Biomedical subjects
Publications and source records attributed to F Papineschi.
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The infectious complications are an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. Our retrospective study has the objective to evaluate the incidence, clinical and bacteriologic features of documented infections in these patients. The frequency of infectious complications was analysed in 42 patients with hematologic malignancies who received HSCT from January to December 2002 at Pisa General Hospital. Thirty-three patients underwent autologous HSCT and 9 received allogeneic HSCT. All patients received acyclovir, fluconazole and fluoroquinolones as prophylactic regimen. A total of 38 infectious episodes were recognized in 22 patients during the early post-HSCT period (N=27) and in the late post-HSCT period (N=11). Infectious complications rate correlated positively with the deepness and length of neutropenia in the early period. There were 21 episodes of sepsis (the majority by coagulase negative staphylococci), 2 pneumonias and 1 vertebral osteomyelitis. All staphylococcus strains were, in vitro, resistant to oxacillin and ciprofloxacin and 8 out of 15 gram negative rods were resistant to ciprofloxacin. Most of the infectious complications were cured with appropriated antimicrobial therapy and/or with engraftment and, in 4 cases, with central catheter removal. One patient developed a positive CMV antigenemia; a pre-core mutant form of HBV reactivation was diagnosed in another patient. No cases of invasive fungal infections were recognised. Five patients died but only one from infection (septic shock). Pneumonia was a coexisting cause of death in 2 patient in the late period. We can conclude that most of infectious complications, that occurred in the early period post-HSCT were due to coagulase negative staphylococci and gram negative rods resistant to ciprofloxacin. For this reason, the usefulness of fluoroquinolone prophylaxis in HSCT recipients should be reevaluated.
A 55-year-old female with standard risk AML in second CR received an allogenic transplant from an HLA-matched sibling, using a nonmyeloablative conditioning regimen (NMST). On day +139, she rejected her graft with autologous reconstitution. She received a second NMST from a different HLA-matched sibling with an identical conditioning regimen and immunosuppression. On day +110, she rejected the second graft, with autologous reconstitution with blasts. She received a third allograft from the first sibling with a myeloablative busulfan-based conditioning regimen. She is now day +270, in CR, with full donor chimerism.
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The main aim of this paper was to compare results of Genescan and real-time PCR methods in order to detect contamination in harvests from patients with follicular lymphoma. The secondary goal was to evaluate the efficacy of Rituximab as an in vivo purging agent. A total of 23 patients had been treated with CHOP followed by either high-dose therapy (12 patients) or high-dose plus Rituximab (11 patients), both followed by autologous transplantation. Results show that 86% of harvests from patients treated with Rituximab were PCR-negative compared to 14.3% from controls. Real-time PCR was more sensitive than Genescan PCR; quantitative analysis revealed a correlation between the amount of contamination in the harvests and relapse after transplantation. Whereas all patients reinfused with negative aphereses achieved complete remission and showed a significantly better 5-year PFS (100%) compared to those reinfused with contaminated samples (41%), a very low amount of contamination does not appear to negatively affect outcome, suggesting that determination of a cutoff in the contamination level of harvests could be useful. Results suggest that real-time PCR is superior to Genescan PCR to select transplantable harvests and confirm the ability of Rituximab as an in vivo purging tool for follicular lymphoma.
RATIONALE: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. PATIENTS: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. RESULTS: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. CONCLUSION: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.
Seventy-two patients with non-Hodgkin's lymphoma were evaluated for the presence of molecular markers (IgH, bcl-1, bcl-2 rearrangement) on bone marrow, at diagnosis and after PBSCT, and on harvests in order to find a possible predictive role of minimal residual disease on treatment outcome. At diagnosis, 41 (59%) out of 69 available bone marrows showed molecular involvement. Fifty-six percent of leukaphereses were involved, mainly indolent lymphoma (P = 0.001) or advanced disease (P = 0.01). Ex vivo purging cleared only one stem collection out of 31 PCR-positive leukaphereses. Aggressive lymphomas showed both a longer overall survival (OS) (P = 0.03) and relapse-free survival RFS (P = 0.02) when transplanted with unpurged stem cells, whereas indolent NHL survival was not influenced by ex vivo purging. Twenty out of 26 samples taken during follow-up had bone marrow involvement at diagnosis. Of these, 15 cleared their bone marrow; both OS and RFS were significantly longer in the PCR-negative cases (P = 0.05 and P = 0.005). At 1 year after PBSCT, 75% of patients were PCR negative, with 50% molecular remissions; the relapse rate was 55% for patients still PCR positive vs 29% for those who were PCR negative. Thus, after high-dose chemotherapy, close molecular monitoring of MRD using qualitative PCR techniques seems to represent a reliable prognostic indicator.
