PURPOSE To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship ...between IM plasma levels and long-term clinical outcomes. PATIENTS AND METHODS Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). CONCLUSION In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST.
This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients enrolled in the International Randomized Study of Interferon ...and STI571 (IRIS). Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time. Analyses of event-free survival (EFS) and time to progression to accelerated phase/blast crisis (AP/BC) at 7 years were based on molecular responses using the international scale (IS) at 6-, 12-, and 18-month landmarks. Patients with BCR-ABL transcripts > 10% at 6 months and > 1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response MMR: BCR-ABL (IS) ≤ 0.1% by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years. The probability of loss of complete cytogenetic response by 7 years was only 3% for patients in MMR at 18 months versus 26% for patients with complete cytogenetic response but not MMR (P < .001). This study shows a strong association between the degree to which BCR-ABL transcript numbers are reduced by therapy and long-term clinical outcome, supporting the use of time-dependent molecular measures to determine optimal response to therapy. This study is registered at www.clinicaltrials.gov as NCT00006343.
Background
Accurate diagnosis of invasive mold diseases (IMD) remains challenging. Here, the performance of panfungal PCR, Aspergillus and MucoralesPCR in bronchoalveolar lavage (BAL) was evaluated.
...Methods
We conducted a single‐center study including 167 hematologic patients at risk for IMD with BAL performed 2011‐2014. Diagnostic performance of single tests (Aspergillus‐, Mucorales‐, and panfungal PCR, galactomannan (GM)≥0.5 and ≥1, culture/cytology) or in combination was calculated for predicting IMD comparing proven/probable or proven/probable/possible IMD vs no IMD, respectively.
Results
IMD was classified as proven (n = 6), probable (n = 31), possible (n = 29) and no IMD (n = 101) according to EORTC/MSG criteria. GM ≥ 0.5 in BAL showed the highest sensitivity with 81% for diagnosing IMD whereas the other tests only 5%‐35%. By contrast, specificity was highest for panfungal PCR with 99% and GM ≥ 1, Mucorales and AspergillusPCR reached specificity ≥91%. When combining the tests, GM ≥ 0.5 and panfungal PCR show a sensitivity and specificity of 87% and 78% for IMD or with AspergillusPCR a sensitivity and specificity of 88% and 72% for invasive pulmonary aspergillosis, respectively. Including possible IMD patients did not improve the sensitivity of PCRs. In probable/proven IMD patients, the addition of panfungal PCR resulted further in detection of Fusarium species and Alternaria species, and the MucoralesPCR was positive in 2 probable IMD cases.
Conclusion
This study illustrates that the diagnosis of IMD is still very problematic and lacks objectivity. Together with GM in BAL, the PCRs may prove an addition to the current available diagnostic armamentarium in IMD because of their ability to identify molds on a species level.
The phase shift between oscillations of blood pressure (BP) and Doppler middle cerebral artery flow velocity (MCAFV) reflects continuous cerebral autoregulatory action. It is not known whether a ...similar phase shift exists for cortical hemodynamics (‘microvascular level’) assessed by near infrared spectroscopy (NIRS) and what the effects are of pathological conditions. This study investigates the phase relations between oscillations of BP, MCAFV and NIRS parameters in 38 healthy older adults and 28 patients with unilateral severe obstructive carotid disease. BP was recorded noninvasively by finger plethysmography. Stable 0.1 Hz oscillations of all hemodynamic parameters were induced by regular breathing at a rate of 6/min. Basic results were that: (1) BP-induced cortical microvascular oscillations (NIRS) follow those of macrovascular oscillations (MCAFV) with a phase of 80–90° (corresponding to 2–2.5 s at 0.1 Hz), most likely reflecting a transit time phenomenon; (2) oxy- and deoxyhemoglobin thereby oscillate in counterphase; (3) hemodynamic compromise in carotid obstruction leads to (a) delayed NIRS oscillations in comparison to BP which are highly correlated to a shorter phase lead of MCAFV against BP and (b) a decoupling of the oxy-/deoxyhemoglobin counterphase to 240°. Cortical hemodynamic responses to BP oscillations follow specific phase relationships due to cerebral autoregulatory action and circulatory transit times. With hemodynamic impairment, as in unilateral carotid obstruction, these phases are significantly changed reflecting disturbed autoregulation.
When there is the suspicion of an allergic reaction to betalactam-antibiotics, the allergological evaluation is an important tool to confirm the allergy and to test alternative medicaments. As all ...the testing methods for the allergologic evaluation (cutaneous tests and in-vitro tests) don't have a high sensitivity, a broad case report and the former documentation of the symptoms and diagnostic findings are essential, to enable a high significance of the examination and to assess the indication for the provocation test which is the gold standard in many cases. The documentation of the time flow is basic, to differentiate between immediate reactions (hours after intake) and nonimmediate reactions (several days after intake). The diagnostic evaluation not later than after six months increases the prospects for a successful allergic evaluation.
