Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines.

BACKGROUND: The aim of this study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of PI3K/AKT/mTOR pathway. PATIENTS AND METHODS: In a prospective, one-arm, phase II study, patients with mRCC received everolimus (10 mg/day) using a 30-day cycle. A prospectively planned evaluation of potential biomarkers of PI3K/AKT/mTOR pathway. RESULTS: The median age of the 58 patients enrolled into the study was 60 years (range 41-78 years). In multivariate analysis, it was found that the adverse independent predictors for everolimus therapy were histological grade G1/2 {hazard ratio (HR): 2.68 [95% confidence interval (CI) 1.29-5.58, P = 0.0082]}, increased lactate dehydrogenase (LDH) level before treatment [HR: 2.55 (95% CI 1.30-4.99, P = 0.0064)] and the PIK3CA gene variant rs6443624 (HR: AC + AA versus CC = 2.08, 95% CI 1 11-3.89, P = 0.0254). In multivariate analysis, it was observed that the adverse independent prognostic factors were: elevated corrected calcium level [HR: 4.17 (95% CI 1.66-10.51; P = 0.0024)] and the PIK3CA gene variant rs6443624 [HR: AC + AA versus CC = 1.97 (95% CI 1.02-3.79; P = 0.0421)]. CONCLUSIONS: The PI3KCA gene polymorphism, LDH, and histologic grade can predict the effects of everolimus treatment. The corrected calcium level and the PIK3CA gene variant rs6443624 may be independent prognostic factors. Further investigation is needed to confirm and validate these findings prospectively in other RCC trials.

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

Insights into cancer surveillance in Central and Eastern Europe, Israel and Turkey.

The current cancer landscape within transitional economies in central and Eastern Europe and the Mediterranean area is not particularly optimistic. Current perceptions are often based on extrapolations from other countries and regions; and hence the authors collaborated with the South Eastern Europe Oncology Group (SEEROG) to collect information on cancer registration in Central and Eastern Europe, Israel and Turkey. Healthcare authorities and specialist oncology centres in 21 countries in the region were contacted for information on cancer registries in their countries. Based on this information, the authors believe that the recording and reporting of data on cancer in the region is at an acceptable level. The authors discuss and compare institution- and population-based registries, and present opinions on elements of an 'ideal registry' based on the survey replies and comparisons with other registries. A comparison with the sources used for GLOBOCAN 2008 illustrates the need for consistent data to be communicated, published and utilised throughout the region and the oncology community. The authors conclude by considering the potential value of collaboration between health authorities across the region, as well as between the clinical and epidemiological communities, to ensure that cancer data are consistently collected, verified and made public.

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.

Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings.

BACKGROUND: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe. PATIENTS AND METHODS: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases. RESULTS: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade ≥3 AEs including hand-foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%, respectively. CONCLUSIONS: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients.

Serum TRAIL levels in patients with epithelial ovarian cancer or primary peritoneal cancer treated with neoadjuvant chemotherapy. A pilot study.

AIMS: The study attempted to evaluate the kinetics of changes in serum TRAIL levels as a potential predictive and prognostic factor in patients with epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC), eligible for an interval debulking surgery (IDS). MATERIAL AND METHODS: 17 patients with primary inoperable EOC or PPC in FIGO Stage IIIC or IV who underwent an exploratory operation were enrolled to the study. Serum TRAIL levels were determined by ELISA method (DIACLONE, Besancon Cedex, France) before and after two courses of neoadjuvant chemotherapy (NAC) based on paclitaxel and platinum analogue (cisplatin or carboplatin). The control group consisted of six healthy volunteers. The median difference in concentration of TRAIL (dTRAIL) between the initial marking and after two courses of NAC in each patient was 192 pg/ml and it was used for dichotomization of the test group. RESULTS: Suboptimal interval debulking surgery (IDS) was performed in 23.5% (4/17) and optimal IDS in 76.5% (13/17) patients. TRAIL concentration before chemotherapy did not differ significantly between patients with EOC or PPC [1426.96 +/- 321.06 pg/ml (mean +/- SD) (U = 26, p = 0.08)] and the control group [1160.40 +/- 256.39 pg/ml (mean +/- SD. After two courses of NAC serum TRAIL concentration level was 1247.49 +/- 378.46 pg/ml (mean +/- SD). The difference was significant (Z = 2.44, p = 0.0147). Statistical analysis showed that dTRAIL did not significantly influence either extent of IDS (U = 35, p = 0.0962) or time to progression (log-rank test, p = 0.1185), overall survival (log-rank test, p = 0.1973) and response to treatment according to RECIST criteria (U = 35.5, p = 0.9616). CONCLUSIONS: Serum TRAIL concentration levels changed significantly during NAC. However, it seems that the concentration of this protein has no critical value as a predictive or prognostic factor in patients with EOC or PPC.

Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation.

Compared with normal littermates, the op/op mice had very few macrophages in the peritoneal cavity and severely reduced numbers of monocytes in the peripheral blood. Moreover, osteopetrotic animals demonstrated an altered distribution of hemopoietic tissue with a 10-fold decrease in the number of marrow cells. Liver hemopoiesis persisted in 4-wk-old mice as evidenced by the presence of hemopoietic stem cells (HSC). Moreover, the concentration of HSC was decreased in marrow and increased in the spleen of op/op mice. In spite of the paucity of cells of monocyte-macrophage lineage in vivo, progenitor cells from hemopoietic tissues of op/op mice formed increased numbers of monocyte-macrophage colonies in vitro in the presence of exogenous colony-stimulating activity (CSA). The source of this critical CSA was a medium conditioned by stromal fibroblastoid colonies formed in vitro by normal marrow cells. Therefore, these data suggest that op/op mice possess normal monocyte-macrophage-osteoclast progenitor cells but these cells are unable to fully differentiate in the op/op mouse microenvironment. In support of this, in cultures of stromal fibroblastoid colonies from op/op marrow or spleen, the concomitant growth of macrophages, normally very dense, was drastically reduced. Moreover, transplantation of op/op spleen cells into lethally irradiated littermate recipients resulted in their hemopoietic reconstitution without signs of macrophage defect. Thus, the op/op splenic cells do not transfer the disease and are capable of normal differentiation in normal in vivo environment. These observations support the hypothesis that the defect in op/op mice is a result of the failure of hemopoietic stromal fibroblastoid cells to release sufficient amounts of CSA necessary for normal differentiation of cells of the monocyte-macrophage lineage.

Growth factor-dependent inhibition of normal hematopoiesis by N-ras antisense oligodeoxynucleotides.

To determine whether N-ras expression is required at specific stages of the process of in vitro normal human hematopoiesis, adherent- and T lymphocyte-depleted mononuclear marrow cells (A-T-MNC) or highly purified progenitors (CD34+ cells) were cultured in semisolid medium, under conditions that favor the growth of specific progenitor cell types, after exposure to N-ras sense and antisense oligodeoxynucleotides. N-ras antisense, but not sense, oligodeoxynucleotide treatment of A-T-MNC and CD34+ cells resulted in a significantly decreased number of granulocyte/macrophage colony-forming units (CFU-GM) induced by interleukin 3 (IL-3) or granulocyte/macrophage colony-stimulating factor (GM-CSF) and of macrophage colonies (CFU-M) induced by M-CSF, but not of granulocytic colonies induced with G-CSF or IL-5. However, the same treatment significantly inhibited colony formation induced by each of the above factors in combination with IL-3. Megakaryocytic colony (CFU-Meg) formation from A-T-MNC or CD34+ cells in the presence of IL-6 + IL-3 + erythropoietin (Epo) was also markedly decreased after antisense oligodeoxynucleotide treatment. Erythroid colonies derived from A-T-MNC in the presence of Epo (CFU-E) were not inhibited upon antisense treatment, whereas those arising from A-T-MNC or CD34+ cells in the presence of IL-3 + Epo (BFU-E) were markedly affected. These results are consistent with the hypothesis that distinct signal transduction pathways, involving N-ras or not, are activated by different growth factors in different hematopoietic progenitor cells.

Regulation of proliferation and cytokine expression of bone marrow fibroblasts: role of c-myb.

The c-myb protooncogene plays a major role in regulating the process of in vitro and in vivo hematopoiesis via its activity as transcriptional regulator in hematopoietic progenitor cells. Since the bone marrow microenvironment appears to regulate in vivo hematopoiesis by maintaining the growth of multipotent progenitors via secretion of specific cytokines, we asked whether c-myb is also required for the proliferation of and/or cytokine production by stromal cells that generate fibroblast-like colonies (fibroblast colony-forming units [CFU-F]). Using the reverse transcriptase polymerase chain reaction technique, we detected low levels of c-myb mRNA transcripts in human normal bone marrow fibroblasts. Treatment of these cells with c-myb antisense oligodeoxynucleotides caused downregulation of c-myb expression, decreased in the number of marrow CFU-F colonies (approximately 54% inhibition) and in the cell number within residual colonies (approximately 80%), and downregulation of granulocyte/macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) mRNA expression. Transfection of T98G glioblastoma cells, in which expression of c-myb, GM-CSF, and SCF mRNAs is undetectable or barely detectable, with a plasmid containing a full-length c-myb cDNA under the control of the SV40 promoter induced the expression of biologically active SCF and GM-CSF in these cells. Regulation of GM-CSF expression by c-myb was due in part to transactivation of the GM-CSF promoter. These results indicate that, in addition to regulating hematopoietic cell proliferation, c-myb is also required for proliferation of and cytokines synthesis by bone marrow fibroblasts.

p120 GAP requirement in normal and malignant human hematopoiesis.