Arsenic trioxide has recently been reported to be successful in the treatment of promyelocytic leukemia. Several concerns about the use of this toxic agent are currently reducing its potential clinical use even in severely ill patients. In this report we describe the results achieved by As2O3 with all-trans retinoic acid in a patient suffering from secondary, relapsed, resistant promyelocytic leukemia. Several complications, including sepsis and an extensive area of skin necrosis, did not allow us to treat the patient further with chemotherapy. With As2O3 and ATRA therapy, the patient obtained a complete molecular remission without any significant toxicity and, subsequently, it was possible to perform a bone marrow autograft in a state of complete remission.
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We report a 21-year-old man who experienced symptoms of colitis following autologous TBI-conditioned PBSC transplantation, which persisted despite conventional treatment. Abdominal echography showed a thickened, stratified wall of the cecum, of the right colon and of part of the transverse colon. Hyperbaric oxygen therapy (20 sessions of 100% oxygen inhalation at 2.5 bar for 120 min in a hyperbaric chamber) achieved a prompt clinical recovery as well as complete disappearance of the ultrasound abnormalities.
The efficacy of alfa-interferon (alfa-IFN) in essential thrombocythemia (ET) patients has been reported by several authors. The aim of this study is to assess the magnitude of the effect of alfa-IFN on the neoplastic clone. As of December 1993, 11 ET patients received alfa-IFN at a dose of 3-6 MU/s.c./day for 6 months. Ten of 11 obtained complete hematological remission (CHR) and one achieved partial hematological remission. Megakaryocyte concentration was reduced in six cases. The spleen,which was enlarged in four patients, decreased in size in two patients. Seven of eight patients who were symptomatic at diagnosis obtained resolution of symptoms. In order to obtain indications about the structural modifications induced by alfa-IFN in ET megakaryocytes (Mks), Fourier-transform infra-red microspectroscopy analysis performed on 10 single Mks of each patient, was done in seven of 11 patients; the analysis showed a reduction of A1/A2 ratios (A1 integrated area of the band at 1080 cm(-1) due to the nucleic acids absorption; A2 integrated area of the band at 1540 cm(-1) due to proteic components absorption) in five cases, and in three of these five patients A1/A2 ratios achieved normal values. After alfa-IFN treatment we did not observe any change in the methylation pattern of DNA from the granulocyte fraction. Our results confirm the efficacy of alfa-IFN in ET patients, and the decrease of A1/A2 ratios in several patients is a demonstration of the depth of the effect of alfa-IFN on the neoplastic clone. The results of clonality studies showed the persistence of clonal hematopoiesis. Whether higher alfa-IFN dose and/or more prolonged alfa-IFN therapy may allow a restoration of polyclonal hematopoiesis remains to be determined and should be explored in future clinical trials.
Chronic myeloid leukemia (CML), polycythemia vera (PV), idiopathic myelofibrosis (IM) and primary thrombocythemia (PT) are myeloproliferative diseases of clonal origin. Megakaryocyte series are commonly involved in these disorders. In a previous paper of us, megakaryocytes (MKs) from PV and PT patients were shown to be more pathological with respect to the MKs from CML. This paper describes a Fourier transform infrared microspectroscopy (FT-IR-M) study analyzing the cytoplasm and nucleus areas of MKs from thrombocythemic patients which exhibited numerous giant cells (from 100 to 190 microm in diameter). The size of these cells makes it possible to analyze the cell parts using FT-IR-M technique. The infrared determinations on 10 single MKs for each case examined in these two different cell regions revealed spectral differences with a high degree of reproducibility. Finally, the spectra of whole MKs from normal donors and from thrombocythemic patients were also compared.
