Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients--Report of the Polish Myeloma Group.

UNLABELLED: The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), ß-2-microglobulin (ß-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.

Optimization of health-care organization and perceived improvement of patient comfort by switching from intra-venous BU four-times-daily infusions to a once-daily administration scheme in adult hematopoietic stem cell recipients.

Previous studies have shown an equivalent pharmacokinetic profile between four-times-daily (4QD) and once-daily (QD) administration of intra-venous (IV) BU, without increased toxicity. We assess the impact of a switch in IV BU from a 4QD to a QD schedule, in terms of health-care organization, staff working conditions, quality of care dispensed and perceived patient comfort. Clinicians, nurses and pharmacists from nine allogeneic transplantation units in five European countries were interviewed face to face. Overall perception of QD versus 4QD BU was very positive. Both administration schemes were evaluated to be equally efficaciousZ. QD BU was perceived to be safer and more convenient. Clinicians and nurses perceived that patient comfort was improved, due to fewer complications associated with repeated infusions, and avoiding night infusions associated with stress, anxiety and decreased quality of sleep. Switching from 4QD to QD BU had a significant impact on health-care organization, with a better integration in the overall management and usual timelines in the pharmacies and transplantation units. Time spent to prepare and administer BU was significantly reduced, leading to potential financial savings that merit further assessment and would be of particular interest in the current economic climate.

Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) refractory to conventional immunosuppression suffer substantial morbidity and mortality due to active disease and treatment toxicity. Immunoablation followed by autologous stem cell transplantation (ASCT) is a novel therapeutic strategy that potentially offers new hope to these patients. METHODS: This retrospective survey reviews the efficacy and safety of ASCT in 28 SLE patients from eight centres reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 2001 and 2008. RESULTS: Median disease duration before ASCT was 52 (nine to 396) months, 25/28 SLE patients (89%) were female, age 29 (16-48) years. At the time of ASCT, eight (one to 11) American College of Rheumatology (ACR) diagnostic criteria for SLE were present and 17 (60%) patients had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte-colony stimulating factor in 93% of patients, and ex vivo CD34 stem cell selection was performed in 36%. Conditioning regimens were employed with either low (n = 10) or intermediate (18) intensities. With a median follow-up of 38 (one to 110) months after ASCT, the five-year overall survival was 81 ± 8%, disease-free survival was 29 ± 9%, relapse incidence (RI) was 56 ± 11% and non-relapse mortality was 15 ± 7%. Graft manipulation by CD34+ selection was associated with a lower RI (p = 0.001) on univariate analysis. There were five deaths within two years after ASCT: three caused by infection, one by secondary autoimmune disease and one by progressive SLE. CONCLUSIONS: Our data further support the concept of immunoablation and ASCT to re-induce long-term clinical and serologic remissions in refractory SLE patients even in the absence of maintenance therapy. This study also suggests a beneficial effect of ex vivo graft manipulation on prevention of relapses post-transplantation in SLE.

A supersaturated calcium phosphate solution seems to effectively prevent and treat oral mucositis in haematopoietic stem cell transplanted cancer patients - single centre experience.

PURPOSE: Oral mucositis (OM) is one of the most frequent and bothersome complications of high-dose chemotherapy with subsequent auto- and allogeneic haematopoietic stem cell transplantation (HSCT). We have assessed the effectiveness of supersaturated calcium phosphate rinse (Caphosol ®) and palifermin (Kepivance®) in the prophylaxis of OM caused by HSCT. METHODS: Caphosol® and Kepivance® were prospectively evaluated in OM prophylaxis in 64 patients after HSCT and compared against themselves and an historical control group. RESULTS: Grade 3 and 4 OM was not observed in patients treated with Caphosol® and palifermin. None of those patients needed total parenteral nutrition (TPN), too. In the Caphosol® group 40.9% of the patients did not develop OM, and 70% of patients treated with palifermin were free of any kind of OM symptoms. In the control group OM was observed in all cases. CONCLUSION: Caphosol® seems to decrease the incidence, severity and duration of OM, the demand for opioids and for TPN. It needs to be tested in randomized trials, because its easy administration and cost-effectiveness may render it a valuable addition to the standard care in the treatment of OM.

Triple drug combination in the prevention of nausea and vomiting following busulfan plus cyclophosphamide chemotherapy before allogeneic hematopoietic stem cell transplantation.

