Two novel prehabilitation apps to help patients stop smoking and risky drinking prior to hip and knee arthroplasty.

PURPOSE: Daily smoking or risky drinking increases the risk of complications after surgery by ~50%. Intensive prehabilitation aimed at complete cessation reduces the complication rate but is time-consuming. The purpose of this study was to carry out preoperative pilot tests (randomized design) of the feasibility (1A) and validation (1B) of two novel prehabilitation apps, habeat® (Ha-app) or rehaviour® (Re-app). METHODS: Patients scheduled for hip or knee arthroplasty with daily smoking, risky drinking, or both were randomised to one of the two apps. In part 1A, eight patients and their staff measured feasibility on a visual analog scale (VAS) and were interviewed about what worked well and the challenges requiring improvement. In part 1B, seven patients and their staff tested the improved apps for up to two weeks before validating the understanding, usability, coverage, and empowerment on a VAS and being interviewed. RESULTS: In 1A, all patients and staff returned scores of ≥5 for understanding the apps and mostly suggested technical improvements. In 1B, the scores varied widely for both apps, with no consensus achieved. Two of four patients (Ha-app) and one-third of the patients (Re-app) found the apps helpful for reducing smoking, but without successful quitting. The staff experienced low app competencies among patients and high time consumption. Specifically, patients most often needed help for the Ha-app, and the staff most often for Re-app; however, the staff reported the Re-app dashboard was more user-friendly. Support and follow-up from an addiction specialist staff member were suggested to complement the apps, thereby increasing the time consumption for staff. CONCLUSIONS: This pilot study to test prototype apps generated helpful feedback for the app developers. Based on the patient and staff comments, multiple improvements in functionality seem required before scaling up the evaluation for effect on prehabilitation and postoperative complications.

"I Tried Forcing Myself to do It, but Then It Becomes a Boring Chore": Understanding (dis)engagement in Physical Activity Among Individuals With Type 2 Diabetes Using a Practice Theory Approach.

Lack of physical activity (PA) is common among individuals with type 2 diabetes (T2D). We apply a practice theory approach to investigate PA engagement in the context of T2D. Data were collected through semi-structured individual interviews (n = 23) and focus groups (n = 3x6) and analyzed by deductive-inductive reflexive thematic analysis using a practice theory framework. Forty-one purposefully selected individuals with T2D (29 men) between the ages of 54 and 77 years were included. The analysis resulted in three main themes informed by five subthemes, reflecting the key elements of practice theory (i.e., meanings, materialities, and competencies). One overarching theme identified PA engagement as an unsustainable and insurmountable project in constant and unequal competition with the practice of physical inactivity. To increase PA among individuals with T2D, future PA interventions and strategies should aim to establish a stronger link between PA and everyday life practices.

EBI3 regulates the NK cell response to mouse cytomegalovirus infection.

Natural killer (NK) cells are key mediators in the control of cytomegalovirus infection. Here, we show that Epstein-Barr virus-induced 3 (EBI3) is expressed by human NK cells after NKG2D or IL-12 plus IL-18 stimulation and by mouse NK cells during mouse cytomegalovirus (MCMV) infection. The induction of EBI3 protein expression in mouse NK cells is a late activation event. Thus, early activation events of NK cells, such as IFNγ production and CD69 expression, were not affected in EBI3-deficient (Ebi3-/- ) C57BL/6 (B6) mice during MCMV infection. Furthermore, comparable levels of early viral replication in spleen and liver were observed in MCMV-infected Ebi3-/- and wild-type (WT) B6 mice. Interestingly, the viral load in salivary glands and oral lavage was strongly decreased in the MCMV-infected Ebi3-/- B6 mice, suggesting that EBI3 plays a role in the establishment of MCMV latency. We detected a decrease in the sustained IL-10 production by NK cells and lower serum levels of IL-10 in the MCMV-infected Ebi3-/- B6 mice. Furthermore, we observed an increase in dendritic cell maturation markers and an increase in activated CD8+ T cells. Thus, EBI3 dampens the immune response against MCMV infection, resulting in prolonged viral persistence.

Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells.

Priming of human NK cells with IL-2 is necessary to render them functionally competent upon NKG2D engagement. We examined the underlying mechanisms that control NKG2D responsiveness in NK cells and found that IL-2 upregulates expression of the amino acid transporters SLC1A5 and CD98. Using specific inhibitors to block SLC1A5 and CD98 function, we found that production of IFN-γ and degranulation by CD56bright and CD56dim NK cells following NKG2D stimulation were dependent on both transporters. IL-2 priming increased the activity of mTORC1, and inhibition of mTORC1 abrogated the ability of the IL-2-primed NK cells to produce IFN-γ in response to NKG2D-mediated stimulation. This study identifies a series of IL-2-induced cellular changes that regulates the NKG2D responsiveness in human NK cells.

NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration.

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1-6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4-6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.

S-1 in combination with docetaxel and oxaliplatin in patients with advanced gastro-esophageal adenocarcinoma: two parallel phase 1/2a studies.

BACKGROUND: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA. METHODS: We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy. RESULTS: Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49-78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m2, O 100 mg/m2 and S-1 25 mg/m2 twice daily and of DOS2w was: docetaxel 40 mg/m2, O 70 mg/m2 and S-1 35 mg/m2 twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients. CONCLUSIONS: At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA. Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10.

Assessment of response to beta-blockers by expression of ßArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients.

BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS: Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (ßArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS: Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of ßArr2 in antrum mucosa. CONCLUSION: This study shows for the first time that the expression of ßArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.

Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review.

BACKGROUND: An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce. MATERIAL AND METHODS: In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included. RESULTS: From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea. CONCLUSION: S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.

Using a Structured Assessment Tool to Evaluate Nontechnical Skills of Nurse Anesthetists.

Nontechnical skills are critical for good anesthetic practice but are seldom addressed explicitly in clinical training. The purposes of this study were (1) to evaluate the reliability and validity of the observation-based assessment tool Nurse Anaesthetists' Non-Technical Skills system (N-ANTS) and (2) to evaluate the effect of training nurse anesthetist supervisors in the use of N-ANTS. This system comprises a global rating score, 4 categories, and 15 elements to rate nurse anesthetists' nontechnical skills. A 1-day workshop was conducted for 22 nurse anesthetist supervisors to rate nurse anesthetists' nontechnical skills in 9 scripted video scenarios. Data were gathered from 2 rating sessions separated by a 2-hour training session. The interrater reliability was high before and after the training. It remained stable for the global rating score in N-ANTS and its category ratings, but improved at the elements level. When the raters' ratings were compared with ratings by an expert reference group, there was no statistically significant effect on training. We conclude that Danish nurse anesthetist supervisors without further rater training besides their work experience can use N-ANTS to assess nontechnical skills of nurse anesthetists.

N-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24.

NKG2D is an activating receptor expressed on several types of human lymphocytes. NKG2D ligands can be induced upon cell stress and are frequently targeted post-translationally in infected or transformed cells to avoid immune recognition. Virus infection and inflammation alter protein N-glycosylation, and we have previously shown that changes in cellular N-glycosylation are involved in regulation of NKG2D ligand surface expression. The specific mode of regulation through N-glycosylation is, however, unknown. Here we investigated whether direct N-glycosylation of the NKG2D ligand MICA itself is critical for cell surface expression and sought to identify the essential residues. We found that a single N-glycosylation site (Asn(8)) was important for MICA018 surface expression. The frequently expressed MICA allele 008, with an altered transmembrane and intracellular domain, was not affected by mutation of this N-glycosylation site. Mutational analysis revealed that a single amino acid (Thr(24)) in the extracellular domain of MICA018 was essential for the N-glycosylation dependence, whereas the intracellular domain was not involved. The HHV7 immunoevasin, U21, was found to inhibit MICA018 surface expression by affecting N-glycosylation, and the retention was rescued by T24A substitution. Our study reveals N-glycosylation as an allele-specific regulatory mechanism important for regulation of surface expression of MICA018, and we pinpoint the residues essential for this N-glycosylation dependence. In addition, we show that this regulatory mechanism of MICA surface expression is likely targeted during different pathological conditions.

