Effect of GLP-1 and GIP on C-peptide secretion after glucagon or mixed meal tests: Significance in assessing B-cell function in diabetes.

BACKGROUND: The aim of the study was to investigate the different B-cell responses after a glucagon stimulation test (GST) versus mixed meal tolerance test (MMTT). METHODS: We conducted GST and MMTT in 10 healthy people (aged 25-40 years) and measured C-peptide, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) at different time points after the administration of 1 mg i.v. glucagon for GST or a liquid mixed meal for MMTT. RESULTS: The GST stimulated C-peptide showed a mean increase of 147.1%, whereas the mean increase of MMTT stimulated C-peptide was 99.82% (Δincrease = 47.2%). Maximum C-peptide level reached with the MMTT was greater than that obtained with the GST (C-pept max MMTT = 2.35 nmol/L vs C-pep max GST = 1.9 nmol/L). A positive and linear correlation was found between the GST incremental area under the curve C-peptide and the MMTT incremental area under the curve C-peptide (r = 0.618, P = .05). After GST, there was no increment of GIP and glucagon like peptide-1 levels compared to baseline levels. A positive and linear correlation between GIP and C-peptide levels was observed only for the MMTT (r = 0.922, P = .008) indicating that in the GST, the C-peptide response is independent of the incretin axis response. CONCLUSIONS: Although the 2 stimulation tests may elicit a similar response in C-peptide secretion, B-cell response to MMTT depends on a functionally normal incretin axis. These results may have implications when investigating the B-cell response in people with diabetes and for studies in which stimulated C-peptide secretion is used as primary or secondary outcome for response to therapy.

Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation.

Peripheral blood used as a source of stem cells for transplantation (PBSCT) is known to exert stronger immune-mediated effects compared with BM (BMT). We decided to retrospectively analyze the impact of stem cell source on the OS of CML patients who relapsed after either matched related donor PBSCT (N=168) or BMT (N=216) and were treated with donor lymphocyte infusions (DLI). Univariate analysis revealed a lower probability of OS after DLI in patients relapsing after PBSCT vs BMT (66% vs 79% at 5 years, P=0.013). However, a multivariate Cox analysis did not reveal any significant impact of PBSCT as a risk factor for decreased OS for patients transplanted in first chronic phase (CP1; hazard ratio (HR) 1.036, 95% confidence interval (CI) 0.619-1.734). A statistical interaction term suggested that the impact of stem cell source on OS after DLI was different for those transplanted in advanced phases (negative impact of previous PBSCT-HR 2.176, 95% CI 0.930-5.091). In summary, the stem cell source does not affect the OS of CML patients who underwent PBSCT in CP1, relapsed and were treated with DLI. However, when the patients were transplanted in advanced phases, previous PBSCT seems to negatively affect OS after DLI compared with BMT.

Oral manifestation associated with multiple pituitary hormone deficiency and ectopic neurohypophysis.

Multiple pituitary hormone deficiency (MPHD) is the diminished secretion of all the hormones produced in the anterior lobe of the pituitary gland. The oral manifestation of this condition includes delayed eruption and prolonged retention of primary teeth, delayed formation and eruption of permanent teeth, delay in development and growth of the jaws, tendency towards development of deep bite and enamel disturbances. This paper reports the case of an adolescent patient with MPHD. Clinical examination revealed partial ankylosis and prolonged retention ofprimary second molars, primary maxillary canines and deep bite. Dental treatment included extraction of all molars with prolonged retention preceded by the necessary medical care with clinical and radiographic follow-up afterwards. The patient was also referred to an orthodontist for orthodontic treatment. Patients' medical condition should always be investigated by clinicians when faced with cases of delayed tooth eruption and bone development.

Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT.

We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.

p53 over-expression identifies a subset of nodal peripheral T-cell lymphomas with a distinctive biological profile and poor clinical outcome.

