Absolute basophil count is associated with time to recurrence in patients with high-grade T1 bladder cancer receiving bacillus Calmette-Guérin after transurethral resection of the bladder tumor.

BACKGROUND: Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. METHODS: We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p < 0.1, have been selected for the development of a multivariable model. RESULTS: A total of 1045 patients with primary T1 HG/G3 were included. A total of 678 (64.9%) recurrences, 303 (29.0%) progressions and 150 (14.3%) deaths were observed during follow-up. Multivariate analysis showed that logarithmic transformation of basophils count was associated with a 30% increment in the hazard of recurrence per unit increase of logarithmic basophils count (HR 1.30; 95% confidence interval 1.09-1.54; p = 0.0026). Basophil count modeled by quartiles was also significantly associated with time to recurrence [second vs. lower quartile HR 1.42 (1.12-1.79); p = 0.003, third vs. lower quartile HR 1.26 (1.01-1.57); p = 0.041; upper vs. lower quartile HR 1.36 (1.1-1.68); p = 0.005]. The limitations of a retrospective study are applicable. CONCLUSION: Baseline basophil count may predict recurrence in BCG-treated HG/G3 T1 bladder cancer patients. External validation is warranted.

Complement Modulation of Anti-Aging Factor Klotho in Ischemia/Reperfusion Injury and Delayed Graft Function.

Klotho is an anti-aging factor mainly produced by renal tubular epithelial cells (TEC) with pleiotropic functions. Klotho is down-regulated in acute kidney injury in native kidney; however, the modulation of Klotho in kidney transplantation has not been investigated. In a swine model of ischemia/reperfusion injury (IRI), we observed a remarkable reduction of renal Klotho by 24 h from IRI. Complement inhibition by C1-inhibitor preserved Klotho expression in vivo by abrogating nuclear factor kappa B (NF-kB) signaling. In accordance, complement anaphylotoxin C5a led to a significant down-regulation of Klotho in TEC in vitro that was NF-kB mediated. Analysis of Klotho in kidneys from cadaveric donors demonstrated a significant expression of Klotho in pre-implantation biopsies; however, patients affected by delayed graft function (DGF) showed a profound down-regulation of Klotho compared with patients with early graft function. Quantification of serum Klotho after 2 years from transplantation demonstrated significant lower levels in DGF patients. Our data demonstrated that complement might be pivotal in the down-regulation of Klotho in IRI leading to a permanent deficiency after years from transplantation. Considering the anti-senescence and anti-fibrotic effects of Klotho at renal levels, we hypothesize that this acquired deficiency of Klotho might contribute to DGF-associated chronic allograft dysfunction.

HLA-A-B-C-DRB1-DQB1 phased haplotypes in 124 Nigerian families indicate extreme HLA diversity and low linkage disequilibrium in Central-West Africa.

The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.

Mixed chimerism in haemoglobinopathies: from risk of graft rejection to immune tolerance.

Mixed chimerism (MC), the simultaneous presence of both host- and donor-derived cells in the recipient, is observed in a large proportion of patients after haematopoietic stem cell transplant (HSCT) to treat haemoglobinopathies. Detected early after transplantation, MC often moves towards complete chimerism, although sometimes it may evolve into graft rejection, especially if the proportion of donor cells is very low. However, some patients develop stable MC, defined as persistent when donor- and host-derived cells coexist for periods longer than 2 years after HSCT. Patients with persistent mixed chimerism (PMC) do not require additional red blood cell support and, regardless of the presence in some cases of an extremely low percentage of donor-derived nucleated cells in the bone marrow, their condition is clinically controlled by an incomplete but functional graft, as they express a two- to fivefold enrichment of donor-derived mature erythrocytes in the peripheral blood. These findings have tremendous implications not only in the context of allogeneic HSCT but also in the design of gene therapy trials based on the autologous transplantation of genetically modified CD34+ cells. Recent studies have shown that durable allograft tolerance has been achieved by induction of haematopoietic chimerism in clinical kidney transplantation, showing the involvement of regulatory T cells. Similarly, it has been shown that the regulatory T cells play a pivotal role in promoting and maintaining immune tolerance in patients that develop a status of PMC after HSCT for Thalassemia.