The secondary structure of human fibrin from normal donors and from bovine and suilline plasma was studied by Fourier transform ir spectroscopy and a quantitative analysis of its secondary structure was suggested. For this purpose, a previously experimented spectrum deconvolution procedure based on the use of the Conjugate Gradient Minimisation Algorithm with the addition of suitable constraints was applied to the analysis of conformation-sensitive amide bands. This procedure was applied to amide I and III analysis of bovine and suilline fibrin, obtained industrially, and to amide III analysis of human fibrin clots. The analysis of both amide I and III in the first case was useful in order to test the reliability of the method. We found bovine, suilline, and human fibrin to contain about 30% alpha-helix (amide I and III components at 1653 cm-1, and 1312 and 1284 cm-1, respectively), 40% beta-sheets (amide I and III components at 1625 and 1231 cm-1, respectively) and 30% turns (amide I and III components at 1696, 1680, 1675 cm-1, and 1249 cm-1, respectively). The precision of the quantitative determination depends on the amount of these structures in the protein. Particularly, the coefficient of variation is < 10% for percentage values of amide I and III components > 15 and 5%, respectively. The good agreement of our quantitative data, obtained separately by amide I and amide III analysis, and consistent with a previous fibrinogen (from commercial sources) study that reports only information about fibrin beta-sheet content obtained by factor analysis, leads us to believe that the amounts of secondary structures found (alpha-helix, beta-sheets, and turns) are accurate.
The management of indolent lymphomas is still controversial. Intensive therapies may improve remission rate but in association with toxicity. Fludarabine and idarubicin are very active drugs in indolent lymphomas. This pilot trial was designed to evaluate the efficacy of a regimen comprising fludarabine, idarubicin and prednisone (FLIDA) in the treatment of low-grade non-Hodgkin's lymphoma at diagnosis. We have assessed the response of 16 adult patients (median age 57 years, range 45-71 years) treated on an outpatient basis: the overall response rate was 93.8 per cent (CR 43.8 per cent, PR > or = 50 per cent). The toxicity of this regimen was very low, with no relevant hematological and infectious complications.
Aggressive treatments in elderly patients with NHL are often responsible for acute complications and increased mortality. The present study confirms that P-VABEC is able to induce a high CR rate (71%), with an overall response rate of 92%. The 4-year actuarial OS was 45%, and the FFS was 38%. Despite these good results 57% of CRs relapsed in a relatively short time (median 9.5 months; range 2-47). Because of this we decided to evaluate the role of a consolidation schedule (CIP), including idarubicin and cisplatin. The toxicity of P-VABEC/CIP regimen was comparable to that of P-VABEC alone. After a median follow-up of 20 months (range 8-49), 93% of CR patients treated with P-VABEC-CIP were still in complete remission. The 4-year actuarial overall survival was 92%, and the failure-free survival in CR patients was 72%. The difference in OS and FFS between the two groups was statistically significant. These results suggest that a short course of additional therapy is feasible in elderly patients treated with P-VABEC and may increase the OS and FFS, without adding toxicity.
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Polycythemia vera (PV) is a chronic myeloproliferative disease. The use of recombinant alpha 2a Interferon (IFN) therapy in this disease is a novel approach. We applied Fourier-transform infrared microspectroscopy (FT-IR-M) to investigate the behavior and therapeutic responsiveness of PV patients treated with IFN. A spectroscopic parameter (A1/A2) was used, corresponding to the ratio of the integrated areas of the bands at 1080 cm-1 and at 1540 cm-1 due to nucleic acids and proteic components, respectively, calculated on the spectra of single megakaryocytes (MKs). In previous studies, we have pointed out that MKs in PV have a surprisingly strong myeloproliferative impulse when compared to MKs from other chronic myeloproliferative diseases. Nine patients out of the 11 studied exhibited a satisfactory responsiveness to the IFN treatment. Ten patients were evaluated by the A1/A2 parameter. In 8 of these, a good agreement was seen between this parameter and the laboratory data commonly used for the assessment of this disease. The infrared parameter, which we propose, proves to be an original, reliable method for the evaluation of recombinant alpha 2a IFN responsiveness in this disease.
Between July 1990 and March 1992, 23 elderly patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL) received a combination chemotherapy (P-VABEC: Etoposide, Adriamycin and Cyclophosphamide on days 1, 15, 29, 43, Vincristine and Bleomycin on days 8, 22, 36, 50 and Prednisolone on weeks 1-9). The regimen was administered on an outpatient basis. The median age of the patients was 67 years (range 60-78); 15 were previously untreated, 8 were on second line therapy; 6 patients (44%) had stage IV disease, 19 (83%) B symptoms, 15 (65%) had bulky disease, and (26%) bone marrow involvement. The complete remission (CR) rate was 57%, and the partial remission (PR) rate 43%, with an overall response rate of (100%). No difference in response rate was observed between previously untreated patients and patients treated with P-VABEC as second-line therapy while hematological and clinical toxicity were very mild.