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MP 2.04.85 | BCR-ABL1 Testing for Diagnosis, Monitoring and Drug Resistance Mutation Detection in Chronic Myelogenous Leukemia |
Medical Policy | ||
Section Medicine |
Original Policy Date 10/2011 |
Last Review Status/Date Reviewed with literature search/10:2012 |
Issue 10:2012 |
Return to Medical Policy Index |
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Various nucleic acid-based laboratory methods are used to detect the BCR-ABL1 fusion gene for confirmation of the diagnosis of chronic myelogenous leukemia (CML); for quantifying mRNA BCR-ABL1transcripts during and after treatment to monitor disease progression or remission; and for identification of ABL kinase domain point mutations related to drug resistance when there is inadequate response or loss of response to tyrosine kinase inhibitors (TKIs), or disease progression.
Disease. Chronic myelogenous leukemia (CML) is a clonal disorder of myeloid hematopoietic stem cells, accounting for 15% of adult leukemias. The disease occurs in chronic, accelerated, and blast phases, but is most often diagnosed in the chronic phase. If left untreated, chronic phase disease will progress within 3 to 5 years to the accelerated phase, characterized by any of several specific criteria such as 10-19% blasts in blood or bone marrow, basophils comprising 20% or more of the white blood cell count, very high or very low platelet counts, etc. (1) From the accelerated phase, the disease progresses into the final phase of blast crisis, in which the disease behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed by the presence of either more than 20% myeloblasts or lymphoblasts in the blood or bone marrow, large clusters of blasts in the bone marrow on biopsy, or development of a solid focus of leukemia outside the bone marrow. (2)
Disease genetics. BCR-ABL1 is an abnormal fusion gene that is expressed in the malignant cells of patients with CML. The fusion gene is created in most cases by a reciprocal t(9;22) chromosomal translocation that fuses the ABL tyrosine kinase gene on chromosome 9 with the breakpoint cluster region (BCR) on chromosome 22 and usually results in the cytogenetically identifiable Philadelphia chromosome (Ph). In a minority of cases, the BCR-ABL1 fusion gene is formed by other genetic changes; in these cases the Ph is not seen in cytogenetic analysis but the fusion gene is detectable by molecular methods. Depending on the exact location of the fusion, the molecular weight of the protein can range from 185 to 210 kDa. Two clinically important variants are p190 and p210; p190 is generally associated with acute lymphoblastic leukemia, while p210 is most often seen in chronic myeloid leukemia. The product of BCR-ABL1 is also a functional tyrosine kinase; the kinase domain of the BCR-ABL protein is the same as the kinase domain of the normal ABL protein. However, the abnormal BCR-ABL protein is resistant to normal regulation. Instead, the enzyme is constitutively activated and drives unchecked cellular signal transduction resulting in excess cellular proliferation.
Treatment and response. Imatinib (Gleevec®) was originally developed to specifically target and inactivate the ABL tyrosine kinase portion of the BCR-ABL1 fusion protein in order to treat patients with CML. In patients with chronic phase CML, early imatinib study data indicated a high response rate to imatinib compared to standard therapy, and long-term follow-up has shown that continuous treatment of chronic phase CML results in "durable responses in [a] large proportion of the patients with a decreasing rate of relapse." (3) As a result, imatinib became the primary therapy for most patients with newly diagnosed chronic phase CML.
Treatment response is evaluated initially by hematologic response (normalization of peripheral blood counts), then by cytogenetic response (percent of cells with Ph-positive metaphase [highly condensed] chromosomes in a bone marrow aspirate). Complete cytogenetic response (CCyR; 0% Ph-positive metaphases) is expected by 6-12 months after initial treatment with the TKI imatinib. (3) Quantitative measurement of BCR-ABL1 gene expression transcript (messenger RNA) levels is the most sensitive method of monitoring treatment response and is recommended in conjunction with cytogenetic monitoring (see Rationale).
However, imatinib treatment does not usually result in complete eradication of malignant cells. Not uncommonly, malignant clones resistant to imatinib may be acquired or selected during treatment (secondary resistance), resulting in disease relapse. In addition, a small fraction of chronic phase malignancies that express the fusion gene do not respond to treatment, indicating intrinsic or primary resistance. The molecular basis for resistance is explained in the following section. When the initial response to treatment is inadequate or there is a loss of response, resistance mutation analysis is recommended to support a diagnosis of resistance (based on hematologic or cytogenetic relapse), and to guide the choice of alternative doses or treatments. (3, 4)
Structural studies of the ABL-imatinib complex have resulted in the design of second-generation ABL inhibitors, including dasatinib [Sprycel®] and nilotinib [Tasigna®], which were initially approved by the U.S. Food and Drug Administration (FDA) for treatment of patients resistant or intolerant to prior imatinib therapy. More recently, trials of both agents in newly diagnosed chronic phase patients showed that both are superior to imatinib for all outcomes measured after one year of treatment, including CCyR (primary outcome), time to remission, and rates of progression to accelerated phase or blast crisis. (5, 6) Although initial follow-up was short, early and sustained complete cytogenetic response was considered a validated marker for survival in CML. (7) On June 17, 2010, the FDA approved nilotinib for the treatment of patients with newly-diagnosed chronic phase CML. Dasatinib was approved on October 28, 2010 for the same indication.
For patients with increasing levels of BCR-ABL1 transcripts, there is no strong evidence to recommend specific treatment; possibilities include continuation of therapy with dasatinib or nilotinib at the same dose, imatinib dose escalation from 400 mg to 800 mg daily, as tolerated or therapy change to an alternate second-generation TKI are all options. (3)
Molecular resistance. Resistance is most often explained at the molecular level by genomic instability associated with the creation of the abnormal BCR-ABL1 gene, usually resulting in point mutations within the ABL1 gene kinase domain that affects protein kinase-TKI binding. BCR-ABL1 kinase domain (KD) point mutations account for 30-50% of secondary resistance*. (4) At least 58 different KD mutations have been identified in CML patients. (8) The degree of resistance depends on the position of the mutation within the kinase domain (i.e. active site) of the protein. Some mutations are associated with moderate resistance and are responsive to higher doses of TKIs, while other mutations may not be clinically significant. Two mutations, designated T315I and E255K (nomenclature indicates the amino acid change and position within the protein), are consistently associated with resistance. The T315I mutation is relatively common at frequencies ranging from 4-19%, depending on the patient population; it is more common in patients with advanced-phase CML than in patients with early chronic phase CML. (9-11)
Compared to imatinib, fewer mutations are associated with resistance to dasatinib or nilotinib. (12, 13) For example, Guilhot et al. (14) and Cortes et al. (15) studied the use of dasatinib in imatinib-resistant CML patients in the accelerated phase and in blast crisis, respectively, and found that dasatinib response rates did not vary by the presence or absence of baseline tumor cell BCR-ABL1 mutations. However, neither dasatinib nor nilotinib are effective against resistant clones with the T315I mutation, (8, 14) and new agents and treatment strategies are in development for patients with T315I resistance.
In a recent follow-up study of nilotinib by le Coutre et al., (16) 137 patients with accelerated phase CML were evaluated after 24 months. Sixty-six percent of patients maintained major cytogenetic responses at 24 months. The estimates of overall and progression-free survival rates at 24 months were 70% and 33%, respectively. Grade 3/4 neutropenia and thrombocytopenia were each observed in 42% of patients.
Rarely, other acquired cytogenetic abnormalities such as BCR-ABL gene amplification and protein overexpression have also been reported. (17) Resistance unrelated to kinase activity may result from additional oncogenic activation or loss of tumor suppressor function, and may be accompanied by additional karyotypic changes. (4)
Regulatory Status
The BCR/ABL1 qualitative and quantitative genotyping tests, and ABL kinase domain mutation tests, are not manufactured test kits and have not been reviewed by the U.S. Food and Drug Administration. Rather, they are laboratory-developed tests (LDT), offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendments (CLIA) for high-complexity testing.
* Note that new BCR-ABL KD mutations also occur in about 80-90% of cases of acute lymphoblastic leukemia in relapse after TKI treatment, and in CML blast transformation.
BCR/ABL1 qualitative testing for the presence of the fusion gene is considered medically necessary for diagnosis of chronic myeloid leukemia (see Policy Guidelines). BCR/ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction at baseline prior to initiation of treatment and at appropriate intervals during therapy (see Policy Guidelines) is considered medically necessary for monitoring of chronic myeloid leukemia treatment response and remission.
Evaluation of ABL kinase domain point mutations to evaluate patients for tyrosine kinase inhibitor resistance is considered medically necessary when there is inadequate initial response to treatment or any sign of loss of response (see Policy Guidelines); and/or when there is progression of the disease to the accelerated or blast phase. Evaluation of ABL kinase domain point mutations is considered investigational for monitoring in advance of signs of treatment failure or disease progression.
Policy Guidelines
Qualitative molecular confirmation of the cytogenetic diagnosis (i.e., detection of the Philadelphia chromosome) and distinction between molecular variants (i.e., p190 vs. p210) is necessary information for accurate diagnosis and for accurate results in subsequent monitoring assays.
