The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011

The United Kingdom Glaucoma Treatment Study:a multicenter, randomized, placebo-controlled clinical trial: design and methodology

Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50% over a 2-year period.

SMART Arm with outcome-triggered electrical stimulation:a pilot randomized clinical trial

The SMART (SensoriMotor Active Rehabilitation Training) Arm is a nonrobotic device designed to allow stroke survivors with severe paresis to practice reaching. It can be used with or without outcome-triggered electrical stimulation (OT-stim) to augment movement. The aim of this study was to evaluate the efficacy of SMART Arm training when used with or without OT-stim, in addition to usual care, as compared with usual care alone during inpatient rehabilitation.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

A Non-Inferiority Randomized Controlled Trial Comparing the Clinical Effectiveness of Anesthesia Obtained by Application of a Novel Topical Anesthetic Putty With the Infiltration of Lidocaine for the Treatment of Lacerations in the Emergency Department

We test the hypothesis that anesthesia, measured as pain scores, induced by a novel topical anesthetic putty is non-inferior (margin=1.3) to that provided by conventional lidocaine infiltration for the repair of lacerations.

Marrow aplasia developing 13 years after HLA-identical sibling allogeneic transplantation for chronic myeloid leukaemia:successful treatment with antithymocyte globulin and peripheral blood stem cell infusion from the original donor

Secondary or late graft failure has been defined as the development of inadequate marrow function after initial engraftment has been achieved. We describe a case of profound marrow aplasia occurring 13 years after sibling allogeneic bone marrow transplantation for chronic myeloid leukaemia (CML) in first chronic phase. Although the patient remained a complete donor chimera, thereby suggesting that an unselected infusion of donor peripheral blood stem cells (PBSC) or bone marrow might be indicated, the newly acquired aplasia was thought to be immune in aetiology and some immunosuppression was therefore considered appropriate. Rapid haematological recovery was achieved after the infusion of unselected PBSC from the original donor following conditioning with anti-thymocyte globulin (ATG).

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia:association with leukaemic relapse and treatment with donor lymphocyte infusions

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD.

Molecular markers in the treatment of metastatic colorectal cancer

Although significant progress has been made in colorectal cancer (CRC) treatment within the last decade with the approval of multiple new agents, the prognosis for patients with metastatic CRC remains poor with 5-year survival rates of approximately 8%. Resistance to chemotherapy remains a major obstacle in effective CRC treatment and many patients do not receive any clinical benefit from chemotherapy. In addition, other patients will experience adverse reactions to treatment resulting in dose modifications or treatment withdrawal, which can severely reduce treatment efficacy. Currently, significant research efforts are attempting to identify reliable and validated biomarkers with which will guide clinicians to make more informed treatment decisions. Specifically, the use of molecular profiling has the potential to assist the clinician in administering the correct drug, dose, or intervention for the patient before the onset of therapy thereby selecting a treatment strategy likely to have the greatest clinical outcome while minimizing adverse events. However, until recently, personalized medicine is a paradigm that has existed more in conceptual terms than in reality with very few validated biomarkers used routinely in metastatic CRC treatment. Rapid advances in genomic, transcriptomic and proteomic technologies continues to improve our understanding of tumor biology, but the search for reliable biomarkers has turned out to be more challenging than previously anticipated with significant disparity in published literature and limited translation into routine clinical practice. Recent progress with the identification and validation of biomarkers to the anti-epidermal growth factor receptor monoclonal antibodies including KRAS and possibly BRAF provide optimism that the goal of individualized treatment is within reach. This review will highlight and discuss current progress in the search for biomarkers, the challenges this emerging field presents, and the future role of biomarkers in advancing CRC treatment.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome.

PURPOSE: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes. EXPERIMENTAL DESIGN: Using single nucleotide polymorphism-based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome. RESULTS: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the "cell death" network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets. CONCLUSIONS: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma.

Abnormalities on 1q and 7q are associated with poor outcome in sporadic Burkitt's lymphoma. A cytogenetic and comparative genomic hybridization study.

Comparative genomic hybridization (CGH) studies have demonstrated a high incidence of chromosomal imbalances in non-Hodgkin's lymphoma. However, the information on the genomic imbalances in Burkitt's Lymphoma (BL) is scanty. Conventional cytogenetics was performed in 34 cases, and long-distance PCR for t(8;14) was performed in 18 cases. A total of 170 changes were present with a median of four changes per case (range 1-22). Gains of chromosomal material (143) were more frequent than amplifications (5) or losses (22). The most frequent aberrations were gains on chromosomes 12q (26%), Xq (22%), 22q (20%), 20q (17%) and 9q (15%). Losses predominantly involved chromosomes 13q (17%) and 4q (9%). High-level amplifications were present in the regions 1q23-31 (three cases), 6p12-p25 and 8p22-p23. Upon comparing BL vs Burkitt's cell leukemia (BCL), the latter had more changes (mean 4.3 +/- 2.2) than BL (mean 2.7 +/- 3.2). In addition, BCL cases showed more frequently gains on 8q, 9q, 14q, 20q, and 20q, 9q, 8q and 14q, as well as losses on 13q and 4q. Concerning outcome, the presence of abnormalities on 1q (ascertained either by cytogenetics or by CGH), and imbalances on 7q (P=0.01) were associated with a short survival.

The detection of contaminating clonal cells in apheresis products is related to response and outcome in multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

In the present paper, we report on the use of the heteroduplex PCR technique to detect the presence of clonally rearranged VDJ segments of the heavy chain immunoglobulin gene (VDJH) in the apheresis products of patients with multiple myeloma (MM) undergoing autologous peripheral blood stem cell (APBSC) transplantation. Twenty-three out of 31 MM patients undergoing APBSC transplantation with VDJH segments clonally rearranged detected at diagnosis were included in the study. Samples of the apheresis products were PCR amplified using JH and VH (FRIII and FRII) consensus primers and subsequently analyzed with the heteroduplex technique, and compared with those obtained at diagnosis. 52% of cases yielded positive results (presence of clonally rearranged VDJH segments in at least one apheresis). The presence of positive results in the apheresis products was not related to any pretransplant characteristics with the exception of response status at transplant. Thus, while no one patient with positive apheresis products was in complete remission (CR), negative immunofixation, before the transplant, five cases (46%) with negative apheresis were already in CR at transplant (P = 0.01). The remaining six cases with heteroduplex PCR negative apheresis were in partial remission before transplant. Patients with clonally free products were more likely to obtain CR following transplant (64% vs 17%, P= 0.02) and a longer progression-free survival, (40 months in patients transplanted with polyclonal products vs 20 with monoclonal ones, P = 0.03). These results were consistent when the overall survival was considered, since it was better in those patients with negative apheresis than it was in those with positive (83% vs 36% at 5 years from diagnosis, P= 0.01). These findings indicate that the presence of clonality rearranged VDJH segments is related to the response and outcome in MM transplanted patients.