Medication Adherence to Tyrosine Kinase Inhibitors: 2-Year Analysis of Medication Adherence to Imatinib Treatment for Chronic Myeloid Leukemia and Correlation with the Depth of Molecular Response.

OBJECTIVE: Adherence to tyrosine kinase inhibitor treatment is a significant factor in the achievement of a good clinical response in chronic myeloid leukemia (CML). The aim of this retrospective study is to investigate 1- and 2-year medication adherence to imatinib treatment, linking adherence rates with the clinical outcome, in accordance with European LeukemiaNet Recommendations for the management of CML. We have tried to find a cutoff value for adherence in order to achieve a good clinical outcome. METHODS: The method used to calculate medication adherence was the ratio between the received and the prescribed daily dose. RESULTS: We observed the levels of mean adherence for each of the following response groups (in years 1 and 2, respectively): complete response (0.96, 0.95), MR4.5 (1.00, -), MR4 (0.93, 0.91), major molecular responses (0.96, 0.97), warning (0.91, 0.89) and failure (0.79, 0.84). CONCLUSION: Results show that the higher the adherence, the lower the level of BCR-ABL1. Furthermore, using cutoffs ≥0.9, outcomes were significantly improved compared to those with cutoffs <0.90. This value of adherence is in line with previous publications.

Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. EXPERIMENTAL DESIGN: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. RESULTS: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. CONCLUSIONS: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

Fluorescence in situ hybridization analysis of minimal residual disease and the relevance of the der(9) deletion in imatinib-treated patients with chronic myeloid leukemia.

Forty-six patients with chronic myeloid leukemia receiving imatinib mesylate (39 in chronic phase, one in accelerated phase, and six in blastic crisis), were studied for a 20-62 month follow-up period by cytogenetics and fluorescence in situ hybridization using dual-color, dual-fusion BCR and ABL probes. This approach provided valuable results for disease management of analysis.

Overexpression of cyclin D1 and interaction between p27Kip1 and tumour thickness predict lymph node metastases occurrence in lower lip squamous cell carcinoma.

We have attempted to identify those subgroups of patients most likely to develop lymph node metastases from squamous cell carcinoma of the lower lip (LLSSC). A total of 97 subjects, who did not undergo elective neck dissection, were recruited into the 60-month disease-free survival study. After univariate analysis, tumour size, histological grading, maximal thickness, perineural invasion and immunoreactivity to cyclin D1 and p27Kip1 proteins proved to be significant factors. Tests of the effect of interaction between p27Kip1 LI and tumour thickness yielded that the impact of tumour thickness on the risk of lymph node metastases was modified by the percentage of p27Kip1 positive cells. Subsequent to models of multivariate analysis, tumour size, positive cyclin D1 protein expression, maximal thickness (> 5 mm), p27Kip1 LI (%) and the interaction term between p27Kip1 LI and tumour thickness retained strong independent predictive values for lymph node metastases. We suggest that immunohistochemistry for cyclin D1 and p27Kip1 may prove to be valuable ancillary tests for identifying LLSSC with metastatic potential.

[Adrenal incidentaloma: a case of subclinical Cushing's syndrome]. / Incidentaloma surrenalico. Caso di sindrome di Cushing subclinica.

The authors describe a case of adrenal incidentaloma that was the cause of subclinical Cushing's syndrome and take the opportunity to weigh up some of the clinical, diagnostic and therapeutic aspects. Besides the particular expression of the symptoms which were difficult to interpret before reaching a diagnosis, the authors describe the diagnostic work-up adopted, aimed at precisely identifying the type of tumour and the surgical procedure implemented laparoscopically, the outstanding validity of which is confirmed compared to traditional adrenalectomy techniques.

Lymph node metastasis in lower lip squamous cell carcinoma in relation to tumour size, histologic variables and p27Kip1 protein expression.

We studied a consecutive series of 95 patients undergoing radical surgical resection of lower lip squamous cell carcinoma (LLSCC) to assess the correlation between lymph node status and several prognostic variables, such as sex and age, tumour size, histologic grading, maximal microscopic tumour thickness, perineural infiltration and p27Kip1 protein status, to see which of these might be predictive of the development of lymph node metastases. Statistical analysis demonstrated a significant association between node status and tumour size, histological grading, maximal thickness, perineural invasion and p27Kip1 protein expression; additionally to node metastasis, low p27Kip1 protein expression was significant correlated with high microscopic thickness. These results indicate that lower lip squamous cell carcinomas of >2 cm, with G3-G4 histological grading, maximal thickness of >6 mm, perineural invasion and low p27Kip1 protein expression (LI<19.7%) are at high risk for the development of lymph node metastases.

A dexamethasone, vinblastine, cyclophosphamide, etoposide, methotrexate and bleomycin (D-VICEMB) protocol as first-line treatment of patients aged 70 years or older affected by intermediate/high grade non-Hodgkin's lymphoma.

We treated 30 consecutive untreated patients aged > 70 years with advanced aggressive non-Hodgkin's lymphoma with 6 courses of cyclophosphamide, mitoxantrone, etoposide, bleomycin, vinblastine and dexamethasone (D-VICEMB). The global response was 93%. The 6-year overall survival and progression-free survival were 50%, and disease-free survival was 63%.