Influence of the HLA characteristics of Italian patients on donor search outcome in unrelated hematopoietic stem cell transplantation.

The information regarding the probability of finding a matched unrelated donor (MUD) within a relatively short time is crucial for the success of hematopoietic stem cell transplantation (HSCT), particularly in patients with malignancies. In this study, we retrospectively analyzed 315 Italian patients who started a search for a MUD, in order to assess the distribution of human leukocyte antigen (HLA) alleles and haplotypes in this population of patients and to evaluate the probability of finding a donor. Comparing two groups of patients based on whether or not a 10/10 HLA-matched donor was available, we found that patients who had a fully-matched MUD possessed at least one frequent haplotype more often than the others (45.6% vs 14.3%; P = 0.000003). In addition, analysis of data pertaining to the HLA class I alleles distribution showed that, in the first group of patients, less common alleles were under-represented (20.2% vs 40.0%; P = 0.006). Therefore, the presence of less frequent alleles represents a negative factor for the search for a potential compatible donor being successful, whereas the presence of one frequent haplotype represents a positive predictive factor. Antigenic differences between patient and donor observed at C and DQB1 loci, were mostly represented by particular B/C or DRB1/DQB1 allelic associations. Thus, having a particular B or DRB1 allele, linked to multiple C or DQB1 alleles, respectively, might be considered to be associated with a lower probability of a successful search. Taken together, these data may help determine in advance the probability of finding a suitable unrelated donor for an Italian patient.

Prone and supine percutaneous nephrolithotomy.

Since the first successful stone extraction through a nephrostomy in 1976, percutaneous nephrolithotomy (PCNL) has became the preferred procedure especially for treatment of large, complex and staghorn calculi. For decades this method has been performed with the patient in the prone position. More recently, particular interest has been taken on supine PCNL due to less anestesiological risks and the possibility of simultaneous anterograde and retrograde access to the whole urinary tract. Although many retrospective studies have been published, only two prospective trials comparing the two positions are reported in the literature. The best access to PCNL represents still a controversial issue. The overall experience reported in literature indicates that each modality is equally feasible and safe. Therefore, to date the surgeon's preference is the prime indication to one access over the other.

Genotypes and haplotypes in the 3' untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia.

Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia.

Radical Nephroureterectomy Tetrafecta: A Proposal Reporting Surgical Strategy Quality at Surgery.

Background: Standardized methods for reporting surgical quality have been described for all the major urological procedures apart from radical nephroureterectomy (RNU). Objective: To propose a tetrafecta criterion for assessing the quality of RNU based on a consensus panel within the Young Association of Urology (YAU) Urothelial Group, and to test the impact of this tetrafecta in a multicenter, large contemporary cohort of patients treated with RNU for upper tract urothelial carcinoma (UTUC). Design setting and participants: This was a retrospective analysis of 1765 patients with UTUC treated between 2000 and 2021. Outcome measurements and statistical analysis: We interviewed the YAU Urothelial Group to propose and score a list of items to be included in the "RNU-fecta." A ranking was generated for the criteria with the highest sum score. These criteria were applied to a large multicenter cohort of patients. Kaplan-Meier curves were built to evaluate differences in overall survival (OS) rates between groups, and a multivariable logistic regression model was used to find the predictors of achieving the RNU tetrafecta. Results and limitations: The criteria with the highest score included three surgical items such as negative soft tissue surgical margins, bladder cuff excision, lymph node dissection according to guideline recommendations, and one oncological item defined by the absence of any recurrence in ≤12 mo. These items formed the RNU tetrafecta. Within a median follow-up of 30 mo, 52.6% of patients achieved the RNU tetrafecta. The 5-yr OS rates were significantly higher for patients achieving tetrafecta than for their counterparts (76% vs 51%). Younger age, lower body mass index, and robotic approach were found to be independent predictors of tetrafecta achievement. Conversely, a higher Eastern Cooperative Oncology Group score, higher clinical stage, and bladder cancer history were inversely associated with tetrafecta. Conclusions: Herein, we present a "tetrafecta" composite endpoint that may serve as a potential tool to assess the overall quality of the RNU procedure. Pending external validation, this tool could allow a comparison between surgical series and may be useful for assessing the learning curve of the procedure as well as for evaluating the impact of new technologies in the field. Patient summary: In this study, a tetrafecta criterion was developed for assessing the surgical quality of radical nephroureterectomy in patients with upper tract urothelial carcinoma. Patients who achieved tetrafecta had higher 5-yr overall survival rates than those who did not.

