Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT.

Assessment of oncology patients' satisfaction from intravenous chemotherapy.

PURPOSE: To assess patient satisfaction from chemotherapy and investigate the effect of demographic factors, disease symptoms and treatment on satisfaction. METHODS: A non-randomized cross-sectional survey was conducted on a sample of 100 patients undergoing chemotherapy at "Metaxa" Cancer Hospital, Piraeus, Greece for 6 months. A demographic data questionnaire, a Cancer Treatment Satisfaction Questionnaire (CTSQ) and visual analog scales were used to evaluate pain, anxiety, fatigue, and nausea while presence or absence of vomit were also assessed. RESULTS: The majority of the patients in the sample were men (51%), with a mean age of 58.5 ± 10.82 years. The mean value of expectations from treatment was 60.55, from treatment's satisfaction was 75.86 and from feelings about treatment's side effects was 44.56. The most serious symptoms were fatigue and anxiety (7.2 ± 1.95 and 6.71 ± 2.5, respectively). Statistical tests have shown that sub-dimensions of CTSQ are associated with pain, anxiety, fatigue, and nausea. CONCLUSIONS: Generally, chemotherapy meets patients' expectations with cancer. Symptoms such as fatigue, anxiety, pain, and nausea affect their satisfaction. Treatment's satisfaction can be improved by evaluating symptoms, which will lead to appropriate interventions.

Correction to: Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

The published version of the article unfortunately contained a mistake.

Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

BACKGROUND: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.

Assessment of quality of life of children and adolescents with cancer during their treatment.

OBJECTIVE: The purpose of this study was to evaluate the quality of life of children and adolescents with any type of cancer in all phases of their treatment. METHODS: Fifty-six newly diagnosed patients diagnosed with malignancy and hospitalized in a Pediatric Hematology-Oncology Unit in Athens were included in the study. Minneapolis-Manchester Quality of Life Instrument was used for data collection from July 2010 to December 2012. The assessment of children and adolescents' quality of life who were under treatment was performed in three different stages of treatment. RESULTS: The results of the study showed that the quality of life of children and adolescents with cancer did not change notably during their treatment (F = 0.16, P = 0.86 and F = 0.03, P = 0.97). For the first measurement, at the beginning of the therapy, the score on the scale for quality of life for children and adolescents was 3.44 and 3.88, respectively, in the middle of the treatment 3.36 and 3.89, respectively, and 3.43 and 3.89, respectively, when therapy was completed. Children and adolescents diagnosed with hematologic cancer stated higher quality of life scores (z = -1.61, P = 0.05 and t = 2.64, P = 0.007). Moreover, teenage patients (F = 13.22, P = 0.001) and male patients (t = 2.31, P = 0.02 and t = 2.27, P = 0.02) expressed better quality-of-life scores. CONCLUSION: According to the results, children and adolescents with any kind of cancer have better quality-of-life scores at the end of their treatment, and when they are supported by their family.

Using Bonferroni, BIC and AIC to assess evidence for alternative biological pathways: covariate selection for the multilevel Embryo-Uterus model.

BACKGROUND: IVF treatments for infertility involve the transfer of multiple embryos in any one treatment cycle. When data is available on individual embryos the outcomes of each embryo are only partially observed, as treatment outcome (live birth) is assessed at the patient level. Two-level Embryo-Uterus (EU) models have been developed which assume a biologically plausible mechanism and assume that effects are mediated directly through the embryo (E) and also through the uterine environment (U), represented by two sub-models. This approach potentially allows inference as to the association of patient variables with outcome. However, when the variable is measured at the patient level either additional decisions have to be made in the modelling process as to in which sub-model the variable should be included or some model selection algorithm has to be invoked. These uncertainties have limited the practical application of these models. METHODS: We have conducted simulation studies based around realistic parameter values of situations where a putative patient-level variable is being considered for inclusion in an EU model and/or the mechanistic interpretation from the sub-model assignment is of interest. Firstly we explore various strategies for inference for a variable of interest where the sub-model is either pre-specified or considered unknown. Secondly we explore the use of information criteria to select the appropriate sub-model and the strength of evidence for that assignment. These are demonstrated in a reanalysis of a previously published dataset. RESULTS: In the absence of prior evidence for potential prognostic factors measured at the patient level, two single degree-of-freedom likelihood ratio tests with a Bonferroni correction including the variable of interest in first the E then the U sub-model performs well as a statistical test for association with outcome. For model building the information criteria can be used, but large differences are required (≥ 6) to provide reasonable evidence of sub-model assignment. Previous interpretations have been over-optimistic. CONCLUSIONS: These results suggest simple strategies and should enable these models to be used more confidently in practical applications.

Embryo morphology as a predictor of IVF success: an evaluation of the proposed UK ACE grading scheme for cleavage stage embryos.

This study aims to provide a first evaluation of the morphological embryo grading scheme proposed in the British Fertility Society and Association of Clinical Embryologist joint guidelines for elective single embryo transfer. Pregnancy data were obtained from a cohort of patients treated at St. Mary's Hospital in Manchester, UK, between April 2007 and July 2009. Embryo morphology was assessed on day 2 or 3 prior to transfer in terms of 3 parameters: cell number, fragmentation and evenness. Cell number was parameterised as a growth rate (doublings/day). An embryo-uterus model with adjustment for other prognostic factors was used to determine the role of the three components as predictors of pregnancy. Embryo growth rate (p < 0.001) and fragmentation (p = 0.004) were strong predictors of pregnancy and after including these, evenness did not improve the prediction significantly (p = 0.39). Normally growing embryos have a higher implantation rate than slow and fast-growing embryos. The grading scheme has proved to be feasible and robust in routine clinical practice. Based on this single-centre retrospective series we propose a selection algorithm for day 2/3 embryos based on fragmentation and growth rate. The 3 parameter grading scheme has the potential for further discrimination as larger datasets become available.

The non-independence of treatment outcomes from repeat IVF cycles: estimates and consequences.

BACKGROUND: It is generally acknowledged that the outcomes of IVF treatments are correlated between repeat cycles in the same couple and that these effects need to be allowed for in the analysis of such treatments. However, there are few studies that have attempted to estimate the magnitude of these effects or their clinical consequences. METHODS: We use the embryo-uterus model, extended to include inter-cycle correlations in both the embryo and uterine components to estimate these effects in a large data set of 12 480 embryo transfer cycles from 8768 UK IVF patients, including embryo grading parameters. Empirical Bayes estimates are used to predict the consequences of previous cycle failures on the prognosis of future cycles. RESULTS: Statistically and clinically significant correlations can be detected which amount to a median odds ratio of 2.3 (95% CI: 1.8-2.9) in the chances of an embryo being viable between any two randomly selected patients. These act predominantly through the embryo component of the model. Inclusion of these effects in the embryo model does alter the estimates and predictions, but not dramatically. Around 10 cycle failures are required to reduce the probability of success in future cycles to half that of the initial cycle. CONCLUSIONS: There are important inter-cycle correlations between embryos transferred across different cycles from the same patients, implying substantial unmeasured prognostic embryo characteristics. The implications for extended culture and cryopreserved embryos need further investigation as well as similar consideration of the other components of treatment, particularly response to stimulation. Although these effects should not be ignored they have limited impact in the development of predictive models for individual cycles, but do need to be accounted for when considering multiple cycle treatment programmes. For individual patients the failure of one or several embryo transfers does not have a big impact on the chances of success in future cycles. The magnitude of the correlations suggests that for any individual couple, previous cycle implantation failures do not imply a greatly reduced prognosis for future cycles.