Peripheral T-cell lymphomas (PTCL) are usually characterized by aggressive clinical behaviour and poor clinical outcome, but their biological background has not been extensively investigated to date, due to their low incidence, about 10% of all non-Hodgkin's lymphoma cases in Western countries, and also to the paucity of specific molecular-genetic abnormalities. Neverthless, there is increasing biological and clinical evidence that primary nodal PTCL should be considered separately from extra-nodal cases, but little is known about biological factors of possible clinical and prognostic impact. This immunohistochemical study has analysed the expression of p53, Mdm2, p21(WAF1), BCL-2 and p-glycoprotein (MDR-1 gene product) in a series of 45 cases of nodal peripheral T-cell lymphomas (PTCL) with 'high-grade' histology. The immunohistochemical findings were then correlated with proliferative activity and clinical outcome. p53 was over-expressed in 13 cases (28.9%). p53 positive cases showed significantly higher proliferative activity (p<0.01), more frequent expression of Bcl-2 (p<0.01) and less frequent expression of p21(WAF1) than p53 negative cases. Mdm2 and p-glycoprotein were expressed in 4/13 (30.8%) and 8/13 (61.5%) p53 positive cases respectively, and in none (0%) of the p53 negative cases (p<0.01). Analysis of the survival curves showed that p53 positive cases were associated with a significantly poorer clinical outcome than p53 negative cases, in terms of both overall survival (p=0.0032) and event-free survival (p=0.0004). Furthermore, multivariate analysis showed that p53 expression was the most important independent prognostic variable. These findings indicate that p53 over-expression identifies a subset of nodal PTCL cases with a distinctive biological profile (higher proliferative activity, less frequent expression of p21(WAF1) and more frequent expression of Bcl-2, Mdm2 and p-glycoprotein than p53 negative cases) and poor clinical outcome. The immunohistochemical analysis of p53 expression is a simple, rapid and low-cost method which may provide information of potential clinical and prognostic value in nodal peripheral T-cell lymphomas.

Risk-assessment in diffuse large cell lymphoma at first relapse. A study by the Italian Intergroup for Lymphomas.

BACKGROUND AND OBJECTIVES: Our aim was to identify risk factors in adults with diffuse large cell lymphoma at first relapse. DESIGN AND METHODS: We studied 474 patients observed at 45 centers in Italy. Median time from diagnosis to relapse was 395 days, median age at relapse was 55 years and median follow-up from relapse was 3.3 years. Salvage therapy consisted of polychemotherapy in 79% of patients, monochemotherapy and/or radiotherapy and/or surgery alone in 16%, and palliative therapy in 5%. Salvage treatment was intensified with high-dose chemotherapy + stem cell transplant in 20% of patients. OS and PFS were compared by sex, International Prognostic Index at diagnosis, histology, B/T phenotype, initial treatment, salvage therapy, and features at relapse: time from diagnosis, LDH, stage, performance status and bone marrow involvement. Cox models, adjusted for salvage therapy, were performed with factors related to overall survival (OS) and progression-free survival (PFS). RESULTS: Overall response (complete + partial) was 63%, OS at 3 years 35% and PFS at 3 years 26%. Relapse within 12 months from diagnosis, elevated serum lactic dehydrogenase (LDH), advanced stage and poor performance status were independent adverse factors for OS and PFS. The cumulative number of adverse factors is proposed as prognostic index for DLCL at first relapse since it identifies risk groups (p<0.0001) and has been validated (p=0.01). Moreover, it predicts OS and PFS in the selected group of patients with a responsive relapse (p<0.0001). INTERPRETATION AND CONCLUSION: Delay from initial diagnosis, LDH, stage and performance status at relapse should be balanced in comparative studies of salvage therapy of adults with DLCL. Patients with more than 2 adverse factors are one third of all cases and deserve more effective salvage treatments.

Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Patients with Ph+ chronic myelogenous leukemia who relapse after a first allogeneic stem cell transplant still have a possibility of long-term survival. To assess the value of the individual therapeutic options, the factors predicting outcome should be identified. We investigated data from 500 patients who relapsed before July 1996; follow-up was updated during 1998. The actuarial survival from relapse was 34.2% (95% confidence interval [CI]: 29. 9%-38.5%) at 5 years and 23.4% (95% CI: 18.9%-27.9%) at 10 years. Survival after relapse was significantly related to 5 factors: time from diagnosis to transplant (< 2 years vs >/= 2 years), disease phase at transplant (first chronic phase vs other), disease stage at relapse (cytogenetic or chronic phase vs advanced phase), time from transplant to relapse (< 1 year vs >/= 1 year), and donor type (HLA-identical sibling vs volunteer unrelated donor). The effects of individual adverse risk factors were cumulative: The probability of survival at 10 years decreased stepwise from 42% (0 factors), 32% (1 factor), 14% (2 factors), 3% (3 factors), to 0% (4 or 5 factors). Novel strategies for high-risk patients are warranted. We conclude that these 5 factors should be taken into account when comparing results of salvage therapies in patients with Ph+ chronic myeloid leukemia relapsing after allogeneic stem cell transplant.

CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous all-trans-retinoic acid and chemotherapy.

PURPOSE: Preliminary reports suggest that leukemic cell expression of CD56, a neural cell adhesion molecule, is associated with adverse clinical outcome in either acute myeloid leukemia with t(8;21) or acute promyelocytic leukemia (APL). We investigated the prognostic relevance of CD56 in a series of patients with APL who were treated homogeneously with all-trans-retinoic acid (ATRA) and chemotherapy. PATIENTS AND METHODS: Clinicobiologic presenting features and therapeutic results were analyzed in a series of 100 patients with genetically proven APL who were treated, according to the example of the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto multicenter trial, with ATRA plus idarubicin (AIDA) and for whom data on CD56 expression were available at diagnosis. RESULTS: Fifteen patients (15%) showed expression of CD56 in greater than or equal to 20% blasts at diagnosis and were considered as CD56(+). No differences were found regarding age, sex, WBC and platelet counts, incidence of coagulopathy, hemoglobin and fibrinogen levels, promyelocytic leukemia/retinoic acid receptor (PML/RAR) alpha fusion type, or complete remission (CR) rate in the comparison of the CD56(+) and CD56(-) populations. Conversely, compared with patients who were CD56(-), patients with CD56(+) APL had shorter CR duration (P =.04) and overall survival (P =.002). In the multivariate analysis, CD56 positivity and initial WBC count greater than 10 x 10(9) cells/L retained statistical significance in overall survival (P =.04 and P =.02, respectively). CONCLUSION: The expression of CD56 is significantly associated with inferior CR duration and survival in patients with APL who were treated with modern frontline treatment that included ATRA and simultaneous chemotherapy. Combined with other well-established prognostic factors such as WBC count, CD56 expression at diagnosis might be used to build prognostic scores for risk-adapted therapy in APL.

Idarubicin intensified BUCY2 regimen in allogeneic unmanipulated transplant for high-risk hematological malignancies.

Twenty-nine consecutive patients with high-risk hematological malignancy aged from 3 to 58 years underwent an unmanipulated graft from an HLA-identical sibling after an irradiation-free preparative regimen consisting of idarubicin (IDA), 21 mg/m2/day administered by continuous infusion on days -12 and -11, followed by busulphan (BU), 4 mg/kg/day orally from day -7 to -4, and cyclophosphamide (CY), 60 mg/kg/day intravenously on days -3 and -2 (IDA-BUCY2). Most clinically relevant extra-hematological regimen-related toxicities consisted of stomatitis observed in all subjects and hemorrhagic cystitis occurred in five cases (17%) within 100 days after transplant. Six patients (21%) developed a grade 2 acute graft-versus-host disease (GVHD) and three (10%) a grade 3 or 4; extensive chronic GVHD was assessed in nine of 22 (41%) evaluable patients. So far, 12 patients have died and 17 are alive, 16 of whom disease-free, 5-41 months after transplant (median, 15 months). The causes of death were related to GVHD in three patients, to sepsis in one and to disease recurrence in the remaining eight. At present, only one of nine relapsed patients is alive. For all patients the actuarial probability of survival (OS) at 1 and 2 years +/- standard error (s.e.) was 63 +/- 9% and 52 +/- 10%, respectively. The actuarial probabilities of disease-free survival (DFS), relapse and transplant-related mortality (TRM) at both 1 and 2 years +/- s.e. were 53 +/- 9%, 35 +/- 9% and 16 +/- 7%, respectively. These results are encouraging but not substantially different from those obtained in 28 patients with malignancy in advanced phase transplanted after the standard BUCY2 regimen, who had an actuarial probability of OS, DFS, relapse and TRM projected at 10 years +/- s.e. of 54 +/- 10%, 57 +/- 9%, 36 +/- 9% and 11 +/- 6%, respectively. Although the retrospective comparison between the two groups does not seem to show any advantage in the use of the IDA intensified regimen, only a prospective randomized trial could answer this question.

