A singular case of multiple myeloma and primary biliary cirrhosis strictly associated in pathogenesis and response to alkylating therapy.
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Biomedical subjects
Publications and source records attributed to Elena Trabacchi.
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PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.
PURPOSE: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.
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Primary pancreatic lymphoma (PPL) is a very rare disease. We report five cases of PPL (4 men and 1 woman, mean age 65 years) diagnosed and treated at our Institution from 1987 to 1997. None of these patients had evidence of extrapancreatic disease and they were categorized as PPL involving pancreas only (stage IE, 3 patients) or pancreas and peripancreatic lymph nodes (stage IIE, 2 patients). The most common presenting symptoms were abdominal pain and weight loss. Imaging techniques showed a mass of the pancreatic head in all cases. The histological diagnosis (3 diffuse-large cell non-Hodgkin's lymphoma and 2 lymphoplasmacytic lymphoma/immunocytoma) was made by ultrasound-guided fine needle aspiration biopsy and tissue core fine-needle biopsy in three patients and by surgery in the remaining two patients. The three patients diagnosed by percutaneous biopsy were treated with chemotherapy as front-line therapy and two of them received also local radiotherapy; one of these patients is still alive in complete remission at 69 months, one died of an unrelated disease at 67 months and one died of lymphoma relapse at 88 months. Two patients underwent pancreaticoduodenectomy plus adjuvant chemotherapy; one of them died of recurrent cholangitis 8 months after surgery while the other one is still alive in complete remission after 160 months. This study shows that: 1) imaging techniques can suggest the suspicion of PPL but are unable to distinguish PPL from pancreatic adenocarcinoma; 2) histological diagnosis can be easily obtained by percutaneous US-guided tissue core biopsy; 3) surgery can be avoided both for diagnosis and therapy but the treatment of choice of PPL may only be evaluated on a larger series of patients.
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Since interferon-alpha and imatinib (IM; STI571, Glivec, Gleevec) are effective for the treatment of chronic myeloid leukemia (CML), and their mechanisms of action are different, we designed an exploratory study investigating the effects of a standard IM dose (400 mg/d) and a variable pegylated interferon-alpha (PegIFN) dose (50 microg/wk, 100 microg/wk, and 150 microg/wk). The criteria for dose adjustment were designed so as to ensure the delivery of the IM dose and to protect life quality. There were 76 patients with previously untreated Philadelphia (Ph)-positive CML enrolled in the study. There were 3 patients who discontinued IM and 45 patients who discontinued PegIFN. The severity of adverse events increased with increasing PegIFN dose. The IM dose could be administered to the patients who were assigned to receive 50 microg/wk or 100 microg/wk PegIFN but not to those who were assigned to receive 150 microg/wk. The median administered dose of PegIFN ranged between 32 microg/wk and 36 microg/wk. The cytogenetic response was 70% complete (Ph-neg 100%) and 83% major (Ph-neg > 65%). The BCR/ABL transcript was reduced by at least 3 logs in 68% of complete cytogenetic responders. These data of toxicity, compliance, and efficacy may assist in the design and preparation of prospective studies.
Lymphoproliferative disorders affecting the lung are infrequent. Therefore the diagnosis is often not easy, specially when the lung is primary affected. Moreover, new clinical-pathological entities are responsible of primary lung lymphoma that require specific treatment. It is important to keep in mind the chance that lung may be involved by lymphoproliferative disorders so to avoid the mistake of the misdiagnosis of this curable diseases since sometimes they have a good prognosis and a very different management from epithelial neoplasia of the lung.
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Imatinib is a tyrosine-kinase inhibitor that binds to ABL proteins and induces cytogenetic remissions in patients with chronic myeloid leukemia (CML). In these patients measuring response by molecular techniques is clearly required. We determined the cytogenetic and molecular response (CgR, MR) to imatinib in 191 patients with late chronic-phase Philadelphia-positive (Ph+) CML, previously treated with interferon alpha. MR was assessed with real-time quantitative (TaqMan) reverse transcription-polymerase chain reaction and was expressed as the ratio between BCR/ABL and beta 2-microglobulin x 100, the lowest level of detectability of the method being 0.00001. A complete CgR (CCgR) was achieved in 85 (44%) of 191 patients and was maintained for 2 years in 67 (79%) of 85 patients. A reduction of the transcript level of more than 2 logs was achieved in all but 9 patients with CCgR versus none of 23 with partial CgR. In the CCgRs the median value of the MR was 0.0008 after 12 months and 0.0001 after 24 months, with the transcript level undetectable in 22 cases. We conclude that in CCgRs the degree of MR may vary from 2 to more than 4 logs, and that there is a progressive decrease of transcript level by time. Only 1 of 22 negative cases has had a relapse as yet.
BACKGROUND AND OBJECTIVES: We compared the early cytogenetic response (CgR) to a combination of imatinib mesylate (Glivec, Novartis Pharma, Basel, Switzerland) and a pegylated form of human recombinant interferon-alpha2b (pegIFN-alpha2b, PegIntron, Schering Plough, Kenilworth, New Jersey, USA) with the relative risk, either according to Sokal's or Euro scoring systems. DESIGN AND METHODS: Seventy-seven patients with early chronic phase, previously untreated, Ph-positive chronic myeloid leukemia (CML) received a combination of imatinib mesylate (400 mg/day) and pegIFN-alpha2b (3 consecutive cohorts treated with 50, 100 or 150 mg/weekly). Fifty-seven patients have completed the first 6 months of treatment and are evaluable for CgR. RESULTS: After 6 months of treatment, the overall major CgR rate was 89% and 90% in low risk patients (Sokal's and Euro, respectively), 76 and 59% in intermediate risk and 23% and 17% in high risk patients. These differences were significant (p=0.0001 for Sokal and 0.001 for e). INTERPRETATION AND CONCLUSIONS: For the first time, these data suggest that the early CgR rate to a imatinib mesylate-based regimen is significantly risk-related.