Hematopoietic stem cell transplantation in thalassemia.

SCT still remains the only cure currently available for patients with thalassemia. Results of transplants in this disease have steadily improved over the last two decades due to improvements in preventive strategies, effective control of transplant-related complications and development of new preparative regimens. Currently, high-resolution HLA typing has enabled physicians to perform transplants from unrelated volunteer donors for thalassemia with results comparable with those obtained employing an HLA-identical sibling. The probabilities for obtaining thalassemia-free survival after transplant in thalassemia from an HLA-identical donor, family member or MUD are between 85 and 87%. Therefore, when an HLA-identical donor is present, the transplant of allogeneic stem cell should be performed as allogeneic gene therapy. In the light of advances in transplantation for thalassemia, patients with an HLA-identical donor should be offered SCT.

"Deviceless" hand-assisted laparoscopic donor nephrectomy.

Hand-assisted laparoscopic nephrectomy (HLN) in living donors is a minimally invasive surgical modality that uses classic laparoscopic techniques combined with the surgeon's hand as a support tool during renal dissection. We describe our experience with 14 donors undergoing HLN with a novel "deviceless" technique (DL-HLN). We used a midline or a paramedian incision. The first 10-mm trocar (camera) was inserted near the umbilicus and another 10-mm trocar placed under laparoscopic vision at the level of the anterior axillary line above the iliac crest. DL-HLN was performed in 14 patients (11 women and 3 men) of overall mean age of 40 years (range=33-60). Left nephrectomy was performed in all cases. Mean surgical time was 105 minutes (range=60-150). Estimated blood loss was 50 to 800 mL (mean=200 mL). Mean warm ischemia time was 3.5 minutes (range=2-11). Mean hospital stay was 4 days (range=3-6). In one case, uncontrollable hemorrhage developed due to a renal vein lesion at the level of the adrenal vein outlet, requiring conversion to open surgery. As to graft function, recipient serum creatinine on day 7 ranged from 0.9 to 2.6 mg/dL (mean=1.6). We used no device in our technique. The pneumoperitoneum was maintained by the sealing effect of the muscular fascia around the surgeon's wrist. Moreover, the kidney was removed through the hand port without an Endobag. Our modified HLN technique avoids the use of costly disposables and offers the advantages of a smaller incision.

Incidentally discovered yellowish lesions in a renal graft from a deceased donor.