Determination of BCR-ABL1 messenger RNA transcript levels should be done by quantitative real-time reverse transcription polymerase chain reaction-based assays, and reported results should be standardized according to the International Scale. Testing is appropriate at baseline before the start of imatinib treatment; every 3 months for 3 years, then every 3-6 months thereafter. Without attainment of a complete cytogenetic response, continued monitoring at 3-month intervals is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib as well and will likely also be applied to bosutinib and ponatinib. See Rationale for more information.
Inadequate initial response to tyrosine kinase inhibitors is defined as failure to achieve complete hematologic response at 3 months, only minor cytological response at 6 months or major (rather than complete) cytogenetic response at 12 months.
Loss of response to tyrosine kinase inhibitors is defined as hematologic relapse, cytogenetic relapse or 1 log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response.
Kinase domain mutation testing is usually offered either as a single test to identify T315I mutation or as a panel (which includes T315I) of the most common and clinically important mutations.
There is specific CPT coding for BCR-ABL1 testing:
81206: BCR/ABL1 (t(9;22))(e.g., chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative
81207: minor breakpoint, qualitative or quantitative
81208: other breakpoint, qualitative or quantitative
Benefit Application
BlueCard/National Account Issues
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Literature Review
Various types of laboratory tests involving BCR-ABL1 detection are associated with chronic myelogenous leukemia (CML) and have different clinical uses. Briefly, these are: Diagnosis While the diagnosis of CML is based on the presence of characteristic cellular abnormalities in bone marrow, the presence of the Philadelphia chromosome (Ph) and/or confirmation of the BCR-ABL1 fusion gene is essential to diagnosis. The initial evaluation of chronic phase CML should include bone marrow cytogenetics, not only to detect the Ph chromosome, but to detect other possible chromosomal abnormalities. (18) If bone marrow is not available, FISH analysis with dual probes for BCR and ABL genes or qualitative reverse transcriptase PCR (RT-PCR can provide qualitative confirmation of the fusion gene and its type. (18) Baseline measurement of BCR-ABL transcript levels are recommended as part of the initial evaluation, providing confirmation of the fusion gene, ensuring that it is detectable (rare variants requiring non-standard probes may occur), as well as a baseline for monitoring response to treatment. (18) Monitoring for residual disease during treatment/disease remission Quantitative RT-PCR measurement of BCR-ABL1 RNA transcript levels is the method of choice for measuring response to treatment because of the high sensitivity of the method and strong correlation with outcomes. (3) Compared to conventional cytogenetics, quantitative PCR (qRT-PCR) is more than 3 logs more sensitive (19) and can detect one CML cell in the background of >100,000 normal cells. Quantitative RT-PCR testing can be conducted on peripheral blood, eliminating the need for bone marrow sampling. The goal of treatment is complete molecular response (CMR; no detectable BCR-ABL transcript levels by qRT-PCR). However, only a small minority of patients achieve CMR on imatinib. (20) More often, patients achieve a major molecular response (MMR; a 3-log reduction from the standardized baseline of the International Scale (not from the actual baseline level of the individual patient). Results from the IRIS trial showed that patients who had a CMR or MMR had a negligible risk of disease progression at 1 year, and a significantly lower risk of disease progression at 5 years compared to patients who had neither. (21) At 8 years' follow-up, none of the patients who achieved a MMR at 1 year progressed to the accelerated phase of disease or to a blast crisis. Similar near absence of progression in patients who achieved an MMR has been reported in registration studies of nilotinib and dasatinib. (5, 6, 20) The degree of molecular response has been reported to correlate with risk of progression in patients treated with imatinib. (22) Timing of the molecular response is also important; the degree of molecular response at early time points predicts the likelihood of achieving CMR or MMR and predicts improved rates of progression-free and event-free survival. (23-26) While early and strong molecular response predicts durable long-term remission rates and progression-free survival, studies have not been conclusive that molecular response is predictive of overall survival. (27-29) Based on imatinib follow-up data, it is recommended that for patients with a complete cytogenetic response, molecular response to treatment be measured every 3 months for 3 years, then every 3-6 months thereafter. (3, 30) Without complete cytogenetic response (CCyR), continued monitoring at 3-month intervals is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib as well, (3) and will likely also be applied to bosutinib and ponatinib. Rising BCR-ABL1 transcript levels are associated with increased risk of mutations and of treatment failure. (31-36) However, the amount of rise that is considered clinically significant for considering mutation testing is not known. Factors affecting the clinically significant change include the variability of the specific assay used by the laboratory, as well as the level of molecular response achieved by the patient. Thresholds used include 2- to 10-fold increases, and increases of 0.5-1 log. (3, 30, 37) Because of potential variability in results and lack of agreement across studies for an acceptable threshold, rising transcript levels alone are not viewed as sufficient to trigger mutation testing or changes in treatment. (38) Standardization of BCR-ABL1 quantitative transcript testing. A substantial effort has been made to standardize the BCR-ABL1 qRT-PCR testing and reporting across academic and private laboratories. In 2006, the National Institute of Health Consensus Group proposed an International Scale (IS) for BCR-ABL1 measurement. (39) The IS defines 100% as the median pretreatment baseline level of BCR-ABL1 RNA in early chronic-phase CML as determined in the pivotal IRIS trial, MMR is defined as a 3-log reduction relative to the standardized baseline, or 0.1% BCR-ABL1 on the IS. (40) In the assay, BCR-ABL1 transcripts are quantified relative to one of 3 recommended reference genes (e.g., ABL) to control for the quality and quantity of RNA and to normalize for potential differences between tests. (41, 42) Percent ratios on the IS are determined at local labs by a test-specific conversion factor (IS % ratio=local % ratio x conversion factor). Until reference standards become broadly available, patient specimens must be exchanged between the local laboratory and an IS Reference Laboratory to establish a laboratory-specific conversion factor (available online at: http://www.whereareyouontheis.com/Default.aspx ). In the U.S., many laboratories offer BCR-ABL quantitative testing (e.g., Quest, ARUP, LabCorp and Mayo) and most specify on their websites that results are standardized to the IS. Identification ofABLkinase domain mutations (mutations associated with TKI-resistance) Screening for BCR-ABL1 kinase domain point mutations (i.e. single nucleotide polymorphisms) in chronic phase CML is recommended for patients with inadequate initial response to TKI treatment, those with evidence of loss of response, and for patients who have progressed to accelerated or blast phase CML. (3) The purpose of testing for kinase domain point mutations is, in the setting of potential treatment failure, to help select among other possible TKI treatments or allogeneic stem-cell transplantation. The following discussion focuses only on kinase domain point mutations. In 2010, the Agency for Healthcare Research and Quality published a systematic review on BCR-ABL1 pharmacogenetic testing for tyrosine kinase inhibitors in CML. (43) The report concluded that the presence of any BCR-ABL1 mutation does not predict differential response to TKI therapy, although the presence of the T315I mutation uniformly predicts TKI failure. However, during the public comment period, the review was strongly criticized by respected pathology organizations for lack of attention to several issues that were subsequently insufficiently addressed in the final report. Importantly, the review grouped together studies that used kinase domain mutation screening methods with those that used targeted methods, and grouped together studies that used mutation detection technologies with very different sensitivities. The authors dismissed the issues as related to analytic validity and beyond the scope of the report. However, in this clinical scenario assay with different intent (screening vs. targeted) and assays of very different sensitivities may lead to different clinical conclusions and an understanding of these points is critical. Point Mutation Detection Methods. Currently, methods for detecting drug resistance mutations are not standardized; clinical laboratories may choose among several different methods. The methods can detect either specific, known mutations (e.g., targeted mutation analysis) or screen for all possible mutations (e.g., direct sequencing); sensitivity also varies by method. The particular methods to detect BCR-ABL kinase domain mutations will have great influence on the detection frequency, analytical sensitivity and the clinical impact of testing. The various mutation detection methods available have widely different analytic sensitivities, from the least sensitive direct Sanger sequencing to the highly sensitive mutation-specific quantitative polymerase chain reaction (PCR) methods. Direct Sanger sequencing screens for all possible mutations but has low sensitivity, detecting a mutation present in approximately 1 in 5 BCR-ABL1 transcripts. Denaturing high-performance liquid chromatography (DHPLC) is also a screening method with initially higher sensitivity to detect the presence or absence of any mutations. Follow-up Sanger sequencing of positive samples is required to identify the mutations present; final sensitivity of this method is the sensitivity of sequencing. Targeted methods, used either to screen for only the most common, clinically relevant mutations or to monitor already identified mutations after a therapy change, can offer either limited sensitivity (e.g., pyrosequencing) or very high sensitivity (e.g., allele-specific PCR). Kinase Domain Point Mutations and Treatment Outcomes. Branford et al. (44) have summarized much of the available evidence regarding kinase domain mutations detected at imatinib failure, and subsequent treatment success or failure with dasatinib or nilotinib. The studies referenced used direct Sanger sequencing, with or without DHPLC screening, to identify mutations at low sensitivity. The authors conducted a survey of mutations detected in patients at imatinib failure at their own institution and compared it with a collation