Die allergologische Abklärung ist bei Verdacht auf eine Allergie auf Beta-Laktam-Antibiotika wichtig, um die Reaktion zu bestätigen und alternative Medikamente zu testen. Da jedoch alle Testmethoden ...der allergologischen Abklärung (Hautteste und in-vitro-Tests) eine nicht sehr hohe Sensitivität haben, ist eine vorherige umfassende Anamnese sowie die Dokumentation der Symptome und Befunde entscheidend, um eine hohe Aussagekraft der Untersuchung zu ermöglichen und die Indikation zum in vielen Fällen notwendigen Provokationstest stellen zu können. Als wesentliche Voraussetzung muss neben der Klinik der zeitliche Ablauf festgehalten werden, um zwischen einer Sofortreaktion (wenige Stunden nach Substanzeinnahme) und einer Spätreaktion (einige Tage nach Einnahme) unterscheiden zu können. Die Abklärung bis spätestens sechs Monate nach der Reaktion erhöht die Chancen einer erfolgreichen allergologischen Abklärung.
En cas de suspicion d'une réaction allergique aux antibiotiques bêta-lactames, l'investigation allergique est un moyen important pour confirmer l'allergie et pour évaluer des médicaments alternatifs. Comme cependant toutes les méthodes des tests de l'évaluation allergique (tests cutanés et in-vitro-tests) n'ont pas de sensibilité élevée, une anamnèse détaillée et la documentation des symptômes sont cruciaux pour rendre hautement significative l'évaluation et pour pouvoir poser l'indication pour le test de provocation qui est souvent la méthode de référence. La documentation du déroulement de l'allergie est capitale pour différencier entre une réponse immédiate (quelques heures après la prise de l'agent) et une réponse retardée (quelques jours après la prise de l'agent). L'investigation au plus tard après six mois augmente les chances de succès d'une évaluation allergique.
When there is the suspicion of an allergic reaction to betalactam-antibiotics, the allergological evaluation is an important tool to confirm the allergy and to test alternative medicaments. As all the testing methods for the allergologic evaluation (cutaneous tests and in-vitro tests) don't have a high sensitivity, a broad case report and the former documentation of the symptoms and diagnostic findings are essential, to enable a high significance of the examination and to assess the indication for the provocation test which is the gold standard in many cases. The documentation of the time flow is basic, to differentiate between immediate reactions (hours after intake) and nonimmediate reactions (several days after intake). The diagnostic evaluation not later than after six months increases the prospects for a successful allergic evaluation.
PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based ...real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin.
Statistical databases aim to provide frequencies, averages, and other statistics about groups of persons (or organizations), while protecting the confidentiality of the individuals represented in the ...database. This objective is difficult to achieve, as users of statistical databases have a host of inference techniques at their disposal for retrieving information about identifiable persons (e.g., see 36,15,16,14,17,26, 31.) There are two broad categories of inference controls: controls that place restrictions on the set of allowable statistics, and controls that add noise to the data or to the released statistics. This paper focuses on restriction techniques.
The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined ...criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1st line or 2nd line who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1st line IM 82% achieved CCyR, an estimated 69% during the 1st year (yr) of treatment. Of 359 pts who received 2nd line IM, 80% achieved CCyR, 62% during the 1st yr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p<0.01). Best observed and estimated molecular responses for CCyR pts. are summarized in the table. The median follow-up for BCR-ABL evaluation on 1st line vs 2nd line IM was 45 and 35 months, respectively.
Molecular response on 1st- and 2nd-line IM in the IRIS study1st-line IM2nd-line IM after IFN/Ara-CAll pts N = 553All pts N = 359Resistance N =174Lack of resistance N =185CcyR454 (82%)288 (80%)131 (75%)157 (85%)Pts with CCyR during treatment and PCR sample(s)N = 401N = 211N = 98N = 113–≥3 log reduction (MMR)323 (81%)154 (73%)63 (64%)91 (81%)–≥ 4 log reduction216 (54%)92 (44%)35 (36%)57 (50%)Estimated % of all pts who achieve CCyR and MMR by– 1 yr36241928– 2 yr59382945– 4 yr67675872– 5 yr85827884
Overall response rates were similar between 1st and 2nd line IM pts, although responses in 2nd line IM pts may have occurred more slowly. However, the number of RQ-PCR samples between 1 and 2 yrs of 2nd line IM was limited as samples were not obtained routinely between Jan 2003 and Aug 2004. In pts who achieved CCyR, the estimated 5-yr progression rate to advanced CML phase was 3% for 1st line IM and 4% for 2nd line IM; using the broader definition of progression (including events such as CML-unrelated deaths and loss of MCyR/CHR) the progression rates were 9% and 8% respectively. In both 1st and 2nd line IM pts with CCyR who also achieved MMR, only an estimated 1% progressed to advanced phase within 5 yrs; the estimated broadly defined event rates were 5% and 4% respectively. In summary, for 1st line IM patients with a RQ-PCR follow-up of up to 5 yrs, an estimated 85% achieved MMR at 5 yrs compared with 59% at 2 yrs. Cytogenetic and molecular response rates were similar for 1st line and 2nd line IM pts, primarily due to responses in pts who crossed over for reasons other than resistance or refractoriness. For IM pts the rate of progression to advanced CML phase at 5 yrs was low in those with CCyR and even lower in pts who also achieved MMR.
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