PURPOSE: A clinical study of triple drug combination (aprepitant+palonosetron+ dexamethasone) was carried out to evaluate its efficacy in preventing both acute and delayed emesis after high-dose chemotherapy (HDC) with busulphan+cyclophosphamide (BuCy) before hematopoietic stem cell transplantation (HSCT). METHODS: The study enrolled 60 patients suffering from various hematological malignancies: 20 in the triple drug antiemetic group and 20 in each of two historical control groups that received dexamethasone plus either ondansetron or palonosetron. The groups were comparable for statistical analysis. The observation period started with the initiation of chemotherapy (0 h) and continued for 24 h after its completion for the acute phase, and during 5 days after finishing chemotherapy for the delayed phase. The response rate of the study drugs was evaluated by a 4-grade scale based on the condition of nausea and vomiting: highly, moderately or slightly effective and not effective. RESULTS: Patients treated with the triple drug combination had significantly higher response rates than those receiving palonosetron or ondansetron (+ dexamethasone) during both the acute and delayed phases: highly effective in early + late phases: 55 vs. 30 vs. 20%; highly effective in early phase: 70 vs. 30 vs. 20%; highly effective in late phase: 55 vs. 55 vs. 30%; highly + moderately effective in early phase: 75 vs. 32 vs. 25%; highly + moderately effective in late phase: 85 vs. 60 vs. 40% for triple drug combination, palonosetron + dexamethasone and ondansetron + dexamethasone, respectively. CONCLUSION: This triple drug combination was more effective than ondansetron or palonosetron (+ dexamethasone) in preventing acute (especially), and delayed nausea and vomiting following BuCy chemotherapy before HSCT.

A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation.

OBJECTIVE: We performed a clinical study of a triple-drug combination to evaluate its efficacy to prevent both acute and delayed emesis after high-dose chemotherapy with BEAM (BCNU [carmustine]+etoposide+ARA-C [cytarabine]+melphalan) before hematopoietic stem cell transplantation (HSCT) by comparison with a historical control group of patients treated with dexamethasone (dex) and ondansetron or palonosetron. METHODS: We evaluated 96 patients non-Hodgkin's lymphomas (n=54), and Hodgkin's disease (n=42). Evaluated patients received: aprepitant+palonosetron and dex. The observation period started with the initiation of chemotherapy (0 hours) and continued for 24 hours after the completion of the chemotherapy for the acute phase, and during 5 days after finishing chemotherapy for the delayed phase. The response rate to study drugs was evaluated using a four-grade scale based on the degree of control of nausea and vomiting: high, modrate, slightly effective, or not effective. RESULTS: Patients treated with the three-drug combination showed a significantly higher response rate than those receiving palonosetron or ondasetron (+dex) during the both the acute and the delayed phases: highly effective early+late phases, 82% versus 70% versus 35%; highly effective early phase, 94% versus 70% versus 35%; highly effective late phase, 85% versus 85% versus 50%; highly+moderately effective early phase, 97% versus 70% versus 40%; highly+moderately effective late phase, 97% versus 90% versus 60%, for triple combination, palonosctron with dexamethasone and ondasetron+dex, respectively. All antiemetic regimens were well tolerated. The three-drug combination showed a similar safety profile; adverse events were generally mild and transient. CONCLUSIONS: The triple-drug combination was more effective than ondansetron or palonosetron (+dex) treatments to prevent acute (especially) and delayed nausea and vomiting following BEAM before HSCT.

Efficiency of supersaturated calcium phosphate mouth rinse treatment in patients receiving high-dose melphalan or BEAM prior to autologous blood stem cell transplantation: a single-center experience.

