A phase I study of temozolomide and lapatinib combination in patients with recurrent high-grade gliomas

We undertook this phase I study to investigate the feasibility of the combination of temozolomide (TMZ) and lapatinib (LP) and to define the maximum tolerated dose (MTD) of LP in patients with relapsed high-grade gliomas. Eligible patients were enrolled in this dose escalation study of LP. TMZ was administered at a fixed dose of 200 mg/m² d1–d5 every 28 days. Starting dose of LP was set at 1,000 mg daily continuously, escalated by 250 mg in cohorts of minimum three patients. Translational research investigations were also undertaken in available biopsy material. Between January 2009 and December 2010, 16 patients were entered into the study at three LP levels: 1,000 mg sid (11 patients), 1,250 mg sid (4 patients) and 1,500 mg sid (1 patient). A total of 55 cycles had been delivered. Fourteen patients had stopped treatment because of disease progression, and two because of toxicity. Three patients received 10, 11 and 17 cycles of treatment. Dose-limiting hematological toxicity was observed in 2 patients at the second LP dose level of 1,250 mg sid. MTD was defined at LP 1,000 mg sid. Median progression-free survival (PFS) and survival were 2.4 and 5.9 months, respectively. EGFR amplification and EGFRvIII expression were not related to PFS. Combination of TMZ and LP is feasible with manageable toxicity. The activity of this combination in patients with recurrent glioblastoma multiforme is further investigated in a recently initiated phase II trial.     

Polyacrylamide hydrogel (Bulkamid®) for stress urinary incontinence in women: a systematic review of the literature

Introduction and hypothesis

Polyacrylamide hydrogel (PAHG, Bulkamid®) is one of several injectable agents currently used for the treatment of women with urinary stress incontinence. Although bulking agents appear to have lower efficacy rates compared to other surgical treatments, current evidence based on large prospective or comparative studies as well as systematic reviews is limited. The purpose of this study was to conduct a systematic review on the efficacy of PAHG in the treatment of female patients with stress urinary incontinence with regard to reproducibility, feasibility, safety and clinical outcome.

Methods

We searched MEDLINE (1966–2015), Scopus (2004–2015), POPLINE (1974–2015) and ClinicalTrials.gov (2008–2015) along with reference lists of electronically retrieved studies. Observational studies, prospective, retrospective and randomized controlled studies were included. Two reviewers independently selected studies, assessed the risk of bias and tabulated data to structured forms.

Results

We included 8 studies, which enrolled a total of 767 patients who received treatment with PAHG. We found that 186 of 767 women (24.3 %, range 12–35 %) required reinjection in order to achieve adequate efficacy. The most frequent adverse effects were pain at the site of injection (4–14 %) and urinary tract infections (3–7 %). Both the number of incontinence episodes/24 h and the number of ml/24 h were significantly reduced 1 year following treatment and the quality of life of patients was significantly improved.

Conclusions

PAHG is a safe intervention for treating women with stress urinary incontinence, but repeat injections are often required. Further research is mandated in the field in order to compare its efficacy to other bulking agents.

     

Quality of life outcome of critical care survivors eighteen months after discharge from intensive care

Aim

To assess the changes in health-related quality of life in patients discharged from the intensive care unit (ICU).

Methods

At the General University ICU, Trauma Hospital in Athens, 242 patients were enrolled prospectively over a study period of 18 months. Out of these, 116 participants (47.9%) completed all survey components at 6, 12, and 18 months. We used Quality of Life-Spanish (QOL-SP) to assess the health-related quality of life. Patients or their relatives were interviewed on ICU admission and at 6, 12, and 18 months after discharge from the ICU.

Results

Mean quality of life score of the patients increased from 2.9 ± 4.8 (out of maximum 25 points) on ICU admission to 7.0 ± 7.2 points at 6 months after discharge, and then decreased to 5.6 ± 6.9 points at 18 months (P<0.001; Friedman test). Multilinear regression analysis showed that the variables which had the strongest association with the quality of life on admission were age (P = 0.002) and male sex (P = 0.001), whereas age (P<0.001), length of ICU stay (P<0.001), and male sex (P = 0.002) had the strongest association 18 months after discharge from the ICU. Survival rate was 66.9% at discharge from ICU and 61.6% at hospital discharge. There were 33% deaths in the ICU, 5.3% in the hospital, and 6.2% after ICU discharge. There were 7.4% patients lost to follow-up.