of mutations derived from the literature. For both, the T315I mutation was most common; although about 100 mutations have been reported, the 7 most common (at residues T315, Y253, E255, M351, G250, F359, and H396) accounted for 60-66% of all mutations in both surveys. Detection of the T315I mutation at imatinib failure is associated with lack of subsequent response to high-dose imatinib, or to dasatinib or nilotinib. For these patients, allogeneic stem-cell transplantation remained the only available treatment until the advent of new agents such as ponatinib. (45) 'Most common,' however, does not necessarily correspond to clinically significant. Based on the available clinical studies, the majority of imatinib-resistant mutations remain sensitive to dasatinib and nilotinib. However, preexisting or emerging mutations T315A, F317L/I/V/C, and V299L are associated with decreased clinical efficacy with dasatinib treatment following imatinib failure. Similarly, preexisting or emerging mutations Y253H, E255K/V, and F359V/C have been reported for decreased clinical efficacy with nilotinib treatment following imatinib failure. In the survey reported by Branford et al., a total of 42% of patients tested had T315I or one of these dasatinib- or nilotinib-resistant mutations. (44) As a result, guidelines recommend mutation analysis only at treatment failure, and use of the T315I mutation and the identified dasatinib- and nilotinib-resistant mutations to select the subsequent treatment. (3, 38) In the absence of any of these actionable mutations, various treatment options are available. Note that these data have been obtained from studies in which patients were all initially treated with imatinib. No data are available regarding mutations developing during first-line therapy with dasatinib or nilotinib. (46) ABL kinase domain mutational analysis is recommended if there is inadequate initial response (failure to achieve complete hematologic response at 3 months, only minor cytological response at 6 months or major [rather than complete] cytogenetic response at 12 months) or any sign of loss of response (defined as hematologic relapse, cytogenetic relapse or 1 log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response). Mutation testing is also recommended for progression to accelerated or blast phase CML. Treatment recommendations based on mutation(s) are shown in Table 1. Table 1: Treatment Options Based on BCR-ABL1 KD Point Mutation Status at Imatinib Treatment Failure
Mutation |
Treatment Recommendation |
Ponatinib*, HSCT or clinical trial |
Consider nilotinib or bosutinib* rather than dasatinib |
Consider dasatinib or bosutinib* rather than nilotinib |
Any other mutation |
Consider high-dose imatinib, or dasatinib, nilotinib or bosutinib* |
HSCT, hematopoietic stem-cell transplantation
*Recently approved; added in advance of National Comprehensive Cancer Network (NCCN) update, from which guidelines this table is modified. Bosutinib active across BCR-ABL1 mutations including dasatinib- and nilotinib-resistant mutations except T315I, and after treatment failure with imatinib, dasatinib, or nilotinib (47, 48); Ponatinib active in treatment-resistant patients with T315I mutation. (45, 49)
Since only a small number of mutations have been recommended as clinically actionable, targeted assays may also be used to screen for the presence of actionable mutations at treatment failure. Quantitative, targeted assays may also be used to monitor levels of already identified clinically significant mutations after starting a new therapy following initial treatment failure. Targeted assays use different technologies, which can be made very sensitive to pick up mutated cell clones at very low frequencies in the overall malignant population. Banked samples from completed trials have been studied with high-sensitivity assays to determine if monitoring treatment can detect low-level mutations that predict treatment failure well in advance of clinical indications. While some results have been positive, not all mutations detected in advance predict treatment failure and more study is recommended before these assays are used for monitoring in advance of treatment failure. (38, 44) A direct correlation of low-sensitivity and high-sensitivity assays and a limited correlation with clinical outcomes supports recommendations of sequencing, with or without DHPLC screening, for identification of mutations. (50) Although high-sensitivity assays identified more mutations than did sequencing, the clinical impact of the additional mutations was viewed as uncertain.
Other types of mutations in addition to point mutations can be detected in the BCR-ABL1 gene, including alternate splicing, insertions, deletions and/or duplications. The clinical significance of such altered transcripts is unclear, and reporting such mutations is not recommended. (4, 46)
Ongoing Clinical Trials
Over 100 ongoing clinical trials resulted from a search of online site clinicaltrials.gov for 'BCR-ABL1 and CML'; many of these trials are treatment regimen-related. (http://www.clinicaltrials.gov/ct2/results?term=BCR%2FABL+CML&recr=Open&no_unk=Y).
Five ongoing trials were found that have direct genetic testing/molecular testing involvement.
- The Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib (STIM 2) will measure the rate of molecular relapse defined by the rate of patients having a significant increasing of BCR-ABL transcript for 2 years after stopping treatment. Secondary outcomes include overall survival, molecular profile of patient, treatment costs, and event-free survival. http://www.clinicaltrials.gov/ct2/show/NCT01343173.
- A Study of Complete Molecular Response for Chronic Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib (CMR-CML) will measure the rate of complete molecular response (CMR) after treatment with dasatinib. Secondary outcomes include progression-free survival, and number of participants with adverse events. http://www.clinicaltrials.gov/ct2/show/NCT01342679
- Nilotinib Versus Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response (CMR) for CML-CP (chronic phase) Pts With Evidence of Persistent Leukemia by RQ-PCR will measure the rate of confirmed best cumulative Complete Molecular Response within the first year of study therapy with imatinib or nilotinib. Secondary outcomes include kinetics of CMR achieved in both treatment arms, progression-free survival, EFS (event-free survival) and OS (overall survival) between the two arms, and kinetics of CMR achieved after cross-over. http://www.clinicaltrials.gov/ct2/show/NCT00760877
- Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients will measure the negative predictive value ratio (rNPV) of dPCR over qRT-PCR. Secondary outcomes include rate of molecular and cytogenetic relapse, rate of dPCR (digital PCR)-positive patients, rate of dPCR negative patients, rate of patients who are maintaining dPCR negativity for 36 month, time to molecular relapse, overall survival, quality of life, and rate of patients progressing or developing resistance. http://www.clinicaltrials.gov/ct2/show/NCT01578213; http://www.clinicaltrials.gov/ct2/show/NCT01580059
- Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in chronic phase (CP) will evaluate efficacy, using molecular response, of nilotinib 300 mg BID in the treatment of newly diagnosed CML-CP patients. No secondary outcomes were defined. http://www.clinicaltrials.gov/ct2/show/NCT01580059
Extensive clinical data have led to the development of congruent recommendations and guidelines developed both in North America and in Europe concerning the use of various types of molecular tests relevant to the diagnosis and management of chronic myelogenous leukemia (CML). These tests are also useful in the accelerated and blast phases of this malignancy. Appropriate uses are summarized as follows:
Diagnosis: Although CML is diagnosed primarily by clinical and cytogenetic methods, qualitative molecular testing is needed to confirm the presence of the BCR-ABL1 fusion gene, particularly if the Philadelphia chromosome (Ph) was not found, and to identify the type of fusion gene, as this information is necessary for subsequent quantitative testing of fusion gene messenger RNA transcripts. If the fusion gene is not confirmed, then the diagnosis of CML is called into question.
Monitoring during treatment with tyrosine kinase inhibitors: quantitative determination of BCR-ABL1 transcript levels during treatment allows for a very sensitive determination of the degree of patient response to treatment. Evaluation of trial samples has consistently shown that the degree of molecular response correlates with risk of progression. In addition, the degree of molecular response at early time points predicts improved rates of progression-free and event-free survival. Conversely, rising BCR-ABL1 transcript levels predict treatment failure and the need to consider a change in management. Quantitative polymerase-chain reaction (PCR)-based methods and international standards (IS) for reporting have been recommended and adopted for treatment monitoring.
Treatment failure: the presence of ABL kinase domain point mutations are associated with treatment failure; a large number of mutations have been detected, but extensive analysis of trial data with low-sensitivity mutation detection methods has identified a small number of mutations that are consistently associated with treatment failure with specific tyrosine kinase inhibitors; guidelines recommend testing for, and using information regarding these specific mutations in subsequent treatment decisions. The recommended method is sequencing with or without denaturing high-performance liquid chromatography (DHPLC) screening to reduce the number of samples that need to be sequenced. Targeted methods that detect the mutations of interest for management decisions are also acceptable if designed for low sensitivity. High sensitivity assays are not recommended.
While the existing evidence is associational in nature, the body of evidence that has been accumulated and the consequences of the management decisions involved, along with international agreement on recommendations of the use of molecular assays, support the medical necessity of the use of the assays as described. Other uses and other types of assays are considered investigational.
Policy Guidelines and Position Statements
The NCCN Practice Guidelines v.3.2013 Chronic Myelogenous Leukemia outline recommended methods for diagnosis and treatment management of CML, including BCR-ABL1 tests for diagnosis, monitoring, and ABL kinase domain mutations, and were referred to extensively in this document. (3) The European LeukemiaNet management recommendations for CML are very similar to those of NCCN and have also been cited in this document. (30) The U.S. Association for Molecular Pathology (4) and European LeukemiaNet recommendations for kinase domain mutation analysis (38) have been referenced; both provide very similar guidelines.
Medicare National Coverage
No national or local coverage information found.
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- Druker BJ, Guilhot F, O'Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355(23):2408-17.
