Value of a 21-gene expression assay on core biopsy to predict neoadjuvant chemotherapy response in breast cancer: systematic review and meta-analysis.

BACKGROUND: A recurrence score based on a 21-gene expression assay predicts the benefit of adjuvant chemotherapy in oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This systematic review aimed to determine whether the 21-gene expression assay performed on core biopsy at diagnosis predicted pathological complete response (pCR) to neoadjuvant chemotherapy. METHODS: The study was performed according to PRISMA guidelines. Relevant databases were searched to identify studies assessing the value of the 21-gene expression assay recurrence score in predicting response to neoadjuvant chemotherapy in patients with breast cancer. The Newcastle-Ottawa Scale was used to assess the quality of the studies. Results are reported as risk ratio (RR) with 95 per cent confidence interval using the Cochrane-Mantel-Haenszel method for meta-analysis. Sensitivity analyses were carried out where appropriate. RESULTS: Seven studies involving 1744 patients reported the correlation between pretreatment recurrence score and pCR. Of these, 777 patients (44.6 per cent) had a high recurrence score and 967 (55.4 per cent) a low-intermediate score. A pCR was achieved in 94 patients (5.4 per cent). The pCR rate was significantly higher in the group with a high recurrence score than in the group with a low-intermediate score (10.9 versus 1.1 per cent; RR 4.47, 95 per cent c.i. 2.76 to 7.21; P < 0.001). A significant risk difference was observed between the two groups (risk difference 0.10, 0.04 to 0.15; P = 0.001). CONCLUSION: A high recurrence score is associated with higher pCR rates and a low-intermediate recurrence score may indicate chemoresistance. Routine assessment of recurrence score by the 21-gene expression assay on core biopsy might be of value when considering neoadjuvant chemotherapy in patients with ER-positive, HER2-negative breast cancer.

Do not resuscitate orders and the cost of death.

BACKGROUND: The appropriate role of cardiopulmonary resuscitation in the hospital continues to be a topic of interest to physicians and patients alike. The use of do not resuscitate (DNR) orders reflects a growing expression of autonomy by patients to refuse medical treatment, and also a growing recognition of its futility in many circumstances by physicians. Although it has been suggested that wider use of advance directives will lead to a reduction in health care costs near the end of life, little empiric data exist to support this prediction. This study was designed to ascertain the rates of DNR orders and their associated costs. METHODS: A retrospective chart review was conducted on the hospital records of 852 of 953 hospital deaths that occurred in a referral hospital. Data were collected on resuscitation status, timing of DNR orders, participants in decision making, and physician and hospital charges. RESULTS: Of the 852 records reviewed, 625 (73%) had a DNR order at the time of death. The use of DNR orders for patients who died ranged from 97% of those on an oncology service to 43% of deaths on cardiology services. One hundred seven patients (17%) had the DNR order before admission. Of 512 patients who had a new DNR order in the hospital, approval was obtained from the patient in only 19%. Patients who died with a DNR order had longer hospital stays (median, 11.0 days) compared with those who died without a DNR order (6.0 days). The time from DNR order to death was 2 days overall with 2.0 days for medical patients and 1.0 day for surgical patients. Average charges for each patient who died were $61,215 with $10,631 for those admitted with a DNR order, and $73,055 for those who had a DNR order made in hospital. CONCLUSION: This study demonstrates high variability in the use of DNR orders between various medical and surgical services. These range from a high of 98% on an oncology service to a low of 43% on cardiology. Most patients have a DNR order at the time of death, but these typically occur late in the course of the hospital stay. Death in the hospital is costly and total hospital and professional charges are significantly lower when a patient is admitted with an established nonresuscitation order compared with those for whom a DNR is established while in the hospital. This study provides a basis against which to measure the impact of efforts such as the Patient Self-Determination Act of 1990 to increase the use of advance directives, as well as monitor their effect on health care expenditures.

Nutritional stunting in Egypt: which nutrient is responsible?

We looked at the relationship between linear growth retardation and deficiencies of certain nutrients in Egyptian children. A group of 107 stunted children aged between 10 and 18 years were subjected to history-taking, physical examination and laboratory investigations. Selected cases were referred to radiology for assessment of bone age. Thirty-nine children were enrolled as controls. Serum haemoglobin, alpha-tocopherol, retinol and magnesium levels were significantly decreased in stunted children compared with the controls. Serum zinc levels were also lower in the stunted group but not significantly so. We conclude that several nutrient deficiencies occur simultaneously in stunted children and all of them may be responsible for stunting.

Transport of Escherichia coli in 25 m quartz sand columns.