Conclusions

After discharge from the ICU, patients’ quality of life was poor and showed an improvement at 18 months after discharge, but was still worse than on admission. Age, ICU length of stay, and male sex were the factors that had the strongest impact on the quality of life on admission and at 18 months after discharge from the ICU.The cost of intensive care and limited resources directed to patients with a poor prognosis raise questions about the utilization of such resources. Since the need for intensive care in several countries exceeds its availability (1), intensive care specialists are forced to admit those patients who will benefit most. There is an increasing pressure that the assessment of long-term survival and quality of life of survivors should be incorporated into outcome evaluation of intensive care unit (ICU) (2).Instruments for assessing quality of life in critically ill patients surviving intensive care include EuroQol-5D (EQ-5D), Nottingham Health Profile (NHP), Sickness Impact Profile (SIP), Medical Outcomes Study 36-item Short Form (SF-36), and Quality Of Life-Spanish (QOL-SP) (3). These instruments aim to evaluate the aspects of health important for all patients. Several cross-sectional studies have used generic, multidimensional quality of life instruments to compare health-related quality of life of intensive care patients with the that of the general population and found a considerable deterioration in the former group (3,4). However, such evidence may be misleading if pre-hospitalization health-related quality of life is not taken into account.Quality of life is an important endpoint in assessing long-term results of intensive care, but the ideal timing for such an assessment is still unclear. This topic has been covered in some reports dealing with pre-ICU assessment of health-related quality of life (3). QOL-SP questionnaire, developed by Fernandez et al (5), is specifically designed for critically ill patients. This is one of the few instruments that have been validated in a critical care population, but it is neither widely used nor well known in the critical care community. A few studies have used QOL-SP to assess medical (6), surgical (7), or multiple trauma patients (8), and to measure the quality of life before ICU, as well as the changes in quality of life from baseline to 6 and 24 months.Despite its limitations, we used this instrument to assess the changes in health-related quality of life in people who survived critical illness in a Greek medical-surgical ICU at 6, 12, and 18 months after ICU discharge, and to compare these data with their pre-admission status.     

Melanin precursor 5,6-dihydroxyindol: protective effects and cytotoxicity on retinal cells in vitro and in vivo

5,6-dihydroxyindole (DHI) is a melanin pigment precursor with antioxidant properties. In the light of a report about cytotoxicity of DHI, the aim of this study was to assess possible toxic effects of DHI on cells related to the eye, such as human ARPE-19 cells and mouse retinal explants. Moreover, DHI was tested on its effects on retinal function in vivo using electroretinography. We found cytotoxicity of DHI against ARPE-19 cells at 100 microM, but not at 10 microM. 10 microM DHI exhibited a slight, though not significant protective activity against UV-A damage in ARPE-19 cells. We found cytoprotection in cultured mouse retinas by 50 microM DHI or its diacetylated derivative 5,6-diacetoxyindole (DAI), respectively. In ERG measurements in vivo, amplitudes were decreased only slightly by 100 microM DHI compared to saline, whereas a better preservation of amplitudes was visible at 10 microM DHI, in particular with respect to cones. In histological sections, more cones were found at 10 microM DHI than at 100 microM DHI. As a conclusion, DHI shows a slight protective effect at 10 microM both in vitro and in vivo. At 100 microM, it shows a strong cytotoxicity in vitro, which is strongly reduced in vivo.     

Health visitors' perceptions on their role to assess and manage postpartum depression cases in the community

The present study gives an insight into the health visitors' perceptions on their role in assessing, managing, and supporting mothers with postpartum depression (PPD). The study took place in Cyprus among health visitors of a community Maternity and Child Welfare Clinic using qualitative approach. Data were collected through individual semistructured interviews. The findings showed that although health visitors are able to identify PPD cases, they stress the importance of protocols and evidence‐based care as well as preventive interventions, and they also point out the importance of home visits. Finally, they support the need for education. It is concluded that health visitors can play an important role in women's health and their intervention on the prevention of PPD in the community especially through home visits is very important.     

Long-term follow-up of children with risk organ-negative Langerhans cell histiocytosis after 2-chlorodeoxyadenosine treatment

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO−) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO− LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3–19·7 years) and the median follow-up after was 5·4 years (range, 0·6–15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO− LCH. Appropriate management of induced immune deficiency is mandatory.