- Press RD, Love Z, Tronnes AA et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood 2006; 107(11):4250-6.
- Branford S, Rudzki Z, Harper A et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia 2003; 17(12):2401-9.
- Wang L, Pearson K, Ferguson JE et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol 2003; 120(6):990-9.
- Quintas-Cardama A, Kantarjian H, Jones D et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood 2009; 113(25):6315-21.
- Müller MC, Hanfstein B, Erben P et al. Molecular Response to First Line Imatinib Therapy Is Predictive for Long Term Event Free Survival in Patients with Chronic Phase Chronic Myelogenous Leukemia – An Interim Analysis of the Randomized German CML Study IV. Blood 2008; 112:129. Abstract 333.
- Hehlmann R, Lauseker M, Jung-Munkwitz S et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011; 29(12):1634-42.
- de Lavallade H, Apperley JF, Khorashad JS et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26(20):3358-63.
- Marin D, Milojkovic D, Olavarria E et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008; 112(12):4437-44.
- Baccarani M, Cortes J, Pane F et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27(35):6041-51.
- Press RD, Galderisi C, Yang R et al. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res 2007; 13(20):6136-43.
- Branford S, Rudzki Z, Parkinson I et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 2004; 104(9):2926-32.
- Wang L, Knight K, Lucas C et al. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica 2006; 91(2):235-9.
- Press RD, Willis SG, Laudadio J et al. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood 2009; 114(13):2598-605.
- Marin D, Khorashad JS, Foroni L et al. Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? Br J Haematol 2009; 145(3):373-5.
- Kantarjian HM, Shan J, Jones D et al. Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol 2009; 27(22):3659-63.
- Branford S, Prime J. Chronic myelogenous leukemia: monitoring response to therapy. Curr Hematol Malig Rep 2011; 6(2):75-81.
- Soverini S, Hochhaus A, Nicolini FE et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118(5):1208-15.
- Hughes T, Deininger M, Hochhaus A et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108(1):28-37.
- Hughes TP, Kaeda J, Branford S et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Medne 2003; 349(15):1423-32.
- Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 2009; 22(3):355-65.
- Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev 2006; 20(1):29-41.
- Terasawa T, Dahabreh I, Castaldi PJ et al. Systematic reviews on selected pharmacogenetic tests for cancer treatment: CYP2D6 for Tamoxifen in breast cancer, KRAS for anti-EGFR antibodies in colorectal cancer, and BCR-ABL1 for tyrosine kinase inhibitors in chronic myeloid leukemia. Rockville: Agency for Healthcare Research and Quality (AHRQ). Technology Assessment. 2010.
- Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 2009; 114(27):5426-35.
- Cortes JE, Kim DW, Pinilla-Ibarz J et al. A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial. American Society of Hematology 54th Annual Meeting, December 2012 2012:Abstract 163.
- Alikian M, Gerrard G, Subramanian PG et al. BCR-ABL1 kinase domain mutations: methodology and clinical evaluation. Am J Hematol 2012; 87(3):298-304.
- Khoury HJ, Cortes JE, Kantarjian HM et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119(15):3403-12.
- Cortes JE, Kantarjian HM, Brummendorf TH et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011; 118(17):4567-76.
- Cortes JE, Kantarjian H, Shah NP et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367(22):2075-88.
- Ernst T, Gruber FX, Pelz-Ackermann O et al. A co-operative evaluation of different methods of detecting BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on second-line dasatinib or nilotinib therapy after failure of imatinib. Haematologica 2009; 94(9):1227-35.
Codes |
Number |
Description |
(See Policy Guidelines) |
ICD-9-CM diagnosis |
205.10-205.12 |
Myeloid leukemia, chronic, code range |
ICD-10-CM (effective 10/1/14) | C92.10-C92.12 |
Chronic myeloid leukemia, BCR/ABL-positive code range |
C92.20-C92.22 | Atypical chronic myeloid leukemia, BCR/ABL-negative code range | |
ICD-10-PCS (effective 10/1/14) | Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. |
Genetic Testing, BCR-ABL1
Policy History
Date | Action | Reason |
02/14/13 | Add to Medicine section, Pathology/Laboratory subsection | New policy. Considered investigational |


text:
AHS Boys Soccer vs Springtown; V-5:30
The Community News • P.O. Box 1031 • 203 Pecan Dr. • Aledo, TX 76008 • 817-441-7661 • FAX: 817-441-5419
Willow Park city employees won't be getting a pay raise this fiscal year and they shouldn't expect more money by the time the next one ends too.
Mayor Ken Hawkins said that with the projects the city has planned in the coming years and a possible population boom in three to five years, there's just not enough to increase the salaries of city workers.
However, he assures that as the private sector of the city grows and improves, the public sector will follow.
The complete story of the Willow Park City Council will be in the Friday print edition of The Community News. Check back with community-news.com for video.
AHS Boys Soccer vs Springtown; V-5:30
AHS Girls Soccer vs Springtown; V-7:30
AHS Boys Soccer at Chisholm Trail; JV-7:30 P.M. V-5:30 P.M.
AHS Girls Soccer at Chisholm trail; V-7:30
Aledo Varsity Tennis hosts the Aledo Tournament
Aledo Varsity Tennis at the Crowley Tournament
Aledo Varsity Tennis competes in the District Tournament at TCU

subset: commoncrawl


text: The Nebraska-Kearney track & field team, in its final regular season outdoor meet of the spring, won 15 events Thursday evening at the NWU Spring Open in Lincoln. Getting ready for the MIAA Outdoor Championships May 3-5 (Fri.-Sun.), the Lopers also recorded four more NCAA provisional efforts. On the men's side, Benkelman senior Kyle Glidden won the discus with a toss of 171-7, good for 11th in the nation. Teammates Colby Jurgens (161-8) and Ryan Hircock (161-4) were right behind him. Ogallala junior Michael Thalken then won the hammer with a heave of 183-1, a season-best throw that places him 20th on the national list. Glidden (176-0) and junior Josh Redman (170-5) were second and third, respectively. Thalken also was runner up in the shot (59-9.25), one of three Lopers to be in the top four. Next, Bellevue sophomore Mark Seeba won the pole vault by clearing 16-4.75. That rockets him up to 10th on the D2 national list. Beatrice junior Andrea Howe is now 24th in D2 in the discus after her winning throw of 144-2. The UNK women were also dominant in the hammer where they placed second through fifth, led by Elm Creek redshirt freshman Danyell Coons (158-2). For a third straight meet, Holdrege sophomore Courtney Fegter reached 12-0 in the pole vault, clearing exactly 12-0. The Lopers were also 1-2 in the long jump, led by Grand Island senior Ariel Krolikowski and Omaha sophomore Jordan Hopkins, each going 17-11.75. Other UNK women to place first were Bennington freshman Demi Hggins in the high jump (5-1.25), Sidney sophomore Kaitlyn Wells in the 800 (2:19.83), Seward sophomore Liz Damman in the 1,500 (4:54.97) and Colorado sophomore Steph Hutsell in the 400 (58.08). In field events, the Loper men went one through four in the long jump, paced by Kimball sophomore Brady Land (23-8) with Kearney senior Marty Molina taking the triple jump (48-11.75). On the track, both the 4 x 1 (41.90) and 4 x 4 (3:27.19) relay teams placed first with Boelus senior Nate Rogers first in the 400 hurdles (54.72) after running the opening leg for the 4 x 4 squad. Finally, Lincoln senior Cornell Leffler took the gold in the 400 (49.03) with teammate Jamey Foster right behind (50.53). This year, the MIAA's are being held at Fort Hays State.


text:
Today in London's Spitalfields Market, I was blown away by this wonderful little automaton, a tiny mechanical poet who writes graceful magnetic poetry when you spin a magnet beneath him. The proud maker -- who goes by Alefs in Wonderland -- let me shoot a little video of it (apologies for the crummy focus later in the shoot).
I write books. My latest is a YA science fiction novel called Homeland (it's the sequel to Little Brother). More books: Rapture of the Nerds (a novel, with Charlie Stross); With a Little Help (short stories); and The Great Big Beautiful Tomorrow (novella and nonfic). I speak all over the place and I tweet and tumble, too.
MORE: Art and Design • Gadgets • Happy Mutants • maker
More at Boing Boing
15 Responses to "Magnetic poetry-writer automaton"
Takuan says:
gives me an ideer… magnetic fridge poetry words, tumbler, sorter/aligner, conveyor, critics….
Anonymous says:
He was probably having a hard time getting it in focus because he wasn't using a lens with a shallow depth of focus, evindenced by the crisp focus of the gentleman holding up the purple papers, bearded face.
Anonymous says:
I only see ten seconds of video, and cannot see what is going on, is this a problem on my end?
Cornan says:
Whoops. Just posted as anonymous, but I was trying to quote Anon @ #9. I'm really not sure what it is I'm looking at here.
nosehat says:
Did you link the wrong video?
This was 10 seconds of what looked like setup.
Jake0748 says:
I'm also seeing about 10 seconds of video and then it quits.