Acute lymphoblastic leukaemia occurring as second malignancy: report of the GIMEMA archive of adult acute leukaemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto.

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre-pre-B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL. The leukaemogenic activity of the cytotoxic drugs employed for the treatment of PM may have played a potential role in only a proportion of patients, opening the possibility that some sALL patients may have developed two or more malignancies due to individual predisposing factors.

Reoperations for acute prosthetic thrombosis and pannus: an assessment of rates, relationship and risk.

OBJECTIVE: Mechanical valvular prostheses have the advantage of longevity but carry a risk of thrombosis which is dependant on valve design, materials and host-related interface. While pannus is common to both biologic and mechanical valves, acute prosthetic thrombosis is mostly a complication of mechanical valves; therefore we investigated to find rates and risk of these obstructive complications. METHODS: Between 1/1/70 and 31/12/97, 2680 patients received at least one mechanical prosthesis in the aortic or mitral or tricuspid position and a total of 3014 operations were performed. Follow-up included 18523 years and was 98% complete. Incidence rates, Kaplan-Meier estimates, modeling of the hazard and multivariate analysis in the hazard domain were used in the analysis. RESULTS: Overall survival was 76%, 64%, 51%, 38.5% and 29% at 5, 10, 15, 20 and 25 years, respectively. It was significantly better in aortic than in mitral than in double prosthesis. 290 patients received a single reoperation, 37 a second, six a third and one a fourth reoperation. Two-hundred and fifty-one of these reoperations were exclusively due to malfunction of mechanical prosthesis, nine to malfunction of both mechanic and biologic prostheses. Most frequent reoperative indications was dehiscence (133), pannus (48) and thrombosis (29). The linearized rate of reoperations for pannus was 0.24%/patient per year, for valvular thrombosis 0.15%/patient per year. The shape of the thrombotic hazard was constant (at random) and the relative risk 12 times higher for tricuspid prosthesis, seven times higher for mitral prosthesis. Multivariate analysis controlling for prosthetic position, age, sex and prosthetic size, showed a 67% risk reduction with larger prosthesis (>27 mm), a 69% risk reduction with the Sorin tilting disk prosthesis and an 83% risk reduction with the bileaflet prosthesis. Pannus hazard shows a delayed exponential rise and was two times higher in tricuspid and three times higher in mitral position. Multivariate analysis showed a 50% risk reduction with larger prosthesis, an 11 times higher hazard of old (caged-disk, caged ball) prosthesis and a three times higher hazard of Lillehei-Kaster prosthesis. Reoperation for thrombosis has a 62% perioperative (30 days) survival compared to 92% survival of pannus reoperation. CONCLUSIONS: Mechanical valves have a low incidence of reoperation, mostly for prosthetic dehiscence. Pannus development is the next frequent complication increasing with time since implant, therefore in this series it was related to old valvular models and tilting disk prosthesis, with longer follow-up. Acute thrombosis occurs significantly earlier than pannus formation. Despite shorter follow-up we are therefore confident that bileaflet prostheses are less prone to this complication and pannus is a rare early etiologic factor. Thrombosis has very high operative risk as compared to pannus, justifying the present trend to thrombolysate selected cases.