OBJECTIVE: Oral mucositis (OM) is an unresolved problem among patients treated with a high-dose therapy supported by hematopoietic stem cell transplantation (HSCT). We tested the ability of supersaturated calcium phosphate mouth rinse (Caphosol) to ameliorate oral mucosal injury induced by a conditioning regimen. PATIENTS AND METHODS: Thirty-two patients with hematologic malignancies were treated with Caphosol to prevent OM during HSCT procedures. The conditioning regimens for 16 patients were BGNU 300 mg/m2, day 6; ARA-C 200 mg/m2 daily, days 5, 4, 3, 2; VP-16 200 mg/m2 daily, days 5, 4, 3, 2; L-PAM 140 mg/m2, day 1 (BEAM) and for 16 patients, MEL 200 (non-Hodgkin's lymphoma). A control group was composed of 24 consecutive patients, who had been treated with HSCT before Caphosol was available. The source of the graft was autologous peripheral blood. RESULTS: Among patients treated with Caphosol no one had to receive total parenteral nutrition. Among the BEAM group no one experienced III to IV degree OM compared with 40% of the control group. The median OM duration was 2.25 days versus controls of 8.6, (P<.001); only one patient received opioids versus 100% of controls. In the MEL 200 group, 93.7% of patients developed 0 to II degree OM vs 94% of the control group (P=.74) with median duration of 1, 73 days versus 2.42 for the controls (P=.73). In both control and Caphosol cohorts one patient received opioids. CONCLUSION: Caphosol may reduce the incidence, severity, and duration of oral mucositis and decrease the number of days with painkillers among patients treated with a BEAM but not a Mel 200 regimen.

Hematologic recovery in patients who are treated with autologous stem cells transplantation taken from bone marrow after granulocyte-colony-stimulating factor stimulation.

BACKGROUND: We sought to compare hematologic recovery between patients who did or did not receive granulocyte-colony-stimulating factor (G-CSF)-stimulated bone marrow (rich bone marrow [RBM]). MATERIALS AND METHODS: The study subjects were 20 patients whose bone marrow was taken without prior stimulation with G-CSF and 15 patients in whom bone marrow was taken after previous G-CSF mobilization. The bone marrow harvest took place on the fifth day after G-CSF initiation. The bone marrow aliquot was 20 mL/kg. RESULTS: The median value of nucleated cells obtained from patients without G-CSF preparation was 3.65×10(8)/kg. The median value of nucleated cells from RBM patients was 4.83×10(8)/kg. The median value of stem cells obtained from patients without G-CSF preparation was 0.96×10(6)/kg versus 1.9×10(6)/kg from RBM patients. The median time to recovery of the hematopoietic system based on an increase in PLT value>20 g/L was 12.6 days for RBM versus 18.8 days without G-CSF preparation. The median time to recovery of the hematopoietic system based on assessment of growth ANC>0.5 g/L was 13.0 days for RBM versus 17.8 days without G-CSF stimulation. Significantly higher values of nucleated cells and increased stem cells were observed among RBM patients compared with those whose bone marrow was harvested without any stimulation (P=.01). There was faster recovery of the hematopoietic system in cases where bone marrow was collected after G-CSF: PLT>20 g/L (P=.015) and ANC>0.5 g/L (P=.01). We also observed that the use of stimulated bone marrow shortened hospital stay after the administration of hematopoietic cells to 17.3 days compared with 23.1 days among patients receiving hematopoietic cells from nonstimulated bone marrow. The number of complications during transplantation was comparable in both cases, the most frequent ones being febrile neutropenia and grade III and IV mucositis. CONCLUSION: RBM is a better method to obtain stem cells from bone marrow. Stimulated bone marrow shows faster engraftment compared with nonstimulated bone marrow helping patients who fail to generate are adequate number of stem cells from peripheral blood.

Palonosetron in prevention of nausea and vomiting after highly emetogenic chemotherapy before haematopoietic stem cell transplantation-single center experience.

OBJECTIVE: A clinical study of palonosetron was performed to evaluate its efficacy in preventing both acute and delayed emesis after high-dose chemotherapy (HDC) before hematopoietic stem cell transplantation (HSCT) using a historical control group of patients treated with ondansetron as the comparative drug. METHODS: Among the 46 evaluated patients 20 with lymphoma received BEAM as the conditioning regimen; 16 has relapsed germ cell tumors treated with CARBOPEC; and 10 with acute myeloid leukemia received BuCY. Increasing severity of nausea was evaluated according to the following 4-grade scale: none (no nausea); mild (slight nausea but no disruption to daily activities); moderate (nausea and some disruption to daily activities); and severe (extreme nausea and severe disruption to daily activities). The emetic response rate was evaluated using the criteria: complete (no emetic episode); major (1-2 episodes); minor (3-5 episodes); and failure (>5 episodes). The response rate of the study drugs was evaluated by the following 4-grade scale based on the condition of nausea and vomiting: highly effective, moderately effective, slightly effective, and not effective. RESULTS: Patients treated with palonosetron showed significantly greater response rates than those receiving ondansetron during the both the acute and the delayed phases: highly and moderately effective: acute phase 15% versus 5% CARBOPEC; 70% versus 35% BEAM and 32% versus 20% BuCY; delayed phase: 60% versus 30% BuCY; 100% versus 50% BEAM and 25% versus 10% CARBOPEC. CONCLUSIONS: Single-dose palonosetron was more effective than ondansetron treatment to prevent acute and delayed nausea and vomiting following HDC before HSCT.