Anonymous says:
Often people move in too close with video cams. Most cams can't focus close enough to resolve a tiny object like this one – yer better off staying farther away and keeping it sharp. Or learn how to use macro. I shoot video for a living, I'm sorry, I see this all the time and it just bugs the living daylights out of me. Can't people see that the darn thing is blurry?
plainclothedman says:
There appears to be a little man sitting at a desk with a quill pen on top of the contraption…
x99901 says:
i thought the previous video in mr. doctorow's flickr stream was better.
KidDork says:
Is it the Atom, or Hank Pym? Because Pym is getting around these days…
Anonymous says:
i wanted that machine to be randomly pulling pieces of magnetic poetry and putting them together. I guess i had the wrong idea.


text:
What's Your Ecological Footprint?
Apr 23, 2003 — David Sommerstein talks with the co-directors of the Global Living Project about calculating how many natural resources each of us consumes. It's called an "ecological footprint" and was used to calculate consumption per student at St. Lawrence University, as a part of an energy-saving campaign.


text:
The Infamous
The Infamous | ||||
Studio album by Mobb Deep | ||||
Released | April 25, 1995 | |||
Recorded | January 1994 - February 1995 Battery Studios, Platinum Island Studios, Firehouse Studios, and Unique Recording in New York City. |
Genre | East Coast hip hop, Hip hop | |||
Length | 66:51 | |||
Label | Loud/RCA/BMG Records 07863-66480 |
Producer | Havoc, Prodigy, The Abstract, Matt Life, Schott Free |
Mobb Deep chronology | ||||
Singles from The Infamous | ||||
The Infamous is the second studio album by the American hip hop duo Mobb Deep, released April 25, 1995, on Loud Records. The album features guest appearances from Nas, Wu-Tang Clan members Raekwon and Ghostface Killah, A Tribe Called Quest member Q-Tip, and close Mobb Deep affiliate Big Noyd. Embedded with hyper-visual lyricism, dark soundscapes, gritty narratives, and hard beats, it marked Mobb Deep's transition from a relatively unknown rap duo to an influential and commercially successful one.
Upon its release, The Infamous achieved notable commercial success. It debuted at number 15 on the Billboard 200, and number three on the Top R&B/Hip Hop Albums chart. The album produced three main singles, which all achieved varying degrees of chart success, with "Shook Ones Pt. II" being the most successful. On June 26, 1995, the album was certified Gold by the Recording Industry Association of America (RIAA).[1]
The album's haunting style, defined by its evocative melodies, rugged beats, and lyrics dealing with crime and poverty in inner-city neighborhoods reflected the dark side of New York's urban landscape in a manner that received special recognition and critical praise. Along with albums such as Enter the Wu-Tang (36 Chambers), Illmatic and Ready to Die, The Infamous is widely credited as a major contributor to the East Coast Renaissance. Furthermore, the album is credited with helping to redefine the sound of hardcore hip-hop, using its production style, which incorporated eerie piano loops, distorted synthesizers, eighth-note hi-hats, and sparse bass lines.
While still in their late-teens, Mobb Deep released their first album, Juvenile Hell, on 4th & B'way Records in spring 1993. The album included production from several revered New York based producers, including Large Professor, DJ Premier, and Public Enemy affiliate Kerwin Young, and included the underground single "Hit It from the Back". Due to Juvenile Hell's failure to achieve significant commercial and critical success, the duo was dropped from their label several months after the album's release.[2] Havoc and Prodigy later described Juvenile Hell as a "learning experience".[2]
In late summer of 1993, Loud Records was looking for another group to sign, owing to the success of Wu-Tang Clan's first single, "Protect Ya Neck", and by fall 1993, the label had signed Mobb Deep.[2] Recording for the album began in early 1994, and ended almost one year later in early 1995. Unlike the duo's first album, The Infamous was almost entirely self-produced by Havoc and Prodigy, with outside help from Matt Life, Schott Free and Q-Tip (credited as the Abstract).
Producer Matt Life later recalled Q-Tip's involvements, stating, "Tip was very involved in The Infamous from early on. Probably more than people know. Tip was just a fan of theirs and I knew him from way back, so he was really helpful, giving them advice. Then he came in later in the sessions and said he'd help mix a couple records. And then he ended up picking a couple of records they did to re-do. Except for "Drink Away the Pain", the songs that Tip produced were already a full song before he got to them. He liked the lyrics on those original songs, but he re-did the beats. It was the same song title, same hook, same rhymes, just new beats."[3] Havoc later commented "Q-Tip definitely bent his style a little bit to get with what we was doing. Like with "Drink Away the Pain" you see him trying to get gangsta with it."[4]
On the group's decision to handle most of the production, Havoc later commented, "We started producing because other producers was giving us shit that we didn't like, or they was just charging too much. I didn't know nothing about producing music at the time, but I learned by watching others."[5] The style of production on The Infamous was part of a change in New York hip-hop from upbeat and jazz-influenced, into raw, gritty beats. This style of production, often characterized by dissonant, minor key samples and heavily filtered bass lines became a hallmark of mid-1990s New York rap.
Initial reaction[edit]
Professional ratings | |
Review scores | |
Source | Rating |
Allmusic | [6] |
Entertainment Weekly | B+[7] |
Los Angeles Times | [8] |
Rolling Stone | 1995[9] |
Rolling Stone | 2004[10] |
The Source | [11] |
Spin | 9/10[9] |
Vibe | favorable[12] |
Upon its release, The Infamous received mostly positive reviews. Entertainment Weekly's Tiarra Mukherjee gave it a B+ rating, stating "Over mostly self-produced, bare-bones beats, the pair's hard-edged rhymes paint a chilling picture of life on their mean streets, New York City's Queensbridge Housing Projects. Underground rap-heads, and those who can break away from Jeep beats will rejoice."[7] In its initial review, The Source gave The Infamous four and a half out of five "mics", with Dimitry Leger stating "Mobb Deep earn credibility, winning the crucial battle between style and substance, who's real and who's a move-faker. Havoc and Prodigy simply report what they know."[11] Elliott Wilson from Vibe wrote a favorable review of the album as well, and stated "Each song is a different chapter in the hard street life Havoc and Prodigy have experienced in their Queensbridge neighborhood ... While describing their lives with brutal realism and raw imagery, Havoc's love for his hometown hits you in the head like a Mike Tyson comeback punch."[12] NME gave the album an eight out of 10 rating, and described it as "Shuttering nitro beats and scratchy jazz samples (that) cut back to reverberating piano chords and odd squealing horn breaks. As rappers they bring the clipped, rolling style of Rakim or EPMD, adding a chill menace to neighborhood boasts like 'Right Back at You' and 'Eye For a Eye.'"[9] Rolling Stone magazine originally rated the album three and a half out of five stars, and called it "a darkly nihilistic masterpiece".[9]
Commercial performance[edit]
This section requires expansion. (May 2010) |
The album spent 18 weeks on the Billboard 200 album chart, peaking at number 15, and it also spent 34 weeks on the Top R&B/Hip-Hop Albums chart, peaking at number three. The Infamous was certified Gold in sales by the RIAA on June 26, 1995.[1]
Since its initial release, The Infamous has earned additional critical praise and has been widely regarded as a cornerstone album of New York hardcore rap.[6] Allmusic's Steve Huey gave it a five star rating, and commented "The Infamous is Mobb Deep's masterpiece, a relentlessly bleak song cycle that's been hailed by hardcore rap fans as one of the most realistic gangsta albums ever recorded [...] it has all the foreboding atmosphere and thematic sweep of an epic crime drama. That's partly because of the cinematic vision behind the duo's detailed narratives, but it's also a tribute to how well the raw, grimy production evokes the world that Mobb Deep is depicting." Huey further stated
"This is hard, underground hip-hop that demands to be met on its own terms, with few melodic hooks to draw the listener in. Similarly, there's little pleasure or relief offered in the picture of the streets Mobb Deep paints here: They inhabit a war zone where crime and paranoia hang constantly in the air. Gangs are bound together by a code of fierce loyalty, relying wholly on one another for survival in a hopeless environment. Hostile forces — cops, rivals, neighborhood snitches are potentially everywhere, and one slip around the wrong person can mean prison or death."[6]
