Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol.

Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols.

Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia.

We analyzed the long-term outcome of 4865 patients treated in Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia (ALL) of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Treatment was characterized by progressive intensification of systemic therapy and reduction of cranial radiotherapy. A progressive improvement of results with reduction of isolated central nervous system relapse rate was obtained. Ten-year event-free survival increased from 53% in Study 82 to 72% in Study 95, whereas survival improved from 64 to 82%. Since 1991, all patients were treated according to Berlin-Frankfurt-Muenster (BFM) ALL treatment strategy. In Study 91, reduced treatment intensity (25%) yielded inferior results, but intensification of maintenance with high-dose (HD)-L-asparaginase (randomized) allowed to compensate for this disadvantage; in high-risk patients (HR, 15%), substitution of intensive polychemotherapy blocks for conventional BFM backbone failed to improve results. A marked improvement of results was obtained in HR patients when conventional BFM therapy was intensified with three polychemotherapy blocks and double delayed intensification (Study 95). The introduction of minimal residual disease monitoring and evaluation of common randomized questions by AIEOP and BFM groups in the protocol AIEOP-BFM-ALL 2000 are expected to further ameliorate treatment of children with ALL.

An assessment of factors related to tumor thickness and delay in diagnosis of melanoma in southern Italy.

BACKGROUND: Since survival of patients with melanoma is strongly correlated with the Breslow tumor thickness of the primary lesion, factors that influence stage at diagnosis and delay in diagnosis are considered to be crucial. To test the relationship between tumor thickness and some social and clinical variables (including diagnosis/treatment delay) and the relationship between the diagnosis/treatment delay and some clinical variables, we analyzed data on 530 patients with melanoma from our Institute. METHODS: In the analysis, Breslow tumor thickness was categorized into two categories (< or =1.49, > or =1.5). Three time intervals were examined to evaluate diagnostic delay: patient delay, time from first symptom to seeking medical advice; medical delay, time from first medical consultation to hospital admission; total delay, time from first symptom to resection. The variables evaluated in the analysis were: age at diagnosis, education, occupational status, first symptom, visibility of tumor, anatomic site, and physician who made the initial diagnosis. RESULTS: A significant risk of having a Breslow tumor thickness > or =1.5 mm was noted in patients who had a low level of education (odds ratio 3.0, 95% confidence interval 1.9-5.0) or who were unemployed (odds ratio 1.7, 95% confidence interval 1.1-2.8). With respect to patient delay, a delay >3 months for anatomic locations visible to patients was associated with significant risk (odds ratio 1.7, 95% confidence interval 1.1-2.6); with respect to medical delay, a delay >3 months was associated with a higher risk in patients examined by a dermatologist (odds ratio 2.0, 95% confidence interval 1.2-3.4). CONCLUSIONS: Our results clearly indicate that in Southern Italy poorly educated and unemployed subjects are at risk of being diagnosed at a more advanced stage, and admission to an oncological hospital causes a delay (waiting list) in the time interval related to the doctor (medical delay).

Prognostic value of serum biological markers in patients with hepatocellular carcinoma.

PURPOSE: Prognosis of patients with hepatocellular carcinoma (HCC) is assessed by using indexes based on clinical and instrumental parameters. The Cancer of the Liver Italian Program (CLIP) staging system combines the Child-Pugh classification with tumor size, portal invasion, and alpha-fetoprotein and predicts the outcome of HCC patients more precisely than the Okuda staging system. Serum levels of a number of biological variables have been found to be increased in patients with HCC and are associated with different outcomes. Our aims in this study were to test the prognostic role of the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble interleukin-2 receptor (sIL-2R), interleukin 6 (IL-6), and anti-p53 and to assess whether the addition of any of the above serum markers could further improve the predictive ability of the CLIP score. EXPERIMENTAL DESIGN: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 were assayed in 80 patients with HCC and correlated with their outcomes. Nonparametric procedures were applied to test correlations between serum sICAM-1, sIL-2R, IL-6, anti-p53, and other prognostic factors. For survival analyses, the product-limit method, log-rank test, and Cox proportional hazards model were applied. RESULTS: Only serum levels of sIL-2R correlated with survival, which was longer for patients with lower values (< or =950 units/ml). However, with multivariate analysis sIL-2R did not confirm its predictive role when tested with the CLIP score as a covariate, with a hazard of death of 1.51 (95% confidence interval, 0.76-3.01). CONCLUSIONS: Serum levels of sICAM-1, sIL-2R, IL-6, and anti-p53 are not useful as prognostic factors for HCC in clinical practice. They do not improve the predictive ability of the CLIP score.

Intermediate dose recombinant interferon-alpha as second-line treatment for patients with recurrent cutaneous melanoma who were pretreated with low dose interferon.

