Comparison between azacitidine and decitabine as front-line therapy in elderly acute myeloid leukemia patients not eligible for intensive chemotherapy.

We compared the efficacy of azacitidine (AZA) and decitabine (DEC) in elderly patients with untreated AML, diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS). The AZA and DEC groups included 139 and 186 patients, respectively. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 136 patient pairs. In the AZA and DEC cohort, median age was 75 years in both, (IQR, 71-78 and 71-77), median WBCc at treatment onset 2.5 × 109/L (IQR, 1.6-5.8) and 2.9 × 109/L (IQR, 1.5-8.1), median bone marrow (BM) blast count 30% (IQR, 24-41%) and 49% (IQR, 30-67%), 59 (43%) and 63 (46%) patients had a secondary AML, respectively. Karyotype was evaluable in 115 and 120 patients: 80 (59%) and 87 (64%) had intermediate-risk, 35 (26%) and 33 (24%) an adverse risk karyotype, respectively. Median number of cycles delivered was 6 (IQR, 3.0-11.0) and 4 (IQR, 2.0-9.0), CR rate was 24% vs 29%, median OS and 2-year OS rates 11.3 (95% CI 9.5-13.8) vs 12.0 (95% CI 7.1-16.5) months and 20% vs 24%, respectively. No differences in CR and OS were found within the following subgroup: intermediate- and adverse-risk cytogenetic, frequency of WBCc at treatment ≥ 5 × 10^9 L and < 5 × 10^9/L, de novo and secondary AML, BM blast count < and ≥ 30%. Median DFS for AZA and DEC treated patients was 9.2 vs 12 months, respectively. Our analysis indicates similar outcomes with AZA compared to DEC.

A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.

Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment.

The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response.

Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors.

BACKGROUND: An increased risk of thrombosis has been reported in primary immune thrombocytopenia (ITP) and with the use of thrombopoietin (TPO) receptor agonists, on the basis of population studies using administrative databases. OBJECTIVES: To evaluate if the incidence of venous and arterial thrombosis in patients with primary ITP is higher than a clinically significant cut-off set at of 3% and 6.4%. PATIENTS/METHODS: We undertook a retrospective multicenter investigation in a large cohort of patients requiring at least one treatment for ITP, enrolled from the major tertiary Italian centers treating ITP. A total of 986 patients were analyzed. RESULTS: During a 3888 patient-year follow-up, 43 first thrombotic events occurred: 28 arterial and 15 venous, resulting in a cumulative incidence of 3.2% for arterial (95% CI, 2.0-5.0) and 1.4% (95% CI, 0.8-2.5) for venous thrombosis at 5 years. The annualized rates for 100 patient-years were 1.14 (95% CI, 0.84-1.54), 0.39 (95% CI, 0.23-0.65) and 0.71 (95% CI, 0.49-1.04) for total, venous and arterial thrombosis. Splenectomy, performed in 136 patients (13.7%), increased thrombotic risk (HR = 3.5, 95% CI) compared with non-splenectomized patients. Age > 60 years, more than two risk factors for thrombosis at diagnosis and steroid use were independently associated with an increased risk of thrombosis. CONCLUSIONS: In this study, we demonstrate that the 5-year cumulative incidence of venous and arterial thrombosis in ITP is well below the predefined thresholds. Venous and arterial thromboembolism are not frequent complications in ITP, except in particular settings, such as in splenectomized and elderly patients.

Surgical training in libya: the way forward.

The General Surgical Training Programmes worldwide are designed to ensure that the advanced surgical trainee in surgery achieves competency in knowledge, skill and attitude, both operative and non-operative in a wide range of common surgical conditions, enabling the trainee to practice competently as a surgeon. Therefore, the goal of the surgical training is to train broad-based, highly qualified surgical specialists who can provide excellence in the care of patients with a wide range of surgical diseases. To this end we have to strive to a training programme that emphasizes education over service, training in all major surgical subspecialties, and strong academic affiliations.

Surgical Training in Libya: the Way Forward

The General Surgical Training Programmes worldwide are designed to ensure that the advanced surgical trainee in surgery achieves competency in knowledge; skill and attitude; both operative and non-operative in a wide range of common surgical conditions; enabling the trainee to practice competently as a surgeon. Therefore; the goal of the surgical training is to train broad-based; highly qualified surgical specialists who can provide excellence in the care of patients with a wide range of surgical diseases. To this end we have to strive to a training programme that emphasizes education over service; training in all major surgical sub- specialties; and strong academic affiliations

Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome.