—Steve Huey
In 2004, The Source re-rated the album to the perfect five "mics" and stated "Prodigy's thugged-out entertainment and Havoc's sonic production on cuts like the bone-chilling 'Shook Ones Pt. ll' and the stick-up-kid anthem 'Give Up The Goods' proved to be timeless street joints in the same vein as 'Life's a Bitch' and 'You Gots To Chill.' The album was a staple for all hardheaded delinquents comin' up in the game."[14] Rolling Stone also re-rated the album in 2004 to a maximum five, while calling The Infamous "one of the greatest rap albums of the '90s".[10] Similar to The Source, XXL magazine gave it a classic rating of "XXL" in its retrospective 2007 issue.[13]
Track listing[edit]
No. | Title | Writer(s) | Producer(s) | Length | |
1. | "The Start of Your Ending (41st Side)" | A. Johnson, K. Muchita | Mobb Deep | 4:24 | |
2. | "The Infamous Prelude" | 2:12 | |||
3. | "Survival of the Fittest" | A. Johnson, K. Muchita | Mobb Deep | 3:43 | |
4. | "Eye For a Eye (Your Beef Is Mines)" (featuring Nas and Raekwon) | A. Johnson, K. Muchita, N. Jones, C. Woods | Mobb Deep | 4:54 | |
5. | "Just Step Prelude" | A. Johnson, T. Perry | 1:06 | ||
6. | "Give Up the Goods (Just Step)" (featuring Big Noyd) | A. Johnson, K. Muchita, J. Davis, T. Perry, M.W. Small Jr. | The Abstract | 4:02 | |
7. | "Temperature's Rising" (featuring Crystal Johnson) | A. Johnson, K. Muchita, J. Davis, P. Rushen, F. Washington | The Abstract, Mobb Deep (co.) | 5:00 | |
8. | "Up North Trip" | A. Johnson, K. Muchita | Mobb Deep | 4:58 | |
9. | "Trife Life" | A. Johnson, K. Muchita, M. Henderson | Mobb Deep | 5:19 | |
10. | "Q.U.- Hectic" | A. Johnson, K. Muchita | Mobb Deep | 4:55 | |
11. | "Right Back At You" (featuring Ghostface Killah, Raekwon and Big Noyd) | A. Johnson, K. Muchita, T. Perry, D. Coles, C. Woods | Mobb Deep, Schott Free (co.) | 4:52 | |
12. | "The Grave Prelude" | 0:30 | |||
13. | "Cradle to the Grave" | A. Johnson, K. Muchita | Mobb Deep | 5:16 | |
14. | "Drink Away the Pain (Situations)" (featuring Q-Tip) | A. Johnson, K. Muchita, J. Davis, B. Maupin, P. Jackson, M. Clark, D. McKnight, P. Potyen, B, Summers, D. Youman | The Abstract, Mobb Deep (co.) | 4:44 | |
15. | "Shook Ones Pt. II" | A. Johnson, K. Muchita, | Mobb Deep | 5:24 | |
16. | "Party Over" (featuring Big Noyd) | A. Johnson, K. Muchita, T. Perry | Mobb Deep, Matt Life (co.) | 5:40 | |
Total length:
66:51 |
Chart history[edit]
Chart positions from Billboard magazine (North America)
Year | Chart positions | |
Billboard 200 | Top R&B/Hip Hop Albums | |
1995 | 15 | 3 |
Year | Song | Chart positions | |||
Billboard Hot 100 | Hot R&B/Hip-Hop Singles & Tracks | Hot Rap Singles | Hot Dance Music/Maxi-Singles Sales | ||
1995 | Shook Ones Pt. II | 59 | 52 | 7 | 7 |
Survival of the Fittest | 69 | 60 | 10 | 6 | |
Temperature's Rising | — | — | 33 | 9 |
- Information regarding accolades is extracted from acclaimedmusic.net,[15]except for lists with additional sources.
- An asterisk (*) indicates unordered lists.
Publication | Country | Accolade | Year | Rank |
About.com | United States | 100 Greatest Hip Hop Albums[16] | 2008 | 74 |
Best Rap Albums of 1995[17] | 2008 | 4 | ||
Blender | 500 CDs You Must Own Before You Die | 2003 | * | |
The Source | The 100 Best Rap Albums of All Time | 1998 | * | |
Vibe | 51 Albums representing a Generation, a Sound and a Movement | 2004 | * | |
Hip Hop Connection | United Kingdom | The 100 Greatest Rap Albums 1995-2005 | 2005 | 4 |
Melody Maker | Albums of the Year | 1995 | 28 | |
Pop | Sweden | Albums of the Year | 1995 | 11 |
OOR | Netherlands | Albums of the Year | 1995 | 43 |
Spex | Germany | Albums of the Year | 1995 | 13 |
- ^ a b "Gold and Platinum Database Searach at Riaa.com". Archived from the original on December 21, 2006. Retrieved December 31, 2006.
- ^ a b c Coleman, Brian, 2007. P:267
- ^ Coleman, Brian, 2007. P:269.
- ^ Coleman, Brian 2007. P:272.
- ^ Coleman, Brian, 2007. P:266
- ^ a b c Huey, Steve. Review: The Infamous. Allmusic. Retrieved on 2009-09-21.
- ^ a b Mukherjee, Tiarra. Review: The Infamous. Entertainment Weekly. Retrieved on 2010-03-19.
- ^ Siegmund, Heidi. Review: The Infamous. Los Angeles Times. P. 68. May 14, 1995.
- ^ a b c d e Columnist. Review snipets: The Infamous. cduniverse.com. Retrieved 2011-12-30.
- ^ a b Hoard, Christian. Review: The Infamous. Rolling Stone. P:547. Retrieved 2010-05-10.
- ^ a b Leger, Dimitry. Review: The Infamous. The Source. Retrieved on 2009-09-21.
- ^ a b Wilson, Elliott. The Infamous. Vibe. Retrieved on 2010-03-19.
- ^ a b XXL (2007). "Retrospective: XXL Albums". XXL Magazine, December 2007 issue.
- ^ Columnist. Re-Rated Albums. The Source. Retrieved on 2010-03-19.
- ^ "The Infamous at Acclaimedmusic.net". Retrieved December 31, 2006.
- ^ Adaso, Henry. About.com's 100 Greatest Hip Hop Albums. About.com. Retrieved 2010-05-10.
- ^ Adaso, Henry. Best Rap Albums of 1995. About.com. Retrieved 2010-05-10.
- Brian Coleman (2007). Check the Technique. Random House. ISBN 978-0-8129-7775-2.
- Nathan Brackett, Christian Hoard (2004). The New Rolling Stone Album Guide: Completely Revised and Updated 4th Edition. Simon and Schuster. ISBN 0-7432-0169-8.
External links[edit]
- The Infamous at Discogs
- Album Review at RapReviews.com
- Album Accolades and Ratings at acclaimedmusic.net


text:
Your search for HIGH NET WORTH INDIVIDUALS in Bush-Era Tax Cuts returned 49 articles
Steps Toward Financial Fitness, for This Year and Beyond
Several tax professionals offer their advice on how people of all income levels can better navigate the tax code and cut down their liabilities.
February 9, 2014, SundayWhite House Budget Curbs Some Deductions for the Wealthy
Under President Obama's budget proposal, deductions for tax breaks like mortgage interest and contributions to charities would be capped at a maximum rate of 28 percent.
April 11, 2013, ThursdayWhite House Budget Curbs Some Deductions for the Wealthy
President Obama is no longer pressing to raise income tax rates on the rich. But that doesn't mean he thinks the wealthy are paying enough in taxes. Outlining his budget proposals to Congress on Wednesday, Mr. Obama pushed to raise more than $600 billion in new revenue,...
April 11, 2013, ThursdayTax Code May Be the Most Progressive Since 1979
The deal struck by Congress raised taxes on a handful of the highest-earning Americans, with about 99.3 percent of households experiencing no change in their income taxes.
January 5, 2013, SaturdaySenate Passes Legislation to Allow Taxes on Affluent to Rise
The Senate easily passed the measure, which also put off cuts in spending, early on Tuesday after the deadline on the so-called fiscal cliff had passed. Republican House aides said a vote Tuesday was possible.
January 2, 2013, WednesdayA Proliferation of Ways to Use a Tax Break as Its End Nears
Time is running out on a generous exemption from gift taxes, but tax advisers have no shortage of ways to get in under the deadline.
December 15, 2012, SaturdayUnlikely Backers in a Battle Over Taxes
As pressure builds to find a compromise for the fiscal impasse in Washington, some of America's leading executives have dropped opposition to tax increases on the wealthiest.
December 12, 2012, WednesdayPolitics Complicates the Math in Ending Tax Breaks for Rich
Experts say that raising revenue without increasing rates would involve wiping out nearly every deduction, credit and preferential rate that affluent households claim.
November 21, 2012, WednesdayTax Talks Raise Bar for Richest Americans
The changes being discussed by the president and Congressional Republicans would take the biggest bite from the highest earners and a smaller share from those earning less than $500,000.
November 20, 2012, TuesdayTax Break on Gifts Soon to End
People of means are scrambling to take advantage of the significant gift tax exemption which, for now, will expire on Dec. 31 with the rest of the Bush tax cuts.
November 9, 2012, FridayWhat Some Investors Are Doing to Anticipate a Tax Increase
The Senate has voted to raise taxes on the wealthy, while the House has voted to keep taxes low for everyone and compromise seems unlikely. How are affluent investors coping with the uncertainty?
August 4, 2012, SaturdayTaxes Needn't Discourage Philanthropy
If Washington increases the top income tax rate, it should also offer strong incentives for charitable giving, Robert H. Shiller says.
July 29, 2012, SundayThe Need to Agree to Agree
President Obama challenges Republicans to keep taxes low for most Americans, and he's right on fairness and the facts.
July 10, 2012, TuesdayIn Senate, Republicans Block Debate on 'Buffett Rule'
Republican opposition ensured that a measure pressed by President Obama and Senate Democrats to raise effective tax rates for the superrich would not come to a decisive vote.
April 17, 2012, TuesdayHow the Buffett Rule Would Affect Small Businesses
Generally, few owners would feel the pinch, but it would be a concern for many of those who sell their businesses.