BACKGROUND: Interferon (IFN) is widely considered the most effective agent in the adjuvant therapy of patients with cutaneous melanoma (CM). However, little is known about the effect of IFN on pretreated CM patients who experience disease recurrence. The authors conducted a Phase II study to determine whether intermediate doses of IFN could be beneficial for these patients. METHODS: A series of 24 consecutive CM patients who had undergone surgery for local, in-transit, or lymph node disease recurrence during adjuvant therapy with low dose IFN (IFNalpha-2b, 3 million units [MU] per day, three times per week) were enrolled for second-line therapy with intermediate dose IFN (IFNalpha-2b, 10 MU per day) for one year. RESULTS: IFN was discontinued in 7 patients (29.2%) because of toxicity. Several patients complained of impairment in their daily activities. Progression of disease was registered in 17 patients (70. 8%), with a median disease free survival of 5.5 months (95% confidence interval, 3.4-14.2). The median follow-up for the 7 patients who did not experience disease recurrence was 15 months (range, 13-22 months). CONCLUSIONS: An increased dose of IFN as second-line adjuvant treatment was poorly tolerated and produced negative clinical outcomes in patients with CM. However, these patients probably were unresponsive to IFN regardless of the dosage level. In fact, the first adjuvant IFN treatment was ineffective in all patients. Thus, the key factor in the treatment of CM seems to be patient responsiveness to IFN rather than the total dosage achieved.

Sensitivity and specificity of epiluminescence microscopy: evaluation on a sample of 2731 excised cutaneous pigmented lesions. The Melanoma Cooperative Study.

To evaluate the role of epiluminescence microscopy (ELM) in the differential diagnosis of cutaneous pigmented lesions, and to improve the early diagnosis of cutaneous malignant melanoma (CMM), 15,719 pigmented lesions from 8782 consecutive patients were evaluated using ELM with a hand-held video microscope imaging system (MS 500B Micro-Scopeman, Moritex). Comparison between risk levels as inferred from ELM screening and histology was performed on 2731 surgically excised lesions. ELM sensitivity, specificity, positive and negative predictive values, as well as agreement with histological results for the different subgroups of lesions, were determined. Overall agreement was 87.3% (ranging from 85.1% to 92.2% for melanocytic and non-melanocytic lesions, respectively); sensitivity and specificity were high (values ranging from 87.3% to 96.3% among different subsets of ELM-analysed lesions) and statistically significant (P < 0.0001). ELM screening identified 165 new cases of CMM with a high proportion of lesions (115; 70%) in an early phase of tumour growth (Breslow thickness

3-year treatment with recombinant interferon-alpha as adjuvant therapy of cutaneous malignant melanoma.

Interferon alpha (IFN alpha) has been demonstrated to possess a significant biological activity for cutaneous malignant melanoma (CMM). Although multiple adjuvant trials utilizing IFNá have been tested, no consensus on the optimal dosing schedule has been reached. From February 1993 to October 1997 we enrolled 86 CMM patients using low doses of IFN alpha-2b (3 MU/d TIW SC for 3 years) in a phase II study. Our present data show a median disease-free survival (DFS) of 30 months (range 2-62), comparable to those obtained in high-dose IFN alpha trials. These findings suggest that positive results may be also obtained using low doses of IFN alpha in adjuvant treatment of CMM patients. in contrast to the high dose, the low dose regimen was well tolerated with an acceptable quality of life of patients.

Epiluminescence microscopy as a useful approach in the early diagnosis of cutaneous malignant melanoma.

The aim of this study was to evaluate the role of epiluminescence microscopy (ELM) in the differential diagnosis of cutaneous pigmented lesions in order to improve the detection of cutaneous malignant melanoma (CMM) at earlier stages of the disease. In total, 3865 pigmented lesions from 2121 selected patients were evaluated using ELM with a hand-held video microscope imaging system (MS 500B Micro-Scopeman, Moritex). Comparison with histology was performed on the 476 surgically excised lesions. ELM sensitivity, specificity, positive and negative predictive values as well as agreement for the different risk levels of the lesions were determined. Of the 476 cutaneous pigmented lesions removed and histologically examined, 101 (21.2%) were non-melanocytic lesions and 375 (78.8%) were melanocytic lesions. Overall agreement was 83.4% (93.1% and 80.8% for non-melanocytic and melanocytic lesions, respectively). Sensitivity and specificity of ELM in the analysis of melanocytic lesions with a pigment network were both very high (92.3% and 91.2%, respectively). Sixty new cases of CMM were identified. A high proportion of melanoma at stage AJCC IA (23 out of 32; 71.8%) was diagnosed exclusively by ELM (four of these were in situ CCM lesions). ELM is therefore a powerful tool to discriminate between melanocytic and non-melanocytic lesions in order to avoid inopportune surgical treatments for low risk lesions. Unfortunately, ELM did not show 100% sensitivity in diagnosing CMM and therefore ELM features should be integrated with data from both the history and clinical evaluation. However, ELM is much more accurate than clinical examination in detecting thin CMM.