The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. ...Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS).
A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models.
A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23–0.57; P < 0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41–0.73, P < 0.001) without heterogeneity (I2 = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02–3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49–2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044).
Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.
Purpose
To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC).
Methods
Non-diabetic women with HER2-negative MBC were randomized ...to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m
2
+ cyclophosphamide (C) 600 mg/m
2
× 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS).
Results
One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range IQR 24.6–50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8–10.4) in arm A and 9.9 (95% CI 7.4–11.5) in arm B (
P
= 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6–11.7) versus 8.5 (95% CI 5.8–9.7) in those with HOMA index ≥ 2.5 (
P
= 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (
P
= 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS.
Conclusions
The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.
Children with Sickle Cell Disease (SCD) show endocrine complications and metabolic alterations. The physiopathology of these conditions is not completely understood: iron overload due to chronic ...transfusions, ischemic damage, and inflammatory state related to vaso-occlusive crises may be involved. Aims of this study were to evaluate the growth pattern, endocrine complications, and metabolic alterations and to detect the relationship between these conditions and the SCD severity in affected children and adolescents.
Fifty-two children and adolescents with SCD 38 homozygous sickle hemoglobin (HbSS) and 14 heterozygous sickle hemoglobin (HbSC); age range 3-18 years were recruited. Anthropometric height, body mass index (BMI), arm span, sitting height, target height (TH), and pubertal status and laboratory blood cell counts, hemolysis indices, metabolic and nutritional status indices and hormonal blood levels data were evaluated. The SCD severity was defined according to hematological and clinical parameters.
Height-SDS adjusted for TH and BMI-SDS were significantly higher in HbSC children than in HbSS ones. Forty-eight out of 52 patients (92%) had at least one metabolic and/or endocrine alteration: insufficiency/deficiency of vitamin D (84.7%), insulin resistance (11.5%), growth hormone deficiency (3.8%), subclinical hypothyroidism (3.8%), and hypogonadism (1.9%). Levels of vitamin D were significantly and negatively correlated with clinical indicators of the SCD severity. Subjects with HbSS genotype show significant lower levels of both insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein 3 than children with HbSC. In the study population IGF-1 values were significantly and positively correlated with Hb and negatively with lactate dehydrogenase.
Metabolic alterations and endocrine complications are very common in children and adolescents with SCD. A regular follow-up is necessary to identify subjects at risk for complications to precociously start an appropriate treatment and to improve the quality of life of SCD patients.
To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments ...on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials.
We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening.
A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R(2) value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker (R(2) = 0.57) but significant.
These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.
While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for ...population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to stepwisely test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers .
While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers.
The cytokinesis-block micronucleus test (MNT), as a marker of chromosomal mutagen sensitivity, was applied in a number of studies enrolling breast cancer (BC) patients and subjects with known or ...putative genetic predisposition to BC. The large majority of them involve the evaluation of induced micronuclei (MN) frequency in peripheral lymphocytes, after the in vitro challenge with ionising radiations.
The aim of the present systematic review and meta-analysis is to investigate the role of MN assay in the identification of individuals at increased risk of BC and its potential use as prescreening test in women with a family history (FH) of BC.
Twelve studies were included in the meta-analysis, covering a time interval 1998-2007, and including 752 cases and 593 controls. Among the cases, 629 are cancer patients and 123 are cancer-free subjects, including 32 first-degree relatives of the susceptible subjects and 91 BRCA1/2 mutation carriers. Our meta-analysis reveals a significant increase of baseline MN frequency related to cancer status, but the association with FH of BC and specifically with BRCA mutations is not clear. A larger difference in MN frequency between cases and controls was observed after in vitro challenge, but response to radiation exposure doesn't appear to better discriminate cancer-susceptible subjects.
Our study suggests the presence of some bias affecting many of these studies, reinforcing the suggestion that a more rigorous study design is needed in this area.
In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and ...relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials.
Individual patient data from a large, placebo-controlled trial of interferon β-1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale EDSS) over the 2-year follow-up.
All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years.
A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS.