Flt3LP3nduces the ex-vivo amplification of umbilical cord blood committed progenitors and early stem cells in short-term cultures.

Umbilical cord blood (UCB) has been successfully used for haemopoietic stem cell transplantation, although its use has been cautiously limited to paediatric patients because of the reduced volume produced. The clinical results have confirmed that either engraftment or survival significantly correlate with cell dose infused. We have standardized a culture method providing in a short time a significant amplification of both committed progenitors and primitive stem cells for clinical use. Eight-day culture of UCB cells with flt3L/SCF/PIXY 321 induced a 10-fold amplification of CD34+ cells and the expansion of multipotent (CFU-GEMM) and committed (CFU-GM, BFU-E) progenitors respectively of 5-, 7- and 9-fold over input cells. As to the early stem cell pool, the primitive CD34+Thy-1+ cell fraction increased 6-fold and the LTC-IC were amplified 17-fold. Furthermore, the in vitro proliferation was detected by the gradual loss of fluorescence of the CD34+ cells tracked at day 0 with the dye PKH26. After 8 d of amplification >6% of the CD34+ cells remained intensely fluorescent. This subpopulation represents a deeply quiescent cell fraction unresponsive to cytokines and very enriched of primitive stem cells. These cells are most likely to be responsible for long-term reconstitution after transplant.

Recurrent myxoma of the left ventricle. Case report and review of the literature.

A 29-year-old female was found to have a left ventricular mass while in the 14th week of gestation. Seven years earlier she had undergone removal of a left ventricular myxoma. At re-operation, after elective interruption of pregnancy, a recurrent left ventricular myxoma was successfully excised. According to a review of the literature recurrence of an isolated, localized left ventricular myxoma has not been previously reported.

HLA-C and HLA-DQB1 compatibility in unrelated cord blood transplants.

BACKGROUND AND OBJECTIVE: Umbilical cord blood (UCB) cells have been definitively proved to be a source of hematopoietic stem cells with repopulating capacity when transplanted into pediatric hosts with neoplastic or non-neoplastic disease. Moreover, due to the immaturity of the UCB lymphoid compartment, these transplants are usually associated with a low incidence and severity of GvHD. This clinical observation and the immaturity of the UCB lymphoid compartment justify the acceptance of UCB units which differ from their recipient by 1 or 2 HLA antigens of the six HLA A, B and DRB1 antigens conventionally typed. Whether the number and type of HLA disparities affect clinical outcome of UCB transplants has not, however, been clearly demonstrated yet. DESIGN AND METHODS: In the present study on 14 pediatric patients with high risk leukemia transplanted with UCB from unrelated donors, evaluation of HLA compatibility was extended to HLA-C and DQB1 genes and correlated to the engraftment rate and occurrence of GvHD. Conditioning regimen and GvHD prophylaxis were identical in all cases. HLA-A and B antigens were typed by serology, whereas DNA based methods were used to define HLA-C gene groups, and HLA-DRB1 and DQB1 alleles. RESULTS: Conventional HLA-A, B and DRB1 typing demonstrated that 12 recipient/donor pairs differed at one HLA locus, while 2 pairs had 2 HLA disparities. The extended HLA-typing showed that only one out of the six pairs with a different HLA-A locus had additional mismatches at HLA-C and DQB1 loci, whereas all the remaining 8 pairs, which already differed at HLA-B and/or DRB1 loci after conventional typing, had additional HLA-C and/or DQB1 mismatches (p = 0.002). By contrast, engraftment rate and occurrence of GvHD did not significantly correlate with level of HLA-mismatches even after extended HLA-typing. INTERPRETATION AND CONCLUSIONS: The present data show that additional mismatched HLA-C and/or DQB1 antigens are significantly more frequent in pairs which after conventional HLA-typing differed at HLA-B and/or DRB1 loci, than in those showing one HLA-A mismatch. This observation provides an additional criterion for selection of UCB donors with the closest HLA-match when more than one unit are available. We did not, however, observe any correlation between engraftment rate, occurrence of GvHD and degree of HLA disparities detected either by standard or extended typing. These data support the notion that certain HLA differences do not affect the clinical outcome of UCB transplants and indicate that the expensive and time consuming molecular typing of HLA-C and DQB1 loci might be avoided for UCB donor selection.

