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Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day ( n =400) could be optimized by doubling the dose ( n =420), adding interferon (IFN) ( n =430) or cytarabine ( n =158) or using IM after IFN-failure ( n =128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1–15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20–30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.

The aim was to investigate the efficacy of neoadjuvant docetaxel–cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m −2 (day 1) plus cisplatin 40 or 50 mg m −2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel–cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

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Mutations in the Hedgehog signaling pathway is responsible for the formation of various cancers, including some forms of basal cell carcinoma (BCC). Uncontrolled Hedgehog signaling leads to overexpression of the zinc-finger Gli transcription factors, among which Gli2 plays a central role. We found that high Gli2 expression induced the concomitant high expression of the caspase 8 inhibitor, cFlip, and thereby counteracts death-ligand-mediated apoptosis. By investigating the cFlip promoter, Gli2 binding sites were identified and confirmed. Gli2 gene silencing by RNA interference broke the apoptosis resistance via cFlip downregulation. The direct functional connection between Gli2 and cFlip was not only demonstrated in a keratinocytic cell line but also in BCC tissue. As cFlip and Bcl-2 are highly expressed in BCCs, as a consequence of high Gli2 expression, this may explain the marked resistance of the tumor to the extrinsic and intrinsic apoptotic pathway. We could now demonstrate that Gli2 gene silencing in BCC tissues made the tumor sensitive to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-mediated cell death by downregulating cFlip. As Gli2 silencing does not only downregulate cFlip, but also Bcl-2, Gli2 could be a key target for a novel therapeutic approach in tumors with dysregulated Hedgehog signaling.

High-dose chemotherapy (HDT) and hematopoietic SCT are effective in patients with relapsing or refractory malignant lymphoma. Collection of sufficient numbers of stem cells is a prerequisite for such a therapy. In a pilot trial, we evaluated the feasibility of stem cell mobilization with vinorelbine/G-CSF in patients with lymphoma, a regimen allowing precise timing and harvesting of sufficient stem cells in myeloma patients. Forty-five patients with lymphoma received vinorelbine 35 mg/m 2 i.v. on day 1 and G-CSF 10 μg/kg/day s.c., divided in two daily doses from day 4 until collection. Stem cell collection was successfully performed in 43 patients (96%) with a median of 3.6 × 10 6 CD34 + cells/kg (range: 1.4–16) in the collected product. In 28 patients (62%), the first stem cell apheresis was performed on day 8, and for 28 patients a sufficient stem cell yield was reached with one apheresis only. All 43 patients underwent high-dose chemotherapy with BEAM and auto-SCT with hematological recovery on time and without unexpected toxicity. In conclusion, vinorelbine/G-CSF allows accurate timing and safe harvesting of sufficient stem cells in patients with malignant lymphoma.

The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda ® ) at a dose of 1250 mg m −2 orally twice daily on days 1–14 every 21 days. The inclusion criteria were PSA serum levels >3 × upper limit of normal, a WHO performance status 0–2, age <85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54–85 years). A median of three cycles of capecitabine was administered (range 1–8). PSA response was observed in three patients (12%, 95% CI 3–31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9–15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand–foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7–41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg m −2 orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.

ObjectivesTo assess chemotherapy patients' perceptions of safety and their attitudes towards participating in error-prevention strategies.DesignSemistructured interviews were conducted with 30 chemotherapy patients at baseline. Follow-up interviews were conducted 9 weeks later.SettingA community hospital in Switzerland.ResultsThough patients had experienced errors in their care, they were only moderately worried about safety, risk of errors and the potential for harm. At follow-up, worries about safety had increased, and patients reported a higher degree of vigilance. Participants unequivocally agreed that patients can make contributions to their safety, and many patients were prepared to get involved. Patients described engaging in their safety as a learning process and highlighted the importance of being proactive, asking questions and communicating any observations of deviations from routines. Commonly recommended error-prevention strategies were rated as highly effective. Instruction by nurses was central for patients, but the underlying reasons varied. There was no indication that patients perceive participation in safety actions as eroding trust in their providers.ConclusionsPatients are prepared to engage in their safety, but the encouragement by staff is vital. Involvement of patients with cancer in medication administration safety needs to acknowledge patients' conceptions of these activities and their varying abilities at different stages in the treatment process.

Several mobilization regimens are used to mobilize stem cells for transplantation in multiple myeloma, but timing of collection is often difficult and the rate of side effects is quite high. To optimize timing of collection of peripheral blood stem cells, to reduce side effects and costs of the procedure, we evaluated vinorelbine, a drug shown to have activity in multiple myeloma, with a single dose of pegfilgrastim as mobilizing regimen. Thirty consecutive patients with newly diagnosed stage I to III multiple myeloma received 2-4 cycles of VAD (vincristine, adriamycin, dexamethasone) induction therapy at two transplantation centers. This was followed by one dose of vinorelbine 35mg/[m.sup.2] iv in an outpatient setting on day one and a single dose of pegfilgrastim 6mg s.c. on day 4. On day eight a median count of 52.5 CD34+ stem cells/microliter (range 2-320) was measured in the blood of 28 patients. Two patients already showed CD34+ cells of 51 and 60 at day 7. One stem cell apheresis was sufficient to collect a median of 8.9 x [10.sup.6] CD34+ cells/kg body weight (range 1.2 -36.6). Four patients (13%) needed two stem cell aphereses to achieve a sufficient number of stem cells for transplantation. Twenty-one (70%) of the 30 patients mobilized had their first apheresis on day 8, 2 (7%) on day 7, and 7 patients (23%) on day 9. No episodes of fever in neutropenia or other side effects were observed during mobilization. After high dose chemotherapy with melpahalan and stem cell transplantation, recovery of neutrophils was within the expected range, indicating no harmful effect of the mobilization scheme to the stem cells collected. The combination of vinorelbine and pegfilgrastim is an effective alternative to cyclophosphamide in the mobilization of stem cells for autologous transplantation in multiple myeloma. Results are reliable and day of apheresis is highly predictable. As all the mobilizing and collection procedures were done in an out patient setting, this mobilization scheme is cost saving compared to the mobilization with cyclophosphamide, that usually requires hospitalization. In addition, a single dose of pegfilgrastim averts the problem of non-compliance of daily filgrastim injections and improves acceptance of the treatment by the patient.

Background: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. Patients and Methods: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. Results: After 16–20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Rα) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. Conclusion: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes