Clinical implications of discordant early molecular responses in CML patients treated with imatinib

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3-and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points

Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year followup of the GIMEMA CML 0307 study

We report the final analysis, with a 10-year follow-up, of the phase II study GIMEMA CML 0307 (NCT 00481052), which enrolled 73 adult patients (median age 51 years; range, 18-83) with newly diagnosed chronic-phase chronic myeloid leukemia to investigate the efficacy and the toxicity of front-line treatment with nilotinib. The initial dose was 400 mg twice daily; the dose was reduced to 300 mg twice daily as soon as this dose was approved and registered. The 10-year overall survival and progression-free survival were 94.5%. At the last contact, 36 (49.3%) patients were continuing nilotinib (22 patients at 300 mg twice daily, 14 at lower doses), 18 (24.7%) patients were in treatment-free remission, 14 (19.2%) were receiving other tyrosine-kinase inhibitors and four (5.5%) patients have died. The rates of major and deep molecular responses by 10 years were 96% and 83%, respectively. The median times to major and deep molecular response were 6 and 18 months, respectively. After a median duration of nilotinib treatment of 88 months, 24 (32.9%) patients discontinued nilotinib while in stable deep molecular response. In these patients, the 2-year estimated treatment-free survival was 72.6%. The overall treatment-free remission rate, calculated on all enrolled patients, was 24.7% (18/73 patients). Seventeen patients (23.3%), at a median age of 69 years, had at least one arterial obstructive event. In conclusion, the use of nilotinib front-line in chronic phase chronic myeloid leukemia can induce a stable treatment-free remission in a relevant number of patients, although cardiovascular toxicity remains of concern

[The role of echo-guided percutaneous cholecystectomy in acute cholecystitis].

Personal experience in the treatment of acute cholecystitis with percutaneous cholecystostomy in high risk patients and in elderly patients is reported. Between January 1989 and November 1990, 28 patients affected by acute cholecystitis were treated with percutaneous cholecystostomy at Emergency Surgery Department, Verona University Hospital. The patients treated included 13 men and 15 women; 8 of them were under 70 years old, 5 between 70th and 75th and the remaining patients over 75 years old. The suspected clinical diagnosis of acute cholecystitis was confirmed in all cases by ultrasonography (accuracy 95.4\%). The percutaneous cholecystostomy was successful in 26 over 28 cases. In all these cases patients had a sudden improvement of their clinical conditions. In one case we failed because the guide-wire slipped out of the gallbladder and we couldn't perform a second attempt for the patient's refuse; in an other case there was the dislodgment of the catheter after less than 12 hours from the cholecystostomy and the patient was operated on. Twenty-two of 26 patients whose conditions were improved by percutaneous cholecystostomy, subsequently underwent elective cholecystectomy. In 2 cases of acalculous cholecystitis the patients did not undergo the operation; in 2 cases because of the elderly age of the patients and their bad cardiorespiratory conditions we preferred not to perform the operation. We had not major complications; 6 patients complained pain irradiating to right shoulder which disappeared within 30-60 minutes from the end of the procedure.(ABSTRACT TRUNCATED AT 250 WORDS

Ruolo della colecistostomia percutanea ecoguidata nella colecistite acuta

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Polymorphonuclear leukocyte integrins in chronic renal failure

Patients with chronic renal failure (CRF), in comparison with general population, show a higher cardiovascular mortality, not fully explained by the "traditional" risk factors. Among the new factors that have been hypothesized, leukocytes might play an important role. In a group of patients with mild CRF we determined, at baseline and after in vitro activation with 4-phorbol-12-myristate-13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (fMLP), the polymorphonuclear leukocytes (PMN) beta2-integrin pattern (CD11a, CD11b, CD11c and CD18) by using indirect immunofluorescence with a flow cytometer. At baseline we observed an increase in the phenotypical expression of CD11b, CD11c and CD18 in CRF patients. In normal subjects, after activation with both agents, we noted an increase of all adhesion molecules, while in CRF patients we found an increase in the expression of CD11b, CD11c and CD18 but not of CD11a. The altered behaviour of the PMN integrin pattern in mild CRF patients, likely reflecting a state of PMN activation, might have a pathophysiological significance, considering the high incidence of cardiovascular events in CRF

[The therapy of symptomatic and/or complicated dysontogenetic liver cysts].

Congenital hepatic cysts are a frequent disease, symptomatic in the 16-18\% of the cases. The authors report a review of the literature of the last 20 years about 135 treated surgically patients with symptomatic and/or complicated hepatic cysts. They analyse the different models of treatment both surgical and conservative, referring in special way about the alcoholization of the cysts. The authors finally report their personal experience about eight cases

Polymorphonuclear leukocyte integrin profile in vascular atherosclerotic disease

Leukocyte-endothelial interactions could have a pathogenic role in atherogenesis. Adhesion molecules expressed by endothelial cells, such as intercellular adhesion molecule 1 (ICAM-1), interact with leukocyte integrins mediating the firm adhesion of leukocytes to endothelium which is followed by their transendothelial migration. The aim of our research was to evaluate polymorphonuclear leukocyte (PMN) integrin expression, at baseline and after activation, in a group of subjects with chronic vascular atherosclerotic disease (VAD). In 27 subjects with VAD we examined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate (PMA), the PMN integrin pattern (CD11a, CD11b, CD11c, CD18) using indirect immunofluorescence and a flow cytometer. At baseline VAD subjects showed an increase of CD11a and CD18 and a decrease of CD11b and CD11c as compared to normal subjects. After activation, in normal subjects, we found an increase in the expression of all integrins, while in VAD subjects we observed an increase of CD11b and CD11c and a decrease of CD11a and CD18. In VAD subjects, at baseline, the upregulation of CD11a and CD18 may reflect PMN in vivo activation; after in vitro activation, the decrease of CD11a may be related to the lack of cytoplasmic deposits of this molecule, while CD18 might be internalized. The integrin behaviour pattern in chronic VAD deserves further investigation, considering that integrins are potential targets of therapeutical strategies, with the aim of preventing the atherosclerotic plaque progression and acute ischaemic events