Umbilical cord blood transplant from unrelated HLA-mismatched donors in children with high risk leukemia.

In the last 3 years, 14 children with high-risk leukemia (11 ALL, 2 AML and 1 CML) underwent cord blood transplantation from unrelated HLA-mismatched donors at a median of 99 days from the start of search. Eight patients were transplanted in second CR, one in accelerated phase, three at relapse and two patients in first CR. Conditioning regimen (fractionated TBI, etoposide, CY and anti-lymphocyte serum) and prophylaxis of GVHD (CsA and 6-methylprednisolone) were identical for all patients. Neutrophils >0.5x10(9)/l were reached at a median of 33 days from transplant, but in four cases we observed an autologous hematopoietic reconstitution (three spontaneous, one after autologous BM rescue). Acute and chronic GVHD were observed in 10/14 and 3/8 evaluable cases, respectively. Three patients died of transplant-related toxicity and three patients relapsed. The probabilities of event-free, disease-free and overall survival were 50, 53 and 64%, respectively. Cord blood transplant from HLA-mismatched unrelated donor is a valid option for the treatment of children with high-risk leukemia. With our eligibility criteria, conditioning regimen and prophylaxis of graft-versus-host disease, the main obstacles to successful transplant were represented by graft failure and fatal acute GVHD.

A prospective molecular study of chimaerism in patients with haematological malignancies receiving unrelated cord blood or bone marrow transplants: detection of mixed chimaerism predicts graft failure with or without early autologous reconstitution in cord blood recipients.

We prospectively studied the chimaerism status in the bone marrow (BM) and peripheral blood (PB) of 23 patients receiving umbilical cord (UCB, 14 cases) or BM (nine cases) transplants from unrelated donors by PCR amplification of four individual-specific VNTR genetic loci. Haematological engraftment, with persistent full donor pattern. was observed in 10/14 (72%) patients receiving UCB and in 9/9 (100%) patients transplanted with marrow from an unrelated donor (MUD). In contrast, the remaining four patients converted to an autologous pattern. Three out of these four patients had an early autologous haematological reconstitution reaching a neutrophil level >0.5 x 10(9)/l at days 27, 33 and 37 after transplant, respectively. In all three of these patients, chimaerism analysis demonstrated an early appearance of donor cells (i.e. within 35 d after UCB transplant) showing a transient full donor (one case) or mixed chimaerism condition (two cases). Despite the early autologous haemopoietic reconstitution, one of the three patients died of GVHD at day 60, which was explained by the demonstration of low levels of donor lymphoid cells. In the MUD group all nine patients converted to a persistent full donor pattern with haematological reconstitution, accompanied in two of them by transient mixed chimaerism lasting to days 60 and 270 after transplant. Our data show that monitoring of chimaerism may predict graft failure with or without early autologous haemopoietic reconstitution in patients receiving unrelated UCB transplants. Furthermore, chimaerism analysis may identify, in patients with autologous reconstitution, those at risk of severe GVHD in whom immunosuppressive therapy should not be discontinued.

The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group.