April 16, 2012, MondaySEARCH 49 ARTICLES ABOUT THE BUSH TAX CUTS:
- The Science of Older and Wiser
- Op-Ed Columnist: The Deepest Self
- Well: To Keep Teenagers Alert, Schools Let Them Sleep In
- Common Sense: A Dragnet at Dewey & LeBoeuf Snares a Minnow
- Art Review: First, They Came for the Art
- Your Money: Consumers Not Powerless in the Face of Credit Card Fraud
- A Kiss Is Just a Kiss, Unless It's an Ad for a Clothing Company
- Op-Ed Contributor: Why Black Women Die of Cancer
- Op-Ed Columnist: The Unhealthy Meat Market
- High Levels of Pollution Spur Paris to Action
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Luxury Istanbul features First Class Turkey travel packages for those times when you are looking to spoil yourself with a romantic getaway or special experience. This is where you will find high quality, exclusively private and personalized travel options to fulfill your individual / corporate travel requirements for your holiday in Turkey.
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With Luxury Istanbul, go beyond the ordinary itinerary and experience the bests of Turkey, Europe's one of the most striking Mediterranean gems. A Luxury Istanbul journey here reveals the heart of this historic Mediterranean country. Experience the treasures of civilizations past as well as modern-day comforts and wonders.
Let Luxury Istanbul be your knowledgeable companion during your vacation in Turkey to living and spending, with abundance and joy.
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In this Jan. 14, 2013 photo, a student pets Junie, the school's "therapy dog," at Prospect High School in Mt. Prospect, Ill. Stress, anxiety and panic attacks are on the rise at many U.S. high schools, due to heightened academic expectations and troubles at home made worse by the shaky economy. So some schools are trying unconventional methods, such as therapy dogs, to help students cope. (AP Photo/Martha Irvine)
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05/03/2012 16:50
By SETH J. FRANTZMAN
Benzion Netanyahu's final book shows the reverence with which he holds Zionism's architects.
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When Theodor Herzl was on his way to Istanbul in 1896 aboard the Orient Express, he happened upon Ziad Pasha, a Turkish statesmen. Chatting with the Ottoman official, the first one he had ever met, Herzl immediately explained the Zionist program. "We want Palestine as an absolutely independent state," he said. This was the essence of the Jewish national movement, though not every Zionist leader agreed. Practical and cultural Zionists saw things differently. In
The Founding Fathers of Zionism
, author Benzion Netanyahu seeks to show readers the pantheon of Jewish thinkers who not only created and articulated Zionism but also forged what became known as its political and revisionist paths: Max Nordau, Israel Zangwill, Leo Pinsker, Theodor Herzl and Ze'ev Jabotinsky.
The book is made all the more pertinent by the fact that its author is the recently deceased Benzion Netanyahu, a confidant of Jabotinsky, scholar of the history of the Jews and Spain and father of the prime minister. This monograph is not laid out as one work but is a collection of five essays that were published between 1937 and 1981. The essays are presented chronologically. It is not altogether clear whether the author would have assembled this cast if he had written a book on the subject after 1981. It appears from the reverence he shows for these men that he views them as part of a particular Zionist tradition, but he notes that "the national movement could not come into being merely by the will of a few individuals, however forceful, convincing and persistent they might be."
Netanyahu begins his book by discussing Leo Pinsker. Pinsker, although born in Poland, grew up in Odessa. The author notes that while other nationalisms developed between 1815 and 1878, the Jewish nationalist movement began later. "The development of the movement was even more hampered by the fact that it was initiated and centered in Russia," he writes. While the Jews were an ancient nation, the realization that they needed a national home "needed external pressure to be crystallized into a movement. This pressure was provided by the pogroms of 1881."
Pinsker, like many of the other leaders profiled, was a writer, but he had first wanted to be a lawyer. He "realized clearly that the field of his vocation was tightly closed to him only because he was a Jew." This set him on a radical course, first to Moscow and then outside Russia, where he preached for reviving "the great past of the Hebrew nation."
Netanyahu admired Pinsker for his rejection of the Jews who were arguing for assimilation. Pinsker asserted that "in the great majority of cases, the Jew is treated as a stepchild… never is he considered a legitimate child of the fatherland." Netanyahu examines early Zionism in light of the major problems it faced in that period. Not only was it up against the enlightenment, which sought to deracinate the Jews from their religion, but Marxist and socialist postnationalism was eating away at the notion of a national homeland as a solution. Jews involved themselves in the politics of the day in Europe, forsaking their own national needs. "Jewish influence was the eternal flame which kept the national revolutionary movements from being extinguished," Netanyahu writes.
Max Nordau knew this when he noted that "from every age of history of the Risorgimento [in Italy], Jewish names shine forth."
Yet, paradoxically, Jews found inspiration in the writings of men like Italian nationalist Giuseppe Mazzini, and in witnessing the activities of Russian Slavophile conservatives they saw a path to their own redemption. Nordau was the curmudgeon of the Zionist movement. A Hungarian Jew and citizen of the Austro-Hungarian Empire, he traveled to Berlin and Paris where he became a philosopher and a writer. Arguing that European thought had stagnated and morality was degenerating, he became a companion to Herzl and co-founder of the First Zionist Congress.
When Netanyahu writes about Israel Zangwill, the English Zionist, it is clear that he identifies strongly with the man as well as with his vision. A "journalist and a publicist, author of novels and novellas, reviewer and essayist, poet and playwright," he followed in the footsteps of Nordau and Herzl. Yet his political path bridged the gap to the one Jabotinsky would eventually undertake. "He did not believe in European Humanism, which was at the root of European Jewry's Emancipation. He did not believe in Cosmopolitanism," Netanyahu writes about Zangwill. He admired the Boers, who had fought the British, and disdained the British Jewish elites who identified too strongly with their country over their people. He eagerly struggled against the cultural Zionists, like Ahad Ha'am (Asher Zvi Hersch Ginsberg), who wanted a "spiritual center" in Jerusalem. Netanyahu notes that "Jerusalem had been a spiritual center for 1,800 years, and such it continued to be."
His essay on Jabotinsky is in some ways the weakest, for it focuses primarily on the revisionist's break with Chaim Weizmann and the betrayal of the Balfour Declaration by the Mandate authorities. This is interesting, but more interesting are his comments about the Arab opposition to Israel. Paraphrasing Jabotinsky he notes that "the answer is the Iron Wall. That is, a strong military and political force that in the last analysis will convince the Arabs they will not succeed in driving us out of here… their opposition will not cease as long as they have even a spark of hope of erasing out political presence."
These were prescient words when he wrote them in 1981, and are certainly still meaningful today.
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Today is National Beer Day! Send a free Beer Day eCard to spread the word! People have been brewing beer ever since they began cultivating domesticated grains 8,000 years ago. Beer has been an important part of human culture ever since. For example, over 4,000 years ago an anonymous poet wrote an ode to Ninkasi—the Sumerian goddess of beer and brewing! Today, beer is the third most popular beverage in the world behind water and tea.
So why is National Beer Day celebrated on April 7th? On this day in 1933, President Franklin Roosevelt took the first step toward ending Prohibition and signed a law that allowed people to brew and sell beer as long as it remained below 4.0% alcohol by volume (ABV). Despite the low ABV, Americans were thrilled to be able to purchase beer for the first time in thirteen years!
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2001 2 Hip Soul
A couple styles of frames are shown
2hip makes some great bikes, Ron Wilkerson, the owner has been an innovator in BMX since he started riding. His passion for riding has pushed the sport to a new level. Besides being a factory rider for Haro, he started the 2hip society, that created many contests and places for freestylers to show their skills. Besides putting on these events, Ron would also ride in them!! Wilkerson airlines was a creation of his that made frames for a short time, then evoleved into 2hip bicyles.
He is still invlolved with bmx today and has a line of complete bike.
Submitted by Guest
Discuss this bike- All-Around
- Company: 2 Hip
- Material: 4130 Chromoly
- Headtube size: 1-1/8"


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Vila Rica
Travel Blogs from Recife
Big city life and "sanque bom"
... to see the center of Recife. It has some nice buildings but yeah...still it is a brazilian big city. It means not much to me. And beside of that it really stinks and is dirty and heavily polluted. We went to Olinda which is supposed to be super nice and one of the most beautiful colonial cities of Brazil. Well, it is nice though...but has just like 3 streets and after these three streets it changes very fast again to the normal brazilian city appearance. We both were ...
Week 4 Trouble Ahead
... ship that way we could take in more sights and maximise our time here. We managed to visit or photograph all the sights we wanted as we made our way back but the heat and humidity was starting to get to us, by now I was beginning to look like an icepole or popsicle, just soaked through with running water from head to foot!
Our last sight was a monument I'd previously fairly seen close to the ships berth and as it ...
... in karma, but id like to think that maybe there is a sort of universal justice that is working to right the wrongs or equal out it all, what ever IT ALL entails.
i wanted to talk about this before, because it so evident in the places i travel. ive heard that karma plays the argument that we are born into our lives and the situations of our lives because of what we did in our past life. so to put it in my words, ...