There is evidence to suggest that the p120 GAP (GAP), originally described as an inhibitor of p21ras, may also serve as a downstream effector of ras-regulated signal transduction. To determine whether GAP expression is required for the growth of human normal and leukemic hematopoietic cells, we used GAP antisense oligodeoxynucleotides to inhibit it and analyzed the effects of this inhibition on the colony-forming ability of nonadherent, T lymphocyte-depleted mononuclear cells and of highly purified progenitors (CD34+ MNC) obtained from the bone marrow and peripheral blood of healthy volunteers or chronic myeloid leukemia (CML, bcr-abl-positive) patients. The acute myelogenous leukemia cell line MO7, the Philadelphia BV173 cell line, and the acute promyelocytic leukemia NB4 and HL-60 cell lines were similarly examined. GAP antisense treatment inhibited colony formation from normal myelo-, erythro-, and megakaryopoietic progenitor cells as well as from CML progenitor cells. Proliferation of MO7 (growth factor-dependent) and BV173 (bcr-abl-dependent) cells, but not that of NB4 and HL-60 (growth factor-independent) cells, was also inhibited, even though a specific downregulation of GAP was observed in each cell line, as analyzed by either or both mRNA and protein expression. Stimulation of MO7 cells with hematopoietic growth factors increased the expression of GAP as well as the levels of active GTP-bound p21ras. Stimulation of GAP expression was inhibited upon GAP antisense treatment. These data indicate that p120 GAP is involved in human normal and leukemic hemopoiesis and strongly suggest that GAP is not only a p21ras inhibitor (signal terminator), but also a positive signal transducer.

Incidence of brain metastases in renal cell carcinoma treated with sorafenib.

BACKGROUND: This retrospective study evaluated the incidence of brain metastases in a subgroup of patients with metastatic renal cell carcinoma (RCC) who were randomly assigned to receive sorafenib, an oral multikinase inhibitor (400 mg b.i.d.), versus placebo in the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). PATIENTS AND METHODS: Patients enrolled in TARGET at two centres (Institut Gustave Roussy, Villejuif, France, n = 85; Central Clinical Hospital of Military Medical Academy, Warsaw, Poland, n = 54) made up the current subgroup, who were retrospectively evaluated for the incidence of brain metastases during follow-up. The association between treatment (sorafenib versus placebo) and occurrence of brain metastases was evaluated by univariate analysis. RESULTS: The overall incidence of brain metastases in patients receiving sorafenib was 3% (2 of 70 patients) compared with 12% (8 of 69 patients) in patients receiving placebo (P < 0.05). The incidence of brain metastases was also significantly lower in the sorafenib group after 1 (P = 0.0447) and 2 years (P = 0.005) of treatment compared with the placebo group. CONCLUSIONS: In this subpopulation, sorafenib may reduce the occurrence of brain metastases. Antiangiogenic therapy, such as sorafenib, could be an effective preventive therapy for brain metastases in advanced RCC.

Oral treatment of metastatic breast cancer with capecitabine: what influences the decision-making process?

The importance of selecting treatment for metastatic breast cancer (MBC) that best suits the needs of the patient while offering a good clinical outcome is becoming more prominent in the decision-making process. We designed a questionnaire-based study to identify factors influencing treatment choice. We prospectively surveyed 218 female MBC patients scheduled to receive chemotherapy who were eligible for capecitabine monotherapy. All 215 patients who answered the questionnaire preferred oral capecitabine to intravenous chemotherapy. The most frequently cited reason for this preference was convenience (72%). The possibility of staying at home during treatment was considered important by 67% of patients overall, 42% of the 71 patients giving only one reason for their preference, 65% of those receiving first-line therapy and 74% treated in the second-line setting. Our study suggests that most patients prefer oral chemotherapy because of the convenience and possibility of staying at home during treatment. The study did not explore patient perceptions of efficacy or tolerability, which play a pivotal role in treatment selection from both the patient and physician perspectives. Capecitabine provides a very effective treatment for MBC and additionally addresses patients' desire to receive treatment at home.