The purpose of this study was to develop a flow cytometric approach to the evaluation of marrow dysplasia in myelodysplastic syndromes (MDS). We first studied a cohort of 103 MDS patients as well as 46 pathological and healthy controls. Flow cytometry data were expressed as percentage of positive cells. Analysis of erythroid cells showed higher proportions of immature cells (P < 0.001) and decreased levels of CD71 expression on nucleated red cells (P = 0.02) in MDS. Analysis of myeloid cells showed lower proportions of CD10+ and higher proportions of CD56+ granulocytes (P < 0.001), and increased ratios of immature to mature cells (P = 0.007). Since no single immunophenotype could accurately differentiate MDS from other conditions, we used discriminant analysis for generating erythroid and myeloid classification functions using combinations of immunophenotypic parameters. These functions were prospectively validated in a testing cohort of 69 MDS patients and 46 pathological controls. A diagnosis of MDS was obtained in 60/69 cases (87%). No false-positive results were noticed among controls. Significant correlations between values of these functions and both degree of morphological dysplasia and the International Prognostic Scoring System were found. These findings indicate that flow cytometry evaluation of marrow dysplasia is feasible and may be useful in the work-up of individual MDS patients.

A multicentre evaluation of a new filtration protocol for leucocyte depletion of high-haematocrit red blood cells collected by an automated blood collection system.

BACKGROUND AND OBJECTIVES: A multicentre trial was set up to evaluate the performance of a new leucodepletion protocol. MATERIALS AND METHODS: Filtration at high haematocrit was started during collection of red blood cell (RBC) products by apheresis with Trima. SAG-M was added after filtration through the filter. Haematocrits and haemoglobin of the filtered RBCs were measured. Residual leucocytes were determined by Nageotte counting. RESULTS: One-hundred and forty seven procedures were carried out. The haematocrit and haemoglobin contents were 57.3 +/- 3.0% and 55.1 +/- 4.3 g/unit, respectively. All products showed low residual leucocyte levels (< or = 0.75 x 106/unit; 99.31% < 1 x 106). CONCLUSION: Immediate, on-line, high-haematocrit filtration of red cells collected on Trima resulted in leucoreduced RBCs, which met the AABB and Council of Europe criteria.

Consolidation treatment with autologous peripheral blood progenitor cell transplantation in acute myeloid leukemia: a single center experience.

Several trials have suggested that intensive post-remission therapy may prolong the duration of complete remission (CR) in acute myeloid leukemia (AML). The purpose of this study was to evaluate the feasibility and the efficacy of high-dose cytarabine (HiDAC) consolidation chemotherapy followed by high-dose therapy and autologous infusion of peripheral blood progenitor cells (PBPC) mobilized by G-CSF in adult patients with AML in first CR. Fifteen consecutive AML patients underwent HiDAC consolidation chemotherapy, used as a method of in vivo purging, followed by G-CSF for the purpose of autologous PBPC collection. Eleven patients collected a median of 6.9x10(8)/kg peripheral blood mononuclear cells (MNC) (range 2.9-23) and a median of 6.67x10(6)/kg CD34+ cells (range 1.8-33.5) with a median of two aphereses (range 1-3). Two patients did not mobilize and two obtained an inadequate number of progenitor cells. The 11 patients with adequate collections received myeloablative chemotherapy followed by the infusion of PBPC. The median number of days to recover neutrophils and platelets was 12 and 13, respectively. After a median follow-up of 28.7 months (range 17.2-43.4), five out of 11 patients who underwent PBPC transplantation are still in CR, five have died in first relapse and one is alive in CR after relapse treated with salvage therapy and second PBPC infusion. These results demonstrate that HiDAC consolidation chemotherapy followed by autologous PBPC transplantation is a feasible procedure with minimal toxicity. Randomized studies should be performed to evaluate whether this form of consolidation may produce a significant improvement in leukemia-free survival.

A model for analysing the cost of autologous peripheral blood progenitor cell (PBPC) transplantation.

Data from autologous peripheral blood progenitor cell (PBPC) transplant recipients were used for cost analysis and modelling so as to link the main intervention procedures and clinical events to resource use and costs. This cohort consisted of 64 patients from 4 to 62 years old at transplantation (mean, 36.9 years) who underwent a first transplant between August 1994 and May 1997. The main indications for transplantation were non-Hodgkin's lymphomas (47%), multiple myeloma (30%) and Hodgkin's lymphomas (15%). The course of a patient during the whole transplant procedure was modelled using a Markov chain of six states of health: (1) mobilisation and recovery of PBPC; (2) post-mobilisation phase; (3) conditioning and transplant; (4) critical haematological reconstitution; (5) non-critical haematological reconstitution; (6) death. The probability of transition between the different health states, together with the estimated costs, were the input for the Markov model. The model also managed transition probabilities depending both on the current health state and on various demographic, clinical and procedure-related covariates unique to the patient. The expected time spent in each clinical state and the expected total cost were, therefore, estimated. This analysis gave an actual total cost per transplanted patient of $26,600 (95% range: $24,700 to $43,500) while mean duration was 197 days. The expenses for in-hospital stay accounted for 80% of the costs. Both the probability of staying in the different states, and the consequent cost were dependent on the number of CD34-positive cells collected, the phase and the type of the disease, the subset of patients (either children or adults), and the post-transplant G-CSF prophylaxis. The sensitivity of the estimates to alternative assumptions was studied, and the method of comparing alternative future scenarios by the model was explored.