Pure red cell aplasia due to parvovirus B19 infection transmitted probably through hematopoietic stem cell transplantation.

Human parvovirus B19 is a very common infectious pathogen in humans. In healthy subjects, B19 infection is the cause of a self-limiting subclinical erythroid aplasia, followed by rash or arthralgia. In immunocompromised patients B19 can cause chronic anemia. This report presents the case of a 19-year-old male who developed severe anemia shortly after successful allogeneic hematopoietic stem cell transplantation. His marrow showed selective erythroid aplasia, and real-time polymerase chain reaction assay confirmed parvovirus B19 infection. Despite repeated high-dose immunoglobulin treatment, he remained anemic. His hematological status markedly improved after cessation of immunosuppression. Retrospective examination of the donor's blood suggests that hematopoietic stem cells could be the source of infection.

Palifermin for prevention of oral mucositis after haematopoietic stem cell transplantation- single centre experience.

PURPOSE: Oral mucositis (OM) is one of the most debilitating and common side effects in patients treated with high-dose chemotherapy supported by haematopoietic stem cell transplantation (HSCT). We tested the effectiveness of palifermin to avoid oral mucosal injury induced by the conditioning regimen. PATIENTS AND METHODS: Twenty patients with haematological malignancies were treated with palifermin for prevention of OM during HSCT procedures. Nine patients received allogeneic haematopoietic stem cells, and in 11 autologous HSCT was performed. The control group was composed of patients who had been treated with HSCT previously, before the palifermin era. The source of graft was peripheral blood. RESULTS: Among patients treated with palifermin no grade 2-4 OM was observed. No patient had to receive opioid analgesics or total parenteral nutrition. 30% of the patients developed grade 1 OM of 4-5 days' duration. In the control group OM was observed in all cases, with 50% of the patients developing grade 3-4 OM. Median duration of OM was 10 and 12 days for auto- and allogeneic patients, respectively. In comparison with the control group, treatment with palifermin was associated with significant reduction of grade 2-4 OM, shorter duration of OM, less analgesics intake, and reduced number of days with antibiotic treatment. Additionally, allogeneic patients treated with palifermin had shorter time to platelet engraftment. CONCLUSION: Palifermin reduces incidence, severity and duration of OM, and decreases the number of days with analgesics and antibiotics. For allogeneic patients it can shorten the time to platelet engraftment, but this observation needs further studies.

Which parameters of nutritional status should we choose for nutritional assessment during hematopoietic stem cell transplantation?

Since changes in nutritional indices after hematopoietic stem cell transplantation (HSCT) have not been well studied, there is no definition of risk factors for the development of malnutrition, and the inception of total parenteral nutrition (TPN). We sought to analyze changes in nutritional status parameters and acute phase protein levels as qualifications for TPN. Nutritional status was assessed in 54 patients during autologous (n = 30) on allogeneic (n = 24) transplantations. Eight of 15 patients who had to be treated with TPN, needed prolonged hospitalization (>5 weeks). We assessed biochemical and anthropometric indices of nutritional status, body fat and resting energy expenditure, and acute phase protein levels on the day before starting a conditioning regimen, after chemotherapy completion, and every 7 days until engraftment, which was at least three times after stem cell infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of body weight and retinol binding protein or transferrin may be useful for nutritional assessment during autologous or allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of the conditioning regimen was helpful to make a decision about starting TPN.

Multimodality treatment of germ cell cancer patients who had progression or relapse after high dose chemotherapy and autologous bone marrow transplantation.