Brazil is in sight!
... and graceful squares. In 1982 it was designated a cultural heritage site by UNESCO. The old city is spread across several small hills looking back towards Recife, but it belongs to a different world. It�s here that many of the larger city�s artists, musicians and liberal professionals live.
There are also lots of lovely handicraft and art shops...Lisa wanted an extra rucksack. ...
Long distance in a big city
... bought new shorts and swim suit because I realized I was not so well prepared for summer :). I could also see the sequels of carnaval downtown. I ended my tour visiting a fortress with a man from the army explaining me the story of the fortress and how portuguese and dutch fought for this land. At least, if you speak portuguese, you can understand the stories. Quite tired at the end of the day. I just went back to the hostel to rest.


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Nu-Life Carpet & Upholstery Cleaner's professional rug-scrubbers, certified by the Institute of Inspection, Cleaning, and Restoration, purify carpets using powerful truck-mounted steam cleaners. Upon their arrival at customers' homes, technicians set to work removing stains and banishing dirt trapped in carpet fibers and the pages of tell-all memoirs. On return visits, homeowners can request that other rooms be cleaned, or space out service to maintain previously steamed carpets. Workers can also clean sofas using dry-cleaning or steam-extraction techniques, depending on the type of fabric. Freshly pressed sofas show fewer signs of aging and wear and enable better naps than couches covered in a fine dust of cheese powder.
One of the oldest independently owned mattress discounters in the mid-Atlantic, Home Mattress Center cushions customers' restful slumbers with first-rate sleeping surfaces from Sealy Posturepedic, Simmons Beautyrest, and Serta Perfect Sleep. Hunt and capture z's atop a Sealy Posturepedic Slipstream king set ($1,399), count a herd of numerically ordered clone sheep from a Simmons Beautyrest Sondra Plush elite twin set ($1,499), enjoy the slumber that only dreams of Rutherford B. Hayes can provide with a Simmons Beautyrest Aliyah classic queen set ($999), or opt for a firmer bed with the Sealy Posturepedic Diamond Hill firm queen set ($1,299). Home Mattress Center's well-trained, noncommissioned sleep doctors guide customers through the process of selecting an ideal bedroom fixture by asking questions, determining sleep preferences, and administering inkblot tests if necessary.
The Zone Fitness and Wellness Center divides its fitness space into private rooms for personal training, group aerobics, and sipping on smoothies. The workout area is lined with strength and cardio machines from notable manufacturers such as Hammer Strength and Life Fitness, which whir to life as guests embark on self-guided fitness regimens. Trainers conduct over 15 group classes in the aerobics room and provide individualized attention during private training sessions. As patrons exercise, the daycare-room staff keeps a watchful eye on tykes, and team members at the juice bar hand out post-workout refreshments.
Just walking distance from the University of Delaware's campus, The Zen Den offers non-competitive yoga and massage services in a calm and welcoming studio focused on helping people find their best self and flourish in their community. The schedule features Pilates and a variety of yoga classes offered seven days a week. Yoga styles include kundalini, prenatal, and hatha flow yoga with an emphasis on Zen meditation, and the staff can work with clients to figure out which classes and teachers best fit their practice. Additionally, The Zen Den's pair of licensed massage-therapists— also the co-owners—soothe bodies and minds with a slate of massages such as deep tissue, Swedish, fertility, and sports.
Caffe Gelato sates appetites with Northern Italian and French- and Mediterranean-inspired fare, house-made gelato, and vino from a 1,500-bottle cellar, all of which has amassed the restaurant an impressive collection of praise and awards from the likes of Delaware Today and Wine Spectator. Meats such as filet mignon and prosciutto-wrapped veal appear alongside a rotating collection of seafood entrees, such as pan-seared scallops, truffle maple-roasted salmon, and local line-caught rockfish. House-made pappardelle and linguine pastas entangle ingredients ranging from littleneck clams to lump crab to chiffonade-cut basil. Twenty-four rotating flavors of gelato are crafted on the restaurant's premises, delighting tongues with a chocolate-hazelnut blend or scoops of raspberry. Sommeliers strap on their headlamps and crampons to belay into the caverns of the restaurant's opulent wine cellar, where more than 100 varietals nestle in bottles.
Half-moon booths welcome companionable groups among sunny yellow-and-red-orange walls in the dining room, and the gleam of a granite bar inspires tipplers to toast the memory of loyal pet rocks.
Village Laundromat delivers fresh-folded laundry seven days per week within a 25-mile radius of Newark. Schedule a pick-up over the phone or send soiled socks up your flagpole and Village Laundromat liaisons will whisk away washables. Blouses, bed sheets, and breeches are given a sudsy bath, complete with fabric softener and bleach if necessary. Each article is then folded neatly and delivered to your doorstep faster than the speed at which electricity flows through copper wiring. Businesses in need of unsullied uniforms and spotless tablecloths can also put this Groupon to good use.


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Film Junkie's Guide to North Carolina
For most of the last 20 years, North Carolina has ranked third in the nation behind California and New York in U.S. film production. North Carolina also boasts more productions studios and sound stages than any state except California. The idea for a travel guide originated when Connie Nelson wrote an article about movie locations across the state for Reel Carolina Journal...more
Paperback, 432 pages
May 1st 2004
by John F. Blair Publisher
(first published April 1st 2004)
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A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. JAMES NEIBURGER:
View the full profile to get information on:
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Patient Reviews
The overall average patient rating of Dr. JAMES NEIBURGER is Excellent.
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Dr. JAMES NEIBURGER, MD is board certified in Allergy & Immunology and Pediatrics.
He has special expertise in 2 Areas, including Asthma and Nasal Allergy Rhinitis.
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Education & Awards
Dr. NEIBURGER graduated from Rosalind Franklin University, North Chicago.
More Education & AwardsAffiliations
Dr. NEIBURGER has 6 hospital affiliations:
- Shawnee Mission Medical Center
- Overland Park Regional Medical Center
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Dr. NEIBURGER accepts these health insurances in at least one office:
- Blue Cross Blue Shield of Kansas City - 8 plans
- United Healthcare - 15 plans
- Humana - 7 plans
- Cigna - 4 plans
- Family Health Partners - 2 plans
- USA H & W Network - 1 plan
- Aetna - 3 plans
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Dr. JAMES NEIBURGER practices Allergy & Immunology, Allergy, and Pediatrics near Leawood, KS.
See Leawood Allergists and Leawood Pediatricians.


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Road Trip
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Take your love on the road
Surf on Costa Rica's Pacific coast today, then parasail on the Caribbean tomorrow. Travel to the Grand Canyon before heading north to Mount Rushmore. And why just stay in Honolulu when you could explore all of the big Island of Hawaii? A road trip honeymoon is about more than just the destination; getting there really can be most of the fun! You travel at your own pace on a road trip honeymoon with the chance to get intimate with the location as much as with each other. You can enjoy the freedom to investigate, say, the ruins of Machu Picchu in Peru on your own timeframe. But then again, you may want to pack it up and check out the Nazca lines a day early. Essentially, your itinerary can be as flexible as you.
While some regions are better suited for road trips than others, your choices are nearly limitless all around the world. With wide-open spaces, the United States has a bounty of opportunity from Old California to New England. US Route 1, known as the Pacific Coast Highway, takes you from Los Angeles to San Francisco with dramatic scenery, ocean-side eateries and excellent weather through beautiful towns like Santa Barbara and Carmel. Then back east, a road trip honeymoon up the coast of Maine, into the White Mountains of New Hampshire or along Vermont's Route 100 is a varied experience that's breathtaking and quaint with covered bridges, charming inns and an easy pace. Likewise, Europe is home to numerous exquisite drives such as the winding, spectacle of Italy's gorgeous Amalfi coast or through the wine country and endless romance of the back roads of Provence in France. Other locations practically demand road trips to get from point A to point B because, for example, major cities or attractions are spread apart as in Australia, Canada or New Zealand's North Island.
Regardless of where you choose to go, preparing in advance for your road trip honeymoon can make the difference between a romantic delight and a rotten disaster. If you're renting from a major agency, if possible test drive the car before leaving the lot. Better to discover a problem then instead of two hours away from Alice Springs in the outback of Australia! Also, avoiding fatigue or boredom may become necessary if you're in the car for a while, so bring along your favorite music or think about some road games the two of you can
Chase your honeymoon dreams and you can catch them in California!
Some of the world's most View
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What could be more romantic than to begin your new life together in the place where the View
Lake Louise
An unrivaled alpine escape is at your fingertips with a honeymoon in View
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There are some destinations where the name alone is enough to conjure View
The state of Pennsylvania is simply a beautiful place to begin your happily-ever-after whether it's city or View
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The old south beckons you to slow down and explore romance the antebellum View
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Tuscany Ferrari Road Trip
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Hotel Eden Roc
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WEBSITE Rincón Beach Resort is a four star boutique hotel with ocean views, located in a corner of Puerto Rico's west coast known as Porta del Sol. MORE
Special Offers at the Jewel in Jamaica
Explore the many facets of this 5-star gem then book one of the fabulous special offers at The Jewel. MORE