The opening of Gerota's fascia, soon after harvesting the kidney, is a standard kidney donor procedure in Italy to exclude a renal cell carcinoma (RCC), a frequent finding in older donors. Herein we have reported our experience with the diagnosis and management of subcapsular yellow areas suggestive of RCC on the kidney surface during back-table procedures. From 2001 to 2006, 12/445 grafts showed a single yellowish subcapsular nodule during the back-table procedure which was excised for frozen section (FS) to rule out RCC. The affected donors were 7 males and 5 females of overall mean age of 60 years (range, 25-77 years). The mean nodule diameter was 0.75 cm (range, 0.3-1.2 cm), and all lesions were located in the upper renal pole. In 5 cases, a diagnosis of RCC could not be excluded by FS, and both kidneys were discarded. The final histology confirmed RCC in only 3 cases, and adrenal heterotopia (AH) in the other 2. In the remaining 7 cases, FS showed AH in 4, 1 angiomyolipoma, and 2 areas of infarction confirmed by histology. The adrenal foci consisted of clear cells and scattered cells with eosinophilic, granular cytoplasm and small round nuclei, some with small nucleoli. Immunostains for cytokeratins, CD10, and epithelial membrane antigen were negative, confirming the adrenal origin. AH is the most common pathological yellowish lesion in the upper kidney pole found incidentally during back-table preparation. A histological differential diagnosis with RCC at FS is difficult, relying on the distinction of normal corticoadrenal spongiocytes from Fuhrman grade 1 clear cancer cells. In Italy, for any renal mass suggestive of RCC, a graft discard is mandatory, even if several reports have described cases of renal transplantation performed after back-table excision of small unifocal tumors.

Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes.

Bone marrow samples from 30 patients with myelodysplastic syndromes (MDS) grouped according to the International Prognostic Scoring System for MDS were investigated for counts of microvessels, total metachromatic mast cells (MC) and MC expressing tryptase, an angiogenesis-inducing molecule. Counts were higher in patients with a poor prognosis. The observation of a high correlation between microvessel counts and both total metachromatic and tryptase-reactive MC in all samples suggests that angiogenesis in MDS increases with their progression and that MC may intervene in the angiogenic response in MDS through tryptase contained in their secretory granules.

Relationship between number of allergic sensitizations and immunity impairment: anything new in immunotherapy for allergies and vaccines planning?

To 106 14-56 year-old allergic people (30 monosensitized, 24 sensitized to 2 pollens, 52 polysensitized) we have evaluated the Global Immune Competence Status (GICS). That's a compound score, made of ten parameters, six regarding cell-mediated immunity (WBC/mmc, Gr/mmc, Ly/mmc, Ly CD3+/mmc, Ly CD4+/mmc, CD4/CD8 Ratio), four regarding nutritional status and humoral immunity (Tot. Protein mg/dl, Albumin mg/dl, Gammaglobulins mg/dl, IgG mg/dl). Each parameter is brought on a grid including 4 worth scores worsening from 4 to 1, related to different ranges of values; this way quickly leads to characterize type and grade of immune deficiency. So doing we found that in 30 monosensitized people 27 (90%) show a complete immune competence, while just 3 people (10%) have impaired GICS: in these 1 (3%) regards cell-mediated immunity, while 2 (7%) regard humoral immunity. In 24 patients sensitized to 2 allergenes, 18 (75%) showed complete immune competence, while 6 (25%) a GICS impairment regarding cell-mediated immunity. In leaving 52 polysensitized patients, 30 people showed complete immune competence (58%), while 20 (38%) showed a GICS impairment regarding cell-mediated immunity and 2 (4%) impaired humoral immunity. This work shows that the higher the number of sensitizations is, the stronger the cell-mediated immunity impairment in allergic people become.

Bone marrow donors other than HLA genotypically identical siblings for patients with thalassemia.

This report describes the successful bone marrow transplantation of three children with thalassemia who received bone marrow, one from an HLA identical but mixed lymphocyte culture-reactive sibling, the other two from an HLA phenotypically identical parent. Evidence of engraftment was detected early (19-21 days) in all three children and only grade II acute GvHD was observed in one patient. Our report indicates that thalassemic patients can be cured by bone marrow transplantation from selected donors other than HLA genotypically identical siblings.

Allogeneic marrow transplantation for thalassemia.