PURPOSE: When a patient with germ cell tumor (GCT) fails to be cured with high dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (auto- BMT) the overall prognosis is very poor and any further treatment has only palliative character. A question requiring answer is how intense should this kind of treatment be, and what can be expected from it. PATIENTS AND METHODS: Of 44 patients with GCT who were transplanted after HDC in our centre between 1999- 2005, 17 experienced treatment failure. Amongst them 14 had marker-positive relapse or confirmed germ cell histology. Another 3 had second primary neoplasms. Of the 17 patients 14 received further treatment that consisted of surgery alone in 2, chemotherapy in 2, radiotherapy in 1, combined surgery + chemotherapy in 5, chemotherapy +surgery + radiotherapy in 3 and chemotherapy + radiotherapy in 1 patient. RESULTS: The median survival from the time of relapse was 3 months in all patients, and 6 months in the 14 patients who received further treatment. In 6 patients with relapse confined to a single site the median survival was 11 months. Three patients in this group are alive with overall survival (OS) of 37.4+, 24.3+ and 6.2+ months (all had multimodal treatment: chemotherapy + surgery or radiotherapy, and all achieved durable complete response/CR). CONCLUSION: Our results suggest that GCT patients who have relapsed/ progressed after HDC may benefit from further treatment. Best chances for long term survival have those who experience relapse confined to one metastatic site and receive combined treatment (surgery or radiotherapy plus systemic therapy).

The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant.

In this multicenter study, we assessed the use of palifermin (recombinant human-keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 mug/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1-4 (58 vs 94%, P<0.001), 3-4 (13 vs 43%, P<0.001) and the median duration of OM (4 vs 9 days, P<0.001) in the palifermin group compared to the control group. The incidence of analgesics (32 vs 75.5%, P<0.001), opioid analgesics (24 vs 64%, P<0.001) and total parenteral nutrition (11 vs 45%, P<0.001) was also significantly reduced. The analysis of distribution of affected organs revealed that aGvHD was less prevalent in the palifermin group (P=0.036). There was no significant difference in the onset of any OM after HSCT, time to engraftment and length of hospitalization between groups. The drug was generally well tolerated and safe. Our results suggest that the use of palifermin reduces OM and probably aGvHD after HSCT, but a randomized trial is needed.

How can we help patients with refractory chronic graft versus host disease- single centre experience.

Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic haematopoietic stem cell transplantation (alloHSCT). Ocular involvement as well as dermal sclerosis, joint contractures and pathological changes in oral cavity are often refractory to treatment. This kind of patients require complex aggressive immunosuppressive therapy. We are still waiting for drugs against cGVHD, characterized by decreased infectious complications, encouraging efficacy and rare and reversible side effects. We describe eight patients who developed extensive chronic graft versus host disease with eye involvement after alloHSCT. All had ocular manifestations, which were refractory to the first and second line of systemic immunosuppressive therapy. All patients responded to the topical cyclosporine therapy, but clinical improvement was seen only since the fifth month of starting treatment. Topical cyclosporine was well tolerated. Other four patients with sclerodermoid type of skin changes, refractory to second line systemic immunosuppressive therapy, were treated with clofazimine. Clofazimine is a drug used to treat leprosy. Because of its anti-inflammatory effects, clofazimine is used also as a second or third line therapy for various skin disorders including: pyoderma gangrenosum, lupus erythematosus, palmoplantar pustulosis and chronic graft versus host disease. All patients,who received clofazimine due to dermal sclerosis, joint contractures and oral manifestations, achieved partial or complete responses and were able to reduce other immunosuppressive drugs. Clofazimine was generally well tolerated.

Biochemical indices for the assessment of nutritional status during hematopoietic stem cell transplantation: are they worth using? A single center experience.

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders, solid tumors and autoimmune diseases. One of the major challenges in the post-transplant period is nutrition. The purpose of this investigation was to assess changes in the biochemical indices of nutritional status during HSCT and compare them with acute-phase protein levels to find the best parameters for nutritional support qualification. Nutritional status was assessed in 54 patients during autologous (30 cases) and allogeneic (24 cases) transplantation. Fifteen patients had to be treated with total parenteral nutrition (TPN), eight of them needing prolonged hospitalization. All nutritional indices and acute-phase protein levels were evaluated during the day before the beginning of conditioning regimen, after chemotherapy completion and every 7 days until engraftment, at least three times after stem cells infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of retinol-binding protein and transferrin can be useful for nutritional assessment during autologous and allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of conditioning regimen, is helpful in making a decision about starting TPN.