To help improve the prediction of bacteria travel distances in aquifers laboratory experiments were conducted to measure the distant dependent sticking efficiencies of two low attaching Escherichia coli strains (UCFL-94 and UCFL-131). The experimental set up consisted of a 25 m long helical column with a diameter of 3.2 cm packed with 99.1% pure-quartz sand saturated with a solution of magnesium sulfate and calcium chloride. Bacteria mass breakthrough at sampling distances ranging from 6 to 25.65 m were observed to quantify bacteria attachment over total transport distances (α(L)) and sticking efficiencies at large intra-column segments (α(i)) (>5m). Fractions of cells retained (F(i)) in a column segment as a function of α(i) were fitted with a power-law distribution from which the minimum sticking efficiency defined as the sticking efficiency of 0.001% bacteria fraction of the total input mass retained that results in a 5 log removal were extrapolated. Low values of α(L) in the order 10(-4) and 10(-3) were obtained for UCFL-94 and UCFL-131 respectively, while α(i)-values ranged between 10(-6) to 10(-3) for UCFL-94 and 10(-5) to 10(-4) for UCFL-131. In addition, both α(L) and α(i) reduced with increasing transport distance, and high coefficients of determination (0.99) were obtained for power-law distributions ofα(i) for the two strains. Minimum sticking efficiencies extrapolated were 10(-7) and 10(-8) for UCFL-94 and UCFL-131, respectively. Fractions of cells exiting the column were 0.19 and 0.87 for UCFL-94 and UCL-131, respectively. We concluded that environmentally realistic sticking efficiency values in the order of 10(-4) and 10(-3) and much lower sticking efficiencies in the order 10(-5) are measurable in the laboratory, Also power-law distributions in sticking efficiencies commonly observed for limited intra-column distances (<2m) are applicable at large transport distances(>6m) in columns packed with quartz grains. High fractions of bacteria populations may possess the so-called minimum sticking efficiency, thus expressing their ability to be transported over distances longer than what might be predicted using measured sticking efficiencies from experiments with both short (<1m) and long columns (>25 m). Also variable values of sticking efficiencies within and among the strains show heterogeneities possibly due to variations in cell surface characteristics of the strains. The low sticking efficiency values measured express the importance of the long columns used in the experiments and the lower values of extrapolated minimum sticking efficiencies makes the method a valuable tool in delineating protection areas in real-world scenarios.

Modulation of human Valpha24(+)Vbeta11(+) NKT cells by age, malignancy and conventional anticancer therapies.

Immunotherapy strategies aimed at increasing human Valpha24(+)Vbeta11(+) natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following alpha-galactosylceramide (alpha-GalCer) stimulation. The percentage and absolute number of peripheral blood NKT cells was assessed in 40 healthy donors and 109 solid cancer patients (colorectal (n=33), breast (n=10), melanoma (n=17), lung (n=8), renal cell carcinoma (n=10), other cancers (n=31)). Responsiveness to alpha-GalCer stimulation was also assessed in 28 of the cancer patients and 37 of the healthy donors. Natural killer T cell numbers were significantly reduced in melanoma and breast cancer patients. While NKT numbers decreased with age in healthy donors, NKT cells were decreased in these cancer subgroups despite age and sex adjustments. Prior radiation treatment was shown to contribute to the observed reduction in melanoma patients. Although cancer patient NKT cells were significantly less responsive to alpha-GalCer stimulation, they remained capable of substantial expansion. Natural killer T cells are therefore modulated by age, malignancy and prior anticancer treatment; however, cancer patient NKT cells remain capable of responding to alpha-GalCer-based immenotherapies.

Effects of leukapheresis protocol, cell processing and cryopreservation on the generation of monocyte-derived DC for immune therapy.

BACKGROUND: Many clinical trials of DC-based immunotherapy involve administration of monocyte-derived DCs (Mo-DC) on multiple occasion. We aimed to determine tbe optimal cell processing procedures and timing (leukapheresis, RBC depletion and cryopreservation) for generation of Mo-DC for clinical purposes. METHODS: Leukapheresis was undertaken using a COBE Spectra. Two instrument settings were compared - the standard semi-automated software (Version 4.7) (n = 10) and the fully automated software (Version 6.0) (N = 40). Density gradient centrifugation using Ficoll, Percoll, a combination of these methods or neither for RBC depletion were compared. Outcomes (including cell yield and purity) were compared for cryopreserved unmanipulated monocytes and cryopreserved Mo-DC. RESULTS: Software Version 6.0 provided significantly better enrichment for monocytes (P < 0.05) but 25% fewer total monocytes. Final Mo-DC purity was not influenced by leukapheresis or RBC depletion method, but was critically dependent on monocyte adherence. Version 6.0 produced significantly lower RBC and platelet contamination (P < 0.0005) but in vitro RBC depletion could not routinely be omitted. Only 5-6% of monocytes harvested resulted in Mo-DC (95% lost in cell processing or failing to differentiate). DISCUSSION: Cell losses remained significant despite attempts to minimise processing steps during Mo-DC generation. Reduction in RBC and platelets achieved with software version 6.0 was insufficient to offset the disadvantage of the lower monocyte yield. Substantial savings in materials and other costs can be achieved if Mo-DC for multiple treatments are generated from cryopreserved monocytes rather than from fresh monocytes.

Nutritional stunting in Egypt: which nutrient is responsible?

We looked at the relationship between linear growth retardation and deficiencies of certain nutrients in Egyptian children. A group of 107 stunted children aged between 10 and 18 years were subjected to history-taking, physical examination and laboratory investigations. Selected cases were referred to radiology for assessment of bone age. Thirty-nine children were enrolled as controls. Serum haemoglobin, alpha-tocopherol, retinol and magnesium levels were significantly decreased in stunted children compared with the controls. Serum zinc levels were also lower in the stunted group but not significantly so. We conclude that several nutrient deficiencies occur simultaneously in stunted children and all of them may be responsible for stunting