Background: Sentinel lymph node (SLN) staging is currently used to avoid complete axillary dissection in breast cancer patients with negative SLNs. Evidence of a similar efficacy, in terms of ...survival and regional control, of this strategy as compared with axillary resection is based on few clinical trials. In 1998, we started a randomized study comparing the two strategies, and we present here its results. Materials and methods: Patients were randomly assigned to sentinel lymph node biopsy (SLNB) and axillary dissection axillary lymph node dissection (ALND arm) or to SLNB plus axillary resection if SLNs contained metastases (SLNB arm). Main end points were overall survival (OS) and axillary recurrence. Results: One hundred and fifteen patients were assigned to the ALND arm and 110 to the SLNB arm. A positive SLN was found in 27 patients in the ALND arm and in 31 in the SLNB arm. Overall accuracy of SLNB was 93.0%. Sensitivity and negative predictive values were 77.1% and 91.1%, respectively. At a median follow-up of 5.5 years, no axillary recurrence was observed in the SLNB arm. OS and event-free survival were not statistically different between the two arms. Conclusions: The SLNB procedure does not appear inferior to conventional ALND for the subset of patients here considered.
Introduction: the purpose of this retrospective multicenter study was to assess whether the risk of developing bloodstream infections (BSI) due to carbapenem-resistant
Klebsiella pneumoniae
(CRKP) in ...colonized patients is influenced by the occurrence of BSI due to other pathogens. Methods: from January 2012 to March 2014, all patients with at least one rectal swab positive for CRKP and at least 30 days of previous hospital stay were included in the study. The primary outcome measure was CRKP BSI, defined as a time-to-event endpoint. The role of potential predictors was evaluated through univariable and multivariable Cox regression analyses, considering previous BSI as a time-dependent variable. Results: during the study period, 353 patients met the inclusion criteria. Thirty-seven developed a CRKP BSI (11%). A higher incidence of CRKP BSI was observed in presence rather than in absence of previous BSI. In the final multivariable model of risk factors for CRKP BSI, multisite colonization (hazard ratio HR 13.73, 95% confidence intervals CI 3.29–57.32,
p
< 0.001), ICU stay (HR 3.14, 95% CI 1.19–8.31,
p
= 0.021), and previous BSI (
p
= 0.026, with the overall effect being mainly due to
Enterococcus
spp. BSI vs absence of BSI, HR 6.62, 95% CI 2.11–20.79) were associated with the development of CRKP BSI, while an inverse association was observed for age (HR 0.98, 95% CI 0.95–1.00,
p
= 0.027). Conclusions: previous BSI due to other pathogens were associated with an increased risk of CRKP BSI that was independent of other factors in colonized patients with prolonged hospital exposure.
Purpose
Bloodstream infections (BSIs) are frequent after allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to identify predictors of mortality after BSI in ...patients who undergo HSCT.
Methods
Patients who underwent HSCT between 1 January 2004 and 31 January 2008 and developed BSI during the first year post-transplantation were included. Variables influencing overall mortality at 7 and 30 days after BSI were analysed.
Results
BSIs developed in 149 patients, within a median of 9 days after undergoing HSCT. Early and late mortality were 15 and 27%, respectively. Of the BSI, 54% were due to Gram-positive microorganisms, 33% were due to Gram-negative microogranisms, 10% were polymicrobial and 3% were fungal. The associated 7-and 30-day mortality was respectively 10 and 24% (Gram positive), 22 and 31% (Gram negative;
Pseudomonas aeruginosa
mortality 67%, all within 7 days), 13 and 27% (polymicrobial) and 40% (fungal, all within 7 days). Early mortality was higher in relapsed disease at HSCT (25.9%,
p
= 0.01), but lower in early (i.e. within 20 days of HSCT) BSI (11.7%,
p
= 0.03) and BSI due to Gram-positive infective agents (10%,
p
= 0.05). Multivariate analysis confirmed a higher mortality in late BSI odds ratio (OR) 3.29,
p
= 0.03 and relapsed disease at HSCT (OR 2.2,
p
= 0.04). Late mortality was associated with the type of underlying disease (OR 0.44 for diseases other than acute leukaemia,
p
= 0.05) and its status (OR 6.04 for relapse at HSCT,
p
= 0.001). Appropriate empirical therapy was associated with lower early and late mortality in single Gram-negative BSI (16 vs. 45% for 7-day mortality,
p
= 0.09; 21 vs. 64% for 30-day mortality,
p
= 0.02).
Conclusions
BSIs are frequent during the first year after HSCT and are associated with a high mortality rate. The aetiology influenced early mortality, while the type and phase of the underlying disease played a pivotal role in late mortality. Appropriate empirical therapy is crucial in BSI due to Gram-negative infective agents.
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