Improving the efficacy of cancer immunotherapy.

A series of cancer vaccines have been evaluated in clinical trials with encouraging results, but the demonstration of clinical benefit in confirmatory studies has so far proven to be difficult. The development of cancer vaccines is hampered by a range of issues particular to this field of research. On 12th March 2008, the Biotherapy Development Association convened a workshop to discuss issues faced by scientists and clinicians involved in the development of cancer vaccines. This paper is a review of the field, based on discussions held at the BDA workshop, and describes biological barriers encountered in generating effective immune responses to tumours, methodological obstacles encountered in the improvement of immunological monitoring which aims to improve inter-laboratory and inter-trial comparisons, challenges in clinical trial design and problems posed by the lack of specific regulation for cancer vaccines and the impact on their development. Ultimately, a number of general solutions are posed: (1) better patient selection, (2) use of multi-modal treatments that affect several aspects of the immune system at once, (3) a requirement for the development of good biomarkers to stratify patients for selection prior to trial and as surrogates for clinical response and (4) harmonisation of SOPs for immunological monitoring of clinical trials.

Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products.

Dendritic cell (DC) active immunotherapy is potentially efficacious in a broad array of malignant disease settings. However, challenges remain in optimizing DC-based therapy for maximum clinical efficacy within manufacturing processes that permit quality control and scale-up of consistent products. In this review we discuss the critical issues that must be addressed in order to optimize DC-based product design and manufacture, and highlight the DC based platforms currently addressing these issues. Variables in DC-based product design include the type of antigenic payload used, DC maturation steps and activation processes, and functional assays. Issues to consider in development include: (a) minimizing the invasiveness of patient biological material collection; (b) minimizing handling and manipulations of tissue at the clinical site; (c) centralized product manufacturing and standardized processing and capacity for commercial-scale production; (d) rapid product release turnaround time; (e) the ability to manufacture sufficient product from limited starting material; and (f) standardized release criteria for DC phenotype and function. Improvements in the design and manufacture of DC products have resulted in a handful of promising leads currently in clinical development.

The use of seclusion is not evidence-based practice.

TOPIC: Published articles on the use of seclusion in psychiatric care. PURPOSE: To present the argument that the use of seclusion in the psychiatric care of children is not evidence-based practice. SOURCES: Review of the scientific study literature of the last 30 years on the use of seclusion. CONCLUSIONS: The scientific evidence available illustrates that the use of seclusion with children is not therapeutic and is, in fact, harmful to patients.

[Epigenetic markers in migrating population burial sites of the Mid-Elbe-Saale area]. / Untersuchung epigenetischer Merkmale an völkerwanderungszeitlichen Gräberfeldern des Mittelelbe-Saale-Gebietes.

The distribution of 122 epigenetic traits of the cranium and the postcranial skeleton (180 skeletal individuals) of six sites of the period of the Middleelbe-Saale-Region was analyzed. Based on these frequencies and using the method of biodistance analysis (MMD after Sjøvold 1973) the relationships of these population groups were investigated which are different concerning their geographical origin. The results did not show distinct differences between these groups, but suggested a possible homogeneity of our populations.

Alcohol and drug use of inter-city versus rural school age children.

The purpose of this study of seventy-nine children was to determine: 1) the prevalence and type of substance use in inter-city and rural eight to twelve-year-old children; and 2) the relationships between child substance use, self-esteem, peer substance use, and family climate. The conceptual framework for the study was a modification of Kumpfer and Turner's Social Ecology Model (1991). Nineteen percent of the children had used alcohol or drugs. Thirty-three percent of the children acknowledged having friends who used substances. Inter-city children reported more alcohol and marijuana use, while the rural children reported more use of inhalants. The responses of both inter-city and rural children also indicated that there were problems with substance use and family violence in the home. Self-esteem and affiliation with drug using peers were significantly correlated with substance use of the child.

[Is head size modified by environmental factors?]. / Werden Kopfmasse von Umweltfaktoren beeinflusst?

In the article the development of skull measurements and head measurements (length and breadth) and of the cephalic index, calculated from these measurements, since the Neolithic period are presented. The results obtained from the historical material are compared with those of living persons. The measurements as well of the skull as of the head show secular changes. The following general trend was found: an increase of body height is connected with a debrachycephalisation and a decrease of body height is connected with a brachycephalisation. It can be emphasized that brachycephalisation/debrachycephalisation are part of the secular trend. Therefore environmental factors are responsible for the described changes of measurements of the skull and the head in a broadest sense.