Thirteen patients with homozygous beta thalassemia underwent allogeneic marrow transplantation from sibling donors, 12 of whom were heterozygous for beta thalassemia. Six patients were transplanted in an advanced stage of their disease while seven were transplanted early in their disease course. Donors and recipients were genotypically identical for the HLA-A, -B and -D loci in 11 cases and mismatched for the D locus in two. A variety of preparative regimens was utilized involving high doses of busulphan (Bu) and/or cyclophosphamide (CY) and/or total body irradiation (TBI). Failure of engraftment or autologous hematologic recovery after transient engraftment was seen after intensive preparative regimens including: CY 200 mg/kg and 800 rad of TBI; Bu 8 mg/kg and CY 200 mg/kg; and Bu 8 mg/kg, CY 200 mg/kg, and 300 rad of TBI. A regimen of Bu 16 mg/kg, CY 200 mg/kg, and 400 rad of TBI resulted in deaths from transplant-related causes in the three patients treated with this regimen. Seven of the 13 patients are surviving 363-665 days after transplant. Five of the seven failed to achieve engraftment or had autologous reconstitution after transient engraftment. Five of the six deaths were transplant related, and one patient died of cardiac failure one year after an unsuccessful transplant attempt. Two patients are surviving with engraftment and without thalassemia major 363 and 491 days after transplantation. Both of these patients were transplanted early in their disease course.

A comparative trial of posttransplant immunosuppression in patients transplanted for thalassemia. Cyclosporine alone versus cyclosporine, cyclophosphamide, and methotrexate.

This study compares the efficacy of 2 posttransplant immunosuppressive regimens for prevention of graft-versus-host disease (GVHD). Forty-four patients, ages 8-15 years, with homozygous beta thalassemia received marrow allografts from HLA-identical siblings following an ablative regimen of busulfan and cyclophosphamide. Twenty-two patients received cyclosporine (CsA) alone and 22 received cyclosporine, cyclophosphamide, and methotrexate for prophylaxis against GVHD. Two who received CsA alone have died (1 of graft rejection and 1 of acute GVHD) as did 4 patients who received 3 drugs (1 of rejection, 1 of acute GVHD, 1 of infection and cardiac failure before engraftment, and 1 of acute respiratory failure before engraftment). One patient in each group rejected the transplant and survives with thalassemia. The probability of developing acute GVHD was 41% for the CsA group and 15% for the 3-drug group (P = less than 0.05). Patients receiving CsA alone had a probability of event-free survival of 86% compared to 77% in the group receiving 3 drugs (P = 0.40) with a followup of 209-706 days. Although the study showed a decrease in the incidence of GVHD in recipients of the more intensive prophylactic regimen, this study was terminated since it was apparent that even if larger numbers of patients were studied it would be difficult to demonstrate a significant survival advantage with the use of this drug regimen.

Graft-versus-host disease after bone marrow transplantation for thalassemia: an analysis of incidence and risk factors.

We analyzed risk factors in 724 patients evaluable for acute graft-versus-host disease (GVHD) and in 614 patients evaluable for chronic GVHD who had received bone marrow transplantation (BMT) from HLA-identical siblings and/or parents for thalassemia and/or microdrepanocytosis, in a single institution. The overall incidence of grade II-IV and III-IV acute GVHD (aGVHD) was 26.9% and 13.5%, respectively. The cumulative incidence of grade II-IV aGVHD in patients treated with cyclosporine (CsA)/methylprednisolone (MP) or CsA/methotrexate (MTX)/MP was 32% and 17%, respectively (P=0.001). In logistic regression analysis, the risk factors associated with the onset of grade II-IV aGVHD in the entire group of patients were: patient age < or = 4 years (P=0.009), male patient sex (P=0.023), GVHD prophylaxis with CsA/MP or MTX/MP (P=0.000), more than twofold elevated alanine aminotransferase (P=0.001), and patient seropositivity for two to three herpes viruses (P=0.007). In patients treated with CsA/MP, splenomegaly > 2 cm (P=0.042) and donor age > or = 17 years (P=0.034) predicted aGVHD. Risk factors for grade III-IV aGVHD were similar to the risk factors identified for grade II-IV aGVHD. Moreover, moderate and severe liver fibrosis or cirrhosis predicted grade III-IV aGVHD (P=0.018). The incidence of chronic GVHD (cGVHD) was 27.3%. The probability of cGVHD at 2 years after BMT in patients with grade 0, I, II, and III-IV aGVHD was 15%, 32%, 53%, and 54%, respectively. Among patients with absent or grade I-IV aGVHD, prior aGVHD (P=0.000), female donor sex (P=0.000), use of alloimmune female donors for male patients (0.009), and GVHD prophylaxis with CsA/MP or MTX/MP (P=0.003) predicted cGVHD. This data should be considered in clinical management and in future investigations for improvement of immunosuppressive prophylaxis in BMT patients with thalassemia.

Immunologic recovery in thalassemic marrow graft recipients following high-dose busulfan and cyclophosphamide.

T lymphocyte subsets, mitogenic response, and immunoglobulin levels were studied in peripheral blood from 95 thalassemic patients before and at different times after bone marrow transplantation. With the exception of patients receiving more than 100 transfusion units before transplant, who showed an increased percentage of CD8-positive cells, thalassemic patients were essentially immunologically normal. Depressed lymphocyte proliferative response to phytohemagglutinin, concanavalin-A, and pokeweed mitogen; decreased IgG, IgM and IgA levels; and abnormal T subpopulation distribution were observed early after transplant. Long-term transplanted patients showed complete recovery of the immunological profile with the exception of the IgA levels, which were significantly decreased up to 2 years after transplant.

Novel approaches to the treatment of chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGvHD) continues to be the major problem in long-term survivors of allogeneic haematopoietic stem cell transplants and is the principal cause of morbidity and non-relapse mortality. Over the past twenty years, diagnosis, prophylaxis and treatment of cGvHD have slowly evolved. An effective therapy for cGvHD is designed to prevent complications through targeting the disease mechanisms. None of the present therapies for cGvHD are successful in the majority of patients. Conventional drugs in different combinations can control the disease in approximately 50% of patients. Attempts to improve survival have led to evaluation of several alternative approaches in the treatment of refractory cGvHD with varying degrees of success. Clinical trials are needed to establish the role of these new approaches in the treatment of cGvHD as first line or salvage therapy without causing significant side effects. This review summarises the currently available knowledge on conventional and new treatment approaches for cGvHD.

CEOP-B/VIMB vs. promace-CytaBOM in the treatment of intermediate or high grade non-Hodgkin's lymphoma: A randomised multicenter study of Southern Italy Cooperative Group.

From January 1992 to December 1995, 129 patients with previously untreated non-Hodgkin's lymphoma were randomised in a phase III multicenter trial to receive CEOP-B/VIMB or ProMACE-CytaBOM. Eligibility criteria included intermediate or high grade lymphoma (follicular large cell, diffuse small cleaved-cell, diffuse mixed, diffuse large-cell and immunoblastic) with an Ann Arbor stage II bulky, III or IV. All patients entered into the study were considered evaluable according to intent to treat analysis. At a median follow-up of 60 months there were no significant differences between the treatment response rates [82% (60%CR) for CEOP-B/VIMB vs. 81% (69% CR) for ProMACE-CytaBOM]. Conversely, with regard to disease-free survival, a significant difference was observed between the two treatment arms (42% for CEOP-B/VIMB vs. 24% for ProMACE-CytaBOM at 5 years; p=0.046). However, this difference did not translate in a significant difference in overall survival (45% vs. 39% at 5 years). Moreover, when response rates and outcome were analysed for different prognostic subgroups according to International Prognostic Index, no significant differences were observed between the treatment groups. It is important to note that neither regimen was able to improve outcome of poor risk patients who fared badly with both treatments (median survival 9 and 8 months respectively). Toxicity was also similar in both treatments with grade 3-4 leukopenia observed in 39% and 47% of cases and grade 3-4 thrombocytopenia in 24% and 27% of cases respectively. In conclusion, in this study CEOP-B/VIMB was not superior to ProMACE-CytaBOM in aggressive lymphomas and the alternating strategy failed to improve outcome of poor risk patients in which newer more aggressive treatments are needed.