The objectives of the present study were to investigate the prognostic value of the International Prognostic Index (IPI) at relapse in the 215 patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) included in the PARMA trial. The IPI at relapse was available in 204 (95%) of these patients. Response rates to 2 courses of DHAP were 77%, 54%, 55%, and 42% in patients with an IPI of 0, 1, 2 and 3, respectively (P <.02), whereas complete response (CR) rates were 33%, 29%, 20%, and 0% in the same groups of patients (P <.03). With a median follow-up period of 79 months, overall survival (OS) at 5 years was 46%, 25%, 25%, and 11% in these four groups (P <.001). One hundred nine patients responding to 2 courses of DHAP were randomized to receive either BEAC (carmustine, etoposide, cytarabine, cyclophosphamide and mesna) followed by autologous bone marrow transplantation (ABMT) or 4 additional courses of DHAP: IPI at relapse was found highly correlated to OS in patients treated in the DHAP arm (5-year OS: 48%, 21%, 33%, and 0% for IPI 0, 1, 2, and 3, respectively; P =.006), but not in the BEAC arm (5-year OS: 51%, 47%, 50%, and 50% for IPI 0, 1, 2, and 3, respectively; P =.90). OS was significantly superior in the BEAC arm as compared with the DHAP arm in patients with an IPI >0 (P <.05), but not in patients with an IPI of 0. In conclusion, these results show that IPI correlates to response and overall survival in patients with aggressive NHL in relapse and enables us to identify patients with a significantly different outcome among those treated with conventional chemotherapy alone.

Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial.

PURPOSE: The purpose of this study was to investigate the prognostic value of time to relapse in 188 adult patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) included on the Parma trial at the time of their first relapse. PATIENTS AND METHODS: The median follow-up of these patients is 102 months after registration onto the Parma study. Time to relapse was calculated from initial diagnosis, and a cutoff of 12 months was used to separate 77 patients defined as early relapse from 111 patients defined as late relapse. RESULTS: Patients with early and late relapses had significantly different overall response rates to salvage therapy with two courses of dexamethasone, high-dose cytarabine, and cisplatin (DHAP; 40% v 69%; P=.00007) and different 8-year survival rates (13% v 29%; P=.00001). Features at relapse with a negative prognostic value in univariate analysis were higher than normal lactic dehydrogenase (LDH) levels, tumor size greater than 5 cm, Ann Arbor stages III to IV, and Karnofsky score less than 80%. Therefore, multivariate analyses were performed. Time to relapse (P=.001) and LDH levels at relapse (P=.003) had independent prognostic value, whereas tumor size did not reach statistical significance in the logistic model that predicted overall response after two courses of DHAP. The study of prognostic factors for overall survival (OS) and progression-free survival (PFS) confirmed the prognostic value of time to relapse (P < .0001 for OS and P=.005 for PFS) independent of response or treatment after two courses of DHAP. CONCLUSION: Time to relapse may be used to stratify patients at time of first relapse of intermediate to high-grade non-Hodgkin's lymphoma.

Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases.

Acute promyelocytic leukaemia (APL), characterized by a specific PML-RARalpha fusion gene resulting from translocation t(15;17) and by a high response rate to differentiation therapy with all-trans retinoic acid, presents clinical (varying WBC counts, age and treatment outcome), morphological (hypergranular M3 and hypogranular M3V) and molecular (three isoforms of PML breakpoint) heterogeneity. We correlated leukaemic immunophenotype with these aspects in 196 molecularly confirmed APLs (63 children and 133 adults) in Italy. The bcr3 isoform (P = 0.05) and FAB M3V (P = 0.05) were more frequent in children. We confirmed in APL an immunophenotype characterized by frequent expression of CD13, CD33 and CD9 and rare expression of HLA-DR, CD10, CD7 and CD11b. However, we recognized CD2 in 28%, CD34 in 23% and CD19 in 11% of cases and demonstrated by double labelling that CD34 and CD2 may be co-expressed. CD2, CD34 and CD19 were significantly intercorrelated, and variably associated to other features: CD2 and CD34 with PML bcr3 (P < 0.001 and P < 0.001, respectively) and with M3V (P < 0.001 and P = 0.002), whereas only CD19 was directly correlated with WBC counts and only CD2 positively influenced CR rate (logistic model) and event-free survival (Cox model). We conclude that immunophenotype plays a role in the determination of the biological and clinical heterogeneity of childhood and adult APL.