Secretory type II phospholipase A2 (PLA2G2A) expression status in colorectal carcinoma derived cell lines and in normal colonic mucosa.

There is good evidence now that the secretory type II phospholipase A2 (Pla2g2a) gene represents the Mom1 locus, a genetic modifier of tumor resistance in the multiple intestinal neoplasia (Min) mouse. Previously we have mapped the human homolog PLA2G2A to 1p35-36.1 within a region that is the target of frequent deletions in sporadic colorectal tumors. Here we show 64% loss of heterozygosity (LOH) at the PLA2G2A locus in primary tumors. We studied PLA2G2A expression in both colorectal tumor cell lines and normal mucosa. Most of the lines lacked detectable PLA2G2A transcripts by Northern analysis. Large differences in expression were seen among normal mucosa of different patients with sporadic tumors. We analysed the coding region of PLA2G2A in eight colorectal cancer cell lines with hemizygous deletion at 1p35-36/PLA2G2A, in none we did detect a mutation. Biallelic expression of PLA2G2A was observed in a cell line heterozygous for an exon 3 polymorphism, rendering unlikely that imprinting is a pathway participating in the loss of PLA2G2A function. It remains uncertain if PLA2G2A, in particular its apparent lack of expression in tumor cells, might be a factor in human colorectal tumorigenesis.

[Secular trend in body height since the Neolithic period]. / Säkularer Trend bei der Körperhöhe seit dem Neolithikum.

The body height of children and adults is estimated on the basis of skeleton material from the middle Elbe-Saale region since the Neolithic period. The men's body height was calculated according to Breitinger (1938), the women's body height according to Bach (1965), and the children's body height according to Telkkä et al. (1962). These estimates are compared with the mean body height of living persons from the adult population and of Jena schoolchildren, respectively. These are the following essential results: 1. Since 7000 years ago changes of body height can be observed. There was an increase of the mean body height from the Neolithic period until the Bronce age. In the A.D. era no clear changes of the average values can be found until about the 12th century, after which there occurred decreases seen until the 19th century. 2. The greatest secular trends in children and adults arise in our century. 3. The influence of different environmental factors on the body height in past and present is discussed and the sex-specific reactions to changes of these environmental factors are described. 4. It is pointed out that social, and/or geographic influences can cause changes of the body height calculated from skeleton material.

An interstitial tandem duplication of 9p23-24 coexists with a mutation in the BRCA2 gene in the germ line of three brothers with breast cancer.

Germ-line mutations of the BRCA2 gene account for the majority of families with both male and female breast cancer. However, among independently ascertained families with the same mutation, cases of male breast cancer often appear to cluster in a single family or in a particular branch of one family. This suggests that the risk of male breast cancer conferred by BRCA2 mutations may be modified by other genetic or environmental factors. We report a family in which three brothers with breast cancer carry in their germ line two genetic abnormalities: an insertion A at nucleotide 2041 in exon 10 of BRCA2, which leads to premature termination of the encoded protein at codon 615, and a tandem interstitial duplication involving chromosome bands 9p23-24. We propose that the coexistence of this rare chromosomal abnormality with BRCA2 mutation may be augmenting the risk of male breast cancer conferred by the BRCA2 mutation.

Expression of CD44 standard and isoforms in human breast cancer xenografts and shedding of soluble forms into serum of nude mice.

