EMR1, the human homolog of F4/80, is an eosinophil-specific receptor

The EGF-TM7 F4/80 is a defining marker of murine macrophage populations. Applying flow cytometric analysis using the newly generated mAb A10, and quantitative real-time PCR, we here report the surprising observation that the human ortholog of F4/80, EGF-like module containing mucin-like hormone receptor (EMR)1, is absent on mononuclear phagocytic cells including monocytes, macrophages, and myeloid dendritic cells. Unexpectedly, we found that EMR1 expression is restricted to eosinophilic granulocytes, where expression is overlapping with the eotaxin receptor CCR3 and the immunoglobulin-like lectin Siglec-8. Absence on other leukocytes, including basophils, implies that EMR1 is a highly specific marker for eosinophils in humans.     

Physical fitness in people after burn injury: a systematic review

Disseldorp LM, Nieuwenhuis MK, Van Baar ME, Mouton LJ. Physical fitness in people after burn injury: a systematic review.

Objective

To gain insight into the physical fitness of people after burn injury compared with healthy subjects, and to present an overview of the effectiveness of exercise training programs in improving physical fitness in people after burn injury.

Data Sources

Electronic databases EMBASE, PubMed, and Web of Science were searched for relevant publications. Additionally, references from retrieved publications were checked.

Study Selection

The review includes studies that provide quantitative data from objective measures of physical fitness of both the intervention group and the control group.

Data Extraction

Characteristics of each study such as study design, institution, and intervention are reported, as well as mean ages and burn sizes of the subjects. Results are divided into 5 components of physical fitness—muscular strength, muscular endurance, body composition, cardiorespiratory endurance, and flexibility—and reported for each component separately.

Data Synthesis

Eleven studies met the inclusion criteria, and their methodological quality was assessed using the PEDro score and a modified Sackett scale. Six studies were used for the comparison of physical fitness in burned and nonburned subjects, and 9 studies for evaluating the effectiveness of exercise training programs.

Conclusions

Physical fitness is affected in people with extensive burns, and exercise training programs can bring on relevant improvements in all components. However, because of the great similarities in the subjects and protocols used in the included studies, the current knowledge is incomplete. Future research should include people of all ages with a broad range of burn sizes, for both short-term and long-term outcomes.     

Genomic evolution from primary breast carcinoma to distant metastasis: Few copy number changes of breast cancer related genes

Cancer initiation and progression is characterized by (epi)genetic aberrations. However, little is known about the changes that occur during breast cancer metastasis. In the present study, multiplex ligation-dependent probe amplification was used to compare copy numbers of 21 established oncogenes and tumor suppressor genes between 55 primary breast cancer samples and corresponding distant metastases. Distant breast cancer metastases generally showed similar gene copy number aberrations compared to their corresponding primary tumors. The few genes that showed differences between primary tumor and metastasis (PRDM14, MED1, CCNE1, TRAF4, MTDH, CDH1) have been implicated in the development of therapy resistance.     

Long-term risk of secondary skin cancers after radiation therapy for Hodgkin’s lymphoma

Purpose

Survivors of Hodgkin’s lymphoma (HL) are at risk of secondary tumors. We investigated the risk of secondary skin cancers after radiotherapy compared to treatment without radiation and to an age-matched population.

Material and methods

We conducted a retrospective cohort study of 889 HL patients treated between 1965 and 2005. Data on secondary skin cancers and treatment fields were retrieved. Incidence rates were compared to observed rates in the Dutch population.

Results

318 skin cancers were diagnosed in 86 patients, showing significantly higher risks of skin cancers, the majority being BCC. The standardized incidence ratio (SIR) of BCC in HL survivors was significantly increased (SIR 5.2, 95% CI 4.0–6.6), especially in those aged <35 years at diagnosis (SIR 8.0, 95% CI 5.8–10.7). SIR increased with longer follow-up to 15.9 (95% CI 9.1–25.9) after 35 years, with 626 excess cases per 10,000 patients per year. Most (57%) skin cancers developed within the radiation fields, with significantly increased risk in patients treated with radiotherapy compared to chemotherapy alone (p = 0·047, HR 2·75, 95% CI 1·01–7.45).

Conclusion

Radiotherapy for HL is associated with a strongly increased long-term risk of secondary skin cancers, both compared to the general population and to treatment with chemotherapy alone.     

Alpe d’HuZes Cancer Rehabilitation (A-CaRe) Research: Four Randomized Controlled Exercise Trials and Economic Evaluations in Cancer Patients and Survivors

Background

Previous studies showed that exercise in cancer patients is feasible and may reduce fatigue and improve physical fitness and quality of life. However, many previous studies had methodological weaknesses related to trial design, sample size, comparison group, outcome measures, short follow-up durations and programme content.

Purpose

This paper aims to present the rationale and design of the clinical research subprogramme of the Alpe d??HuZes Cancer Rehabilitation (A-CaRe) programme.

Method

A-CaRe Clinical Research includes four randomized controlled trials in patients: (a) after chemotherapy, (b) during chemotherapy, (c) after stem cell transplantation and (d) during childhood cancer. These trials compare high-intensity resistance and endurance exercise interventions with usual care or a waiting list control group. In two studies, a second intervention arm consisting of low-to-moderate intensity exercise is included. All four A-CaRe trials use similar methods.

Results

Outcome measures are carefully chosen based on the International Classification of Functioning Disability and Health model. Measurements will be performed prior to randomization (T0), after completion of the intervention (T1) and at follow-up (T2). The primary outcome measures are cardiorespiratory fitness, muscle strength and fatigue. Secondary outcome measures include health-related quality of life and psychosocial functioning. Furthermore, cost-effectiveness and cost-utility analyses are performed from a societal perspective.

Conclusion

We hypothesize that exercise is more effective at improving physical fitness and thereby reducing fatigue and more cost-effective compared with usual care or a waiting list control group. If so, the programmes will be implemented in the Dutch clinical practice.     

Receptor conversion in distant breast cancer metastases

Introduction

When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.

Methods

A total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ERα, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result.

Results

Using a 10% threshold, receptor conversion by IHC for ERα, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ERα and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR- to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ERα and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases.

Conclusions

Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ERα and HER2, and is more frequent for PR, especially in brain, liver and gastro-intestinal metastases.     

Functional antagonism by GM-CSF on TNF-alpha-induced CD83 expression in human neutrophils

TNFalpha-induced expression of CD83 in leukocytes is mediated by NF-kappab. The aim of our present study was to investigate the underlying mechanism of a unique functional antagonism between GM-CSF and TNFalpha-induced up-regulation of CD83 in human neutrophils. CD83 was down-regulated by co-stimulation of neutrophils with TNFalpha and GM-CSF compared to TNFalpha alone both at the level of mRNA and protein. In marked contrast, the expression of IL-1RA was up-regulated under the same conditions. The down-regulation of CD83 was not mediated by modulation of the NF-kappab signaling pathway. Neither was it mediated by a decrease in mRNA stability of CD83. NF-kappab was modulated under these conditions as both the expression of the target gene IL-1RA as well as the phosphorylation of IkBalpha were up-regulated. Our results show that co-stimulation with pro-inflammatory cytokines such as TNFalpha and GM-CSF can have differential effects on inflammatory pathways initiated in the same target cell. GM-CSF can both synergize with TNFalpha in the case of expression of IL1-RA and antagonize in the case of CD83. Therefore, expression of CD83 as read out for activation of neutrophils in patients with inflammatory diseases is complicated by the presence of cross-modulating cytokines such as GM-CSF.