution of high-level whole blood samples, and clinical utility was demonstrated by correlation with the reference method using 56 de-identified pediatric patient samples. RESULTS: The total imprecision was less than 12% across the concentrations tested. The method was linear from 2.6 to 31 nM. The immunoassay showed a mean positive bias of 11.5% in patient specimens relative to high-performance liquid chromatography/mass spectrometry (p<0.001), with a correlation coefficient (R) of 0.953. CONCLUSION: We conclude that the reintroduced immunoassay is useful for therapeutic drug monitoring of sirolimus.

Factors associated with involvement of four or more axillary nodes for sentinel lymph node-positive patients.

PURPOSE: Sentinel lymph node-positive (SLN+) patients who are unlikely to have 4 or more involved axillary nodes might be treated with less extensive regional nodal radiation. The purpose of this study was to define possible predictors of having 4 or more involved axillary nodes. METHODS AND MATERIALS: The records of 224 patients with breast cancer and 1 to 3 involved SLNs, who underwent completion axillary dissection without neoadjuvant chemotherapy or hormonal therapy were reviewed. Factors associated with the presence of 4 or more involved axillary nodes (SLNs plus non-SLNs) were evaluated by Pearson chi-square test of association and by simple and multiple logistic-regression analysis. RESULTS: Of 224 patients, 42 had involvement of 4 or more axillary nodes. On univariate analysis, the presence of 4 or more involved axillary nodes was positively associated with increased tumor size, lobular histology, lymphovascular space invasion (LVSI), increased number of involved SLNs, decreased number of uninvolved SLNs, and increased size of SLN metastasis. On multivariate analysis, the presence of 4 or more involved axillary nodes was associated with LVSI, increased number of involved SLNs, increased size of SLN metastasis, and lobular histology. CONCLUSIONS: Patients with 1 or more involved SLN, LVSI, or SLN macrometastasis should be treated to the supraclavicular fossa/axillary apex if they do not undergo completion axillary dissection. Other SLN+ patients might be adequately treated with less extensive radiation fields.