Allogeneic non-myeloablative hematopoietic stem cell transplantation for treatment of metastatic renal cell carcinoma -- single center experience.

We evaluated the efficacy of allogeneic non-myeloablative stem cell transplantation (NST) in patients with metastatic renal cell carcinoma (RCC). A total of 5 patients received blood stem cells from HLA identical siblings. Conditioning consisted of: cyclophosphamide 60 mg/kg/d, days -7 to -6 and fludarabine 25 mg/m2/d for consecutive days [days -5, -4, -3, -2, -1]. The median CD34+ cell dose was 3.34 million/kg. Immunosuppression consisted of cyclosporine A and methotrexate. Among all, four patients achieved full donor chimerism with a median of 89 days. One patient rejected the graft and received the second transplantation. Grade II-III acute GVHD occured in 3 patients. None of patients achieved complete or partial response and there were only two mixed responses. All patients died due to cancer progression. There were no transplant-related deaths. Summarising, NST regimen allows allogeneic engraftment with low treatment related mortality in this high-risk population of patients. Acute and chronic GVHD are the major morbidities. Progression is common after NST in unselected patients with advanced RCC. However, regression of some metastases suggests that the graft versus tumor effect may occur after this type of treatment. At present such a procedure should be considered as an experimental approach.

New heterocyclic beta-sheet ligands with peptidic recognition elements.

A detailed and comprehensive overview is presented about the design, modeling, and synthesis, as well as spectroscopic characterization, of a new class of beta-sheet ligands. The characteristic feature of these compounds is a peptidic chimeric structure formed from a specific combination of aminopyrazolecarboxylic acids with naturally occurring alpha-amino acids. These hybrid peptides are designed with the aid of molecular modeling to exist mainly in an extended conformation. All their hydrogen bond donors and acceptors can be aligned at the bottom face in such a way that a perfect complementarity toward beta-sheets is obtained. Thus the aminopyrazoles impart rigidity and a highly efficient DAD sequence for the recognition of whole dipeptide fragments, whereas the natural alpha-amino acids are designed to mimick recognition sites in proteins, ultimately leading to sequence-selective protein recognition. The synthetic protocols either rely upon solution phase peptide coupling with a PMB protecting group strategy or solid-phase peptide coupling based on the Fmoc strategy, using the same protecting group. In solution, a key building block was prepared by catalytic reduction of a nitropyrazolecarboxylic acid precursor. Subsequently, it was (N-1)-protected with a PMB group, and elongated by HCTU- or T3P-assisted peptide coupling with dipeptide fragments, followed by PyClop-assisted coupling with another nitropyrazolecarboxylic acid building block. Final simultaneous deprotection of all PMB groups with hot TFA completed the high-yield protocol, which works racemization-free. After preparing a similar key building block with an Fmoc protection at N-3, we developed a strategy suitable for automated synthesis of larger hybrid ligands on a peptide synthesizer. Attachment of the first amino acid to a polystyrene resin over the Sieber amide linker is followed by an iterative sequence consisting of Fmoc deprotection with piperidine and subsequent coupling with natural alpha-amino acid via HATU/HOAt. High yields of free hybrid peptides are obtained after mild acidic cleavage from the resin, followed by deprotection of the PMB groups with hot TFA. The new aminopyrazole peptide hybrid compounds were characterized by various spectroscopic measurements including CD spectra, VT, and ROESY NMR experiments. All these accumulated data indicate the absence of any intramolecular hydrogen bonds and strongly support an extended conformation in solution, ideal for docking on to solvent-exposed beta-sheets in proteins. Initial results from aggregation tests of pathological proteins with these and related ligands look extremely promising.

[Five cases of acquired pure red cell aplasia]. / Piec przypadków nabytej wybiórczej aplazji ukladu czerwonokrwinkowego.

Acquired pure red cell aplasia is rare disorder of hematopoiesis. Because of the variety of reasons for PRCA optimal treatment is based on highly specialistic diagnostics. Both humoral and cellular mechanisms are involved in the pathogenesis of PRCA. Corticosteroids, cyclosporin A, high-dose intravenous immunoglobulin therapy are recommended in PRCA. Treatment failures may be successfully managed with antihuman thymocyte globulin, cyclophosphamide or azathioprine. We describe also the lots of five patients with this disorder.