Management of acute promyelocytic leukemia relapse in the ATRA era.

BACKGROUND AND OBJECTIVE: The use of all-trans retinoic acid (ATRA) has changed the natural course of acute promyelocytic leukemia (APL), increasing the percentage of lasting complete remissions. However, management of the few relapses remains undefined. The purpose of the present study was to evaluate the different behavior of APL patients relapsed after induction chemotherapy which had or had not included ATRA. DESIGN AND METHODS: We retrospectively studied 8 patients (3 male and 5 female) who had relapsed after a clinical and molecular complete remission (CR). Five patients relapsed after conventional chemotherapy including anthracyclines, without ATRA which was not available at the onset (group A), 3 relapsed after induction treatment according to AIDA protocol (Idarubicin + ATRA) (group B). Seven patients had both molecular and clinical relapses, 1 (group B) had only a molecular relapse. The median first CR duration was 33 months (range 8-63). To induce a second CR all patients were treated with ATRA 45 mg/m2/day given orally until CR, combined with mitoxantrone 6 mg/m2/day for 6 days and cytarabine 1 g/m2/day for 6 days. RESULTS: Seven out of 8 patients (87.5%) achieved second CR, 1 (group A) did not respond and died within two months. Second CR duration was 21, 43+, 56+, 62+ months in group A and 5, 10, 12+ (with molecular relapse) months in group B. Therefore, only one patient relapsed in group A, while all the group B patients relapsed. INTERPRETATION AND CONCLUSIONS: ATRA combined with chemotherapy is an effective approach to treating APL relapse. It produces a high incidence of second CR with an acceptable toxicity. The duration of the second CR seems, however, to be longer in patients never treated with ATRA before than in patients who relapsed after the AIDA protocol. Therefore, it might be appropriate to adopt more aggressive protocols in this latter subset of patients.

DEHP-induced alterations in the lining tissue of the rat air pouch.

The direct effects of D(2-ethylhexyl)phthalate (DEHP), on subcutaneous tissue were studied in the rat, using the air pouch technique. Two ml of DEHP either undiluted or diluted in olive oil (10 microm/ml), were introduced into a previously created air pouch in the rats. The air pouch was removed and specimens of the lining tissue examined by optical and electron microscopy. The persistence of DEHP for 7 days is sufficient to cause alterations in the tissue. The major histological changes were the destruction of the tissue organization with cytoplasmic and nuclear alterations resulting in apoptotic bodies. The histochemical data showed an increase of sulphated glycosaminoglycans, showing proof of alterations in fibroblast functions. The authors suggest that the hyperplastic-type alteration induced by DEHP may be connected with the sclerosis of the peritoneal membrane described in uremic patients in CAPD.

[Gastric pull-up in pharyngo-esophageal reconstruction: a personal experience]. / Il pull-up gastrico nella ricostruzione faringo-esofagea: esperienza personale.

During the five-year period from 1992 to 1997 a total of 62 patients with advanced hypopharyngeal carcinoma extended to the cervical esophagus came to our attention. Of these 42 (67.7%) were deemed operable and of these 31 (23 males, 8 females; age range 48 to 74 years; mean age 58.5 years) underwent total pharyngolaryngoesophagectomy and gastric pull-up reconstruction. Post-operative mortality was seen in 3 cases (9.7%). In addition, the following complications were encountered: dehiscence of the anastomosis (3 cases), neck hemorrhage (2 cases), pyloric stenosis (1 case). Two patients required intraoperative splenectomy to stop the hemorrhage caused by gastric mobilization and one required thoracic drainage, again because of hemorrhage. The average period of hospitalization was 36 days (range: 20 to 63 days). Per os feeding was restored from 20 to 63 days after surgery (average 20 days). Three patients (9.6%) showed functional failure--that is the inability to feed without the nasogastric probe. To date 10 patients (32.2%) are alive and disease free at an average 18.8 months after surgery (min. 1 month, max. 66 months); 7 patients (22.5%) are alive but not disease free; 11 (35.5%) passed away (in addition to the 3 post-operative cases) and 10 (32.2%) of these deaths were due to recurrence while 1 patient was still disease free at the time of autopsy. In conclusion the authors feel that total pharyngolaryngoesophagectomy with gastric pull-up is a safe treatment; i.e. with an acceptable mortality rate. Post-operative morbidity is high but the final functional outcome is good and, in most cases, can certainly improve the quality of the patients' remaining life. Even though prognosis is quite severe, with average survival of around one year, some of our patients are still alive and disease free 4-5 years after treatment.