Renal carcinoma CD105-/CD44- cells display stem-like properties in vitro and form aggressive tumors in vivo.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. Prognosis for ccRCC is generally poor since it is largely resistant to chemo- and radiotherapy. Many studies suggested that cancer stem cells/tumor initiating cells (CSCs/TICs) are responsible for development of tumor, disease progression, aggressiveness, metastasis and drug resistance. However, tumorigenic potential of CSCs/TICs isolated from established RCC cell lines - basic ccRCC research model - has never been investigated in vivo. CD105+, CD105-, CD44+ and CD44- as well as CD44-/CD105- CD44+/CD105+ and CD44-/CD105+ cells were isolated from Caki-1 RCC cell line, confirming coexistence of multiple subpopulations of stem-related phenotype in stable cell line. Sorted cells were injected subcutaneously into NOD SCID mice and tumor growth was monitored with MRI and PET/CT. Tumor growth was observed after implantation of CD105+, CD44+, CD44-, CD44-/CD105+ and CD44-/CD105- but not CD105- or CD44+/CD105+. Implantation of CD44-/CD105- cells induced tumors that were characterized by longer T1 and distinct metabolic pattern than other tumors. All the tumors were characterized by low uptake of [18F]FDG. CD105+ and CD44- tumors expresses Nanog and Oct-4, while CD44- tumors additionally expressed endothelial cell marker - CD31.

Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer.

BACKGROUND: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) are standard first-line treatments for patients with metastatic colorectal cancer (mCRC). The aim of this multicentre, open-label, phase IIIb study was to assess the addition of oxaliplatin to two different 5-FU regimens. PATIENTS AND METHODS: Patients with previously untreated mCRC were randomised to arm A [two-weekly oxaliplatin 85 mg/m(2) + either continuous intravenous infusion (CIV) of 5-FU without LV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B (5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was planned on progression. RESULTS: A total of 725 patients were enrolled. After a fixed follow-up of 2 years for each patient, 2-year survival rates were 27.3% and 24.8% in arms A and B, respectively (hazard ratio 0.93; 95% confidence interval 0.78-1.10). The addition of oxaliplatin significantly improved response rates (54.1 versus 29.8%; P < 0.0001) and median progression-free survival (7.9 versus 5.9 months; P < 0.0001). The most common grade 3-4 toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea (arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%). CONCLUSIONS: Despite improved rates of tumour control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.

Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides.

To determine the role of the BCR-ABL gene in the proliferation of blast cells of patients with chronic myelogenous leukemia, leukemia blast cells were exposed to synthetic 18-mer oligodeoxynucleotides complementary to two identified BCR-ABL junctions. Leukemia colony formation was suppressed, whereas granulocyte-macrophage colony formation from normal marrow progenitors was unaffected. When equal proportions of normal marrow progenitors and blast cells were mixed, exposed to the oligodeoxynucleotides, and assayed for residual colony formation, the majority of residual cells were normal. These findings demonstrate the requirement for a functional BCR-ABL gene in maintaining the leukemic phenotype and the feasibility of gene-targeted selective killing of neoplastic cells.

Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features.

BACKGROUND: Temsirolimus, a novel inhibitor of mammalian target of rapamycin, has demonstrated prolonged overall survival and progression-free survival compared with interferon alfa (IFN) in patients with advanced renal cell carcinoma (RCC) and poor prognostic features. Adverse events (AEs) of any causality were previously reported, but AEs that were deemed temsirolimus related are of particular relevance for poor-risk patients and for defining mammalian target of rapamycin inhibitor-specific side-effects. PATIENTS AND METHODS: Patients with advanced RCC, no prior systemic therapy, and three or more of six poor-risk factors were randomly assigned to one of three groups: (i) IFN s.c. up to 18 MU thrice weekly, (ii) temsirolimus i.v. 25 mg weekly, or (iii) temsirolimus i.v. 15 mg weekly plus interferon s.c. 6 MU thrice weekly. RESULTS: Among 208 patients, the most common temsirolimus-related grades 3-4 AEs were anemia (13%), hyperglycemia (9%), and asthenia (8%). Grades 3-4 hypercholesterolemia (1%), hypertriglyceridemia (3%), and hypophosphatemia (4%) were also seen. Although pneumonitis occurred infrequently, vigilance for its development is needed. Guidelines for management of toxic effects are presented on the basis of available clinical experience. CONCLUSIONS: Temsirolimus-related grades 3-4 AEs were primarily metabolic in nature and easily controlled medically. In general, these did not negatively impact patient quality of life.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

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.

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.