Standard CD44 (CD44s) and variant isoforms (CD44v) are expressed on different malignant cells and tissues. Their upregulation has been implicated, in the progression and metastasis of malignomas. In this work we addressed the question of whether these molecules are also expressed on xenografted human breast carcinomas and if certain expression patterns are correlated with biological parameters like tumour size, hormone receptor status, histology, growth rate, chemoresistance and microenvironment. Additionally, we were interested in the shedding of soluble CD44 (sCD44) into the blood circulation of tumour bearing nude mice. The human breast carcinomas MCF-7, MCF-7/ADR, 4296 and MDA-MB435, 4134 and 4151 were transplanted subcutaneously (sc.) or into the mammary fat pad (mfp.) of nude mice. The expression of the CD44s, -v6, and -v9 isoforms was determined at different time points on tissue samples by immunohistochemistry or RT-PCR employing human-specific antibodies or primers, respectively. The serum concentration of CD44s and -v6 was measured by human specific ELISAs. All tumours expressed CD44s. The lowest level was observed in the MCF-7 cancer. The CD44v6 and -v9 sequences and epitopes were distinctly expressed in MCF-7/ADR. MDA-MB435, 4134, 4151 and 4296, while MCF-7 lacked these isoforms. The highest serum concentration of the v6 isoform was detected in mice bearing the tumour 4296 with a high tendency for lymphogenic metastasis. The serum levels of sCD44 were in 5/6 xenografts linearly correlated with the tumour size. Interestingly, there was a remarkable difference between the two sublines MCF-7 and MCF-7/ADR: Both the tissue and serum levels of CD44 isoforms indicated that the development of multidrug resistance is accompanied by an alteration in the expression of membrane proteins discussed to be involved in metastasis. There was no relation of tissue expression with the transplantation site and the hormone receptor status of the tumour lines. CD44s and its variant isoforms are expressed in human xenotransplanted breast cancers in very different levels and patterns. The highest expression in the tumour 4296 is related to lymphogenic metastasis while the absence of isoforms in the model MCF-7 is related to non-metastatic behaviour. CD44 is shed into the serum and can be used for monitoring of tumour growth.

Factors in childhood drug and alcohol use: a review of the literature.

TOPIC: Drug and alcohol use in children. PURPOSE: To identify the prevalence of drug and alcohol use in children 12 and younger and the factors associated with this use. SOURCE: A review of the literature. CONCLUSIONS: The identified factors include: a) differences in use between boys and girls; b) influence of family members' drug and alcohol use; c) influence of peers; d) the child's self-esteem; and e) the child's knowledge about drug and alcohol use. Awareness by child psychiatric nurses of the identified factors is crucial to prevent, assess, and treat the problem of drug and alcohol use by children.

Nurses referred to a peer assistance program for alcohol and drug problems.

Investigation into nurses referred to peer assistance programs for substance abuse is essential to program development and the development of primary prevention strategies. The purpose of this study was to (1) describe the characteristics, substance use, and program participation of 221 nurses referred to a state nursing organization peer assistance program, and (2) identify factors associated with program participation. The highest percentage of nurses (63%) used narcotics; 36% had diverted drugs from patients for their own use. Sixty-four percent of the referred nurses successfully completed the program. This model was found to be effective in addressing substance abuse in nursing.

Drug and alcohol use of school-age children in a rural community.

Drug abuse affects the physical and psychological well-being of the user as well as creating heavy societal costs--which are amplified if the user is a child. This study examined the relationship between drug and alcohol use and self-esteem, school climate, peer effects, and family climate among a small sample of fourth graders in a rural community.

Intracompartmental pressure during hyperthermic isolated limb perfusion for melanoma and sarcoma.

Side effects of isolated limb perfusion (ILP) include rhabdomyolysis, paresthesia, or nerve palsy. The increase in intracompartmental pressure during ILP is thought to be linked to neuro- and muscular toxicity, and fasciotomy is recommended for protection. In 24 patients, intracompartmental pressure was measured. A flexible 5 F probe was placed into the non-tumour-bearing compartment of the perfused limb. Interstitial fluid pressure was measured using a piezoresistant tip. Compartmental pressure values were continuously recorded during and after ILP. The drugs used were a combination of doxorubicin, cisplatinum and melphalan or rhTNF-alpha combined with melphalan. The median overall compartmental pressure prior to ILP was 13 mmHg (range: 11-21 mmHg); during the heat-up phase the median pressure rose to 28 mmHg. During therapeutic perfusion a further increase could be documented and the maximum pressure measured was 90 mmHg; the median of the pressure maxima of all patients was 34 mmHg. During wash-out, at the end of the perfusion, a clear reduction in compartment pressures could be observed and the median dropped to a value of 27 mmHg. In all patients a continuous decrease in compartmental pressure could be recorded, reaching the pre-ILP values by 48 h post-operatively. A dramatic increase in compartmental pressure during ILP can be observed by continuous monitoring. Because of our observation that during the wash-out phase elevated compartmental pressures return to normal, there is no general indication for a fasciotomy. However, for patients maintaining a peak compartmental pressure above a critical threshold of 35 to 40 mmHg fasciotomy may be indicated.