Analogs of cord red blood cell membrane components displayed on placenta, amnion and amniotic cells in culture.

Placenta and amnion were analyzed to ascertain the presence of antigens in common with red blood cells (RBC) from cord or fetuses. The expression of distinct antigens displayed on a subpopulation of cord RBC and detected by anticord RBC membrane antibodies was particularly investigated, concomitantly with the presence of transferrin receptors (TR) by employing immunohistochemistry. The placenta showed both cord antigen and TR; on the contrary, amnion--which was labelled by anti-cord RBC membrane antibodies--was not stained by the anti-TR antibody. The results of inhibition and double labelling assays further excluded TR as the relevant antigen in the labelling of both placenta and amnion. The staining of fetal membranes disappeared after absorption of antibodies with cord RBC membranes. These results suggest that the antigens externally expressed on a subpopulation of cord RBC are shared by amnion and placenta.

Red blood cells expressing fetal antigens: their presence in adults with certain forms of anemia.

Using the IgG fraction of an antiserum against cord red blood cell (RBC) membranes (F-IgG), antigenic properties of RBC of newborns (n = 24) and patients suffering from anemia (n = 46) [either due to beta-thalassemia intermedia (n = 37) or hemorrhage (n = 9)] as compared to those of normal adults (n = 18) were examined with fluorescence microscopy, flow cytometry and radioimmunoassays (RIA). With fluorescence microscopy and flow cytometry 1.01 +/- 0.31 and 0.82 +/- 0.28% (mean +/- SD), respectively, of cord RBC and 0.79 +/- 0.31 and 0.53 +/- 0.28% of RBC from anemic patients reacted with F-IgG. RBC of normal adults showed virtually no F-IgG reactivity. In anemic patients there was a good correlation between the percent of F-IgG-reactive cells and the percent of reticulocytes, although the former were only two thirds of the latter; the ratio of F-IgG-reactive cells to reticulocytes was higher in posthemorrhagic anemia than in thalassemia. Moreover, double stainings revealed that the majority of F-IgG-reactive RBC were at the reticulocyte stage (80%), and coexpressed transferrin receptor (96%). Furthermore, the F-IgG-positive RBC correlated inversely with Hb levels. When RIA was employed, F-IgG binding to RBC of anemic patients and newborns was similar and considerably and significantly higher than that to RBC from healthy adults. The results demonstrate the reappearance in certain forms of anemia of F-IgG-reactive RBC, which are likely to represent a subpopulation of reticulocytes.

[Primary carcinoma of the thyroglossal duct. 2 case reports]. / Il carcinoma primitivo del dotto tireoglosso. Due casi clinici.

AA. present two cases of carcinoma arising on thyroglossal duct's cystic. Those carcinomas are a rare event and will be suspected in the patients that present an irregular tumefaction of medial neck's district. Etiology is unknown; is possible that a preceding irradiation on the neck will represent a factor risk. AA. retained that in case of medial neck's district tumefactions is necessary executed a total examination of neck's and head's district, an echography, a thyroid scintigraphy, a thoracic radiography, a panendoscopy and a FNAB. When we found a squamous carcinoma on residual thyroglossal duct the therapy is chirurgical in function of dimension of T and N with following radiotherapy in function of stage (possible lymph node metastasis). When we found a different adenoma is necessary chirurgical removal of tumefactions with hyoid bone's a body resection (Sistrunk's operation) with total thyroidectomy and following Pochin's test for seeking eventual residual with radiometabolic and suppressive therapy.

[The randomized double-blind study of postoperative tonsillectomy pain control by muscle relaxants]. / Studio randomizzato a doppio cieco per il controllo del dolore postoperatorio nell'intervento di tonsillectomia per dissezione con miorilassanti.

Tonsillectomy is accompanied by 7 to 14 days of pain. We entered 36 patients into a double blind placebo controlled study with dantrolene sodium, lioresal to evaluate modification of tonsillectomy pain and analgesic requirements after tonsillectomy. Patients were randomly assigned either dantrolene or lioresal or placebo orally four times a day for 5 days postoperatively. On a standardized questionnaire the patients recorded pain, activity level, analgesic requirements and side effects. We conclude that there is no significant differences in subjective pain or analgesic requirements between 3 groups. The muscle spasm is not the only factor of tonsillectomy pain. There is the association of other factors: nerve endings, individual sensitivity, local products of inflammation. In conclusion to control tonsillectomy pain we must use drugs with different action.