Mouse Schwann cells activate MHC class I and II restricted T-cell responses,but require external peptide processing for MHC class II presentation

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS). In inflammatory neuropathies like the Guillain-Barré syndrome (GBS) Schwann cells become target of an autoimmune response, but may also modulate local inflammation. Here, we tested the functional relevance of Schwann cell derived MHC expression in an in vitro coculture system. Mouse Schwann cells activated proliferation of ovalbumin specific CD8+ T cells when ovalbumin protein or MHC class I restricted ovalbumin peptide (Ova_257–264 SIINFEKL) was added and after transfection with an ovalbumin coding vector. Schwann cells activated proliferation of ovalbumin specific CD4+ T cells in the presence of MHC class II restricted ovalbumin peptide (Ova_323–339 ISQAVHAAHAEINEAGR). CD4+ T-cell proliferation was not activated by ovalbumin protein or transfection with an ovalbumin coding vector. This indicates that Schwann cells express functionally active MHC class I and II molecules. In this study, however, Schwann cells lacked the ability to process exogenous antigen or cross-present endogenous antigen into the MHC class II presentation pathway. Thus, antigen presentation may be a pathological function of Schwann cells exacerbating nerve damage in inflammatory neuropathies.     

Can cost utility evaluations inform decision making about interventions for low back pain?

Background contextLow back pain (LBP) is associated with high health-care utilization and lost productivity. Numerous interventions are routinely used, although few are supported by strong evidence. Cost utility analyses (CUAs) may be helpful to inform decision makers.PurposeTo conduct a systematic review of CUAs of interventions for LBP.Study designSystematic review.MethodsA search strategy combining medical subject headings and free text related to LBP and health economic evaluations was executed in MEDLINE. Cost utility analyses combined with randomized controlled trials for LBP were included. Studies that were published before 1998, non-English, decision analyses, and duplicate reports were excluded. Search results were evaluated by two reviewers, who extracted data independently related to clinical study design, economic study design, direct cost components, utility results, cost results, and CUA results.ResultsThe search produced 319 citations, and of these 15 met eligibility criteria. Most were from the United Kingdom (n=8), published in the past 3 years (n=12), studied chronic LBP or radiculopathy (n=13), and had a follow-up >12 months (n=13). Combined, there were 33 study groups who received a mean 2.1 interventions, most commonly education (n=17), exercise therapy (n=13), spinal manipulation therapy (n=7), surgery (n=7), and usual care from a general practitioner (n=7). Mean baseline utility was 0.57, improving to 0.67 at follow-up; the mean difference in utility improvement between study groups was 0.04. Based on available data and converted to US dollars, the cost per quality-adjusted life year ranged from $304 to $579,527, with a median of $13,015.ConclusionsFew CUAs were identified for LBP, and there was heterogeneity in the interventions compared, direct cost components measured, indirect costs, other methods, and results. Reporting quality was mixed. Currently published CUAs do not provide sufficient information to assist decision makers. Future CUAs should attempt to measure all known direct cost components relevant to LBP, estimate indirect costs such as lost productivity, have a follow-up period sufficient to capture meaningful changes, and clearly report methods and results to facilitate interpretation and comparison.     

Ciliary neurotrophic factor null alleles are not a risk factor for Charcot-Marie-Tooth disease, hereditary neuropathy with pressure palsies and amyotrophic lateral sclerosis

Growth factors, such as ciliary neurotrophic factor (CNTF), have been implicated in neuronal survival and proliferation. About 2% of the human population is homozygous for a polymorphism that induces truncated and biologically inactive CNTF but does not obviously change the phenotype. In a population of patients with hereditary neuropathy, a higher rate of the CNTF null mutation would indicate greater susceptibility for clinically significant disease, and a recent report attributes early onset and rapid deterioration in a case of familial ALS (FALS) to this mutation. We have, therefore, genotyped the CNTF polymorphism in a large group of patients with CMT 1a, HNPP, sporadic ALS, in one pedigree with FALS, and controls. All groups exhibited a similar distribution of the polymorphism. We conclude that absence of CNTF does not increase susceptibility for these disorders and confirm that it does not affect onset and course of familial and sporadic ALS.     

Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review

Background.

Currently, only Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status is used as a decisional marker for epidermal growth factor receptor (EGFR) inhibitor therapy in colorectal cancer (CRC) patients. Concordance of KRAS status between primary tumors and metastases has always been considered to be close to perfect; however, cases of discordance have been reported. The actual rate of concordance of KRAS status remains unclear, as is the same for v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatidylinositol 3-kinase CA subunit (PIK3CA), and loss of phosphatase and tensin homologue deleted on chromosome ten (PTEN). Therefore, it is unknown whether it is necessary to perform mutational analysis on metastases instead of on (or in addition to) primary tumors.

Design.

A systematic literature search was conducted to collect all studies testing concordance of KRAS in CRC, and also of BRAF, PIK3CA, and loss of PTEN.

Results.

Twenty-one studies have reported concordance of KRAS, with an overall concordance rate of 93% (range, 76%–100%). Overall concordance rates of studies testing concordance of BRAF status and loss of PTEN were 98% and 68%, respectively. Three studies reported concordance of PIK3CA status (range, 89%–94%).

Conclusion.

Though discordance of KRAS status does occur, it is uncommon. When considering the downsides of testing metastatic tissue in all patients along with the low incidence of discordance, we conclude that that testing the primary tumor (or whatever tissue available) is sufficient for clinical decision making on EGFR inhibitor therapy.     

Integrating pain metrics into oncology clinical trials

Cancer-related pain is highly prevalent and often severe, and as a result is often one of the defining experiences for patients with malignancy. Patients and patients' families almost always live with the ever-present reality that cancer treatment and progression may be accompanied by pain. For patients nearing the end of life, most fear that their final days will be spent living with the terrible effects of the disease, the most important of which is pain. Despite this, there is far less systematic research on the mechanisms of cancer-related pain or on the development of new agents to reduce or eliminate pain in cancer patients compared with research to combat the disease itself. Further, even when the focus of research is treatment of the tumor, the effects of anticancer treatments on pain are often underreported in publications and other forums. To illustrate the relative drought in the cancer pain control area, there have been no new drugs approved for cancer-related pain in recent years. A number of methodologic and logistical challenges that hinder the ability to assess pain response in clinical trials are discussed in this article. Possible ways to address these challenges are also discussed.