2-deoxy D-glucose prevents cell surface expression of NKG2D ligands through inhibition of N-linked glycosylation.

NKG2D ligand surface expression is important for immune recognition of stressed and neotransformed cells. In this study, we show that surface expression of MICA/B and other NKG2D ligands is dependent on N-linked glycosylation. The inhibitor of glycolysis and N-linked glycosylation, 2-deoxy-D-glucose (2DG), potently inhibited surface expression of MICA/B after histone deacetylase inhibitor treatment; the inhibition occurred posttranscriptionally without affecting MICA promoter activity. Transient overexpression of MICA surface expression was also inhibited by 2DG. 2DG blocks N-linked glycosylation of MICA/B by a reversible mechanism that can be alleviated by addition of d-mannose; this does not, however, affect the inhibition of glycolysis. Addition of d-mannose restored MICA/B surface expression after 2DG treatment. In addition, specific pharmacological or small interfering RNA-mediated targeting of glycolytic enzymes did not affect MICA/B surface expression, strongly suggesting that N-linked glycosylation, and not glycolysis, is essential for MICA/B surface expression. Corroborating this, tunicamycin, a selective inhibitor of N-linked glycosylation, abolished MICA/B surface expression without compromising activation of MICA promoter activity. NK cell-mediated killing assay and staining with a recombinant NKG2D-Fc fusion protein showed that all functional NKG2D ligands induced by histone deacetylase inhibitor treatment were abolished by 2DG treatment and fully reconstituted by further addition of d-mannose. Our data suggest that posttranslational N-linked glycosylation is strictly required for NKG2D ligand surface expression. Cancer and infection often result in aberrant glycosylation, which could likely be involved in modulation of NKG2D ligand expression. Our data further imply that chemotherapeutic use of 2DG may restrict NKG2D ligand surface expression and inhibit secretion of immunoinhibitory soluble NKG2D ligands.

Developmental competence of oocytes isolated from surplus medulla tissue in connection with cryopreservation of ovarian tissue for fertility preservation.

OBJECTIVE: Evaluating the developmental competence of immature oocytes collected from surplus medulla tissue in connection with ovarian tissue cryopreservation for fertility preservation. DESIGN: Cohort comparative study. SETTING: University laboratory in Denmark from 2011-2012. POPULATION: 69 girls and women (0-38 years of age) who each had one ovary cryopreserved for fertility preservation. METHODS: Ovaries were obtained directly from the local hospital or from collaborating hospitals (two to five hours' transport on ice). Immature oocytes were aspirated from large antral follicles visible on the ovaries, and collected from the saline solution, containing surplus medulla tissue, following dissection of the ovarian cortical tissue for cryopreservation. The immature oocytes were cultured for 48 h in an Embryoscope™ Time-lapse System or in culture dishes overlaid with liquid paraffin using commercial and in-house supplemented culture media. MAIN OUTCOME MEASURES: Maturation rate for immature oocytes reaching metaphase II. RESULTS: With a maturation rate of 3.1%, only 21 of 682 immature oocytes reached metaphase II. Immature oocytes from ovaries that had been transported on ice for two to five hours performed significantly poorer than those recovered immediately after surgery. Addition of epidermal growth factor and follicle fluid from human small antral follicles to the culture medium did not augment the maturation rate. Immature oocytes cultured in the Embryoscope performed significantly better than those in conventional culture dishes. CONCLUSIONS: In vitro maturation of immature oocytes should only be attempted clinically from visible antral follicles and where the ovary is not subjected to a cooling period prior to recovery of immature oocytes.

Satisfaction with and perceived benefits of needs-assessment related to rehabilitation after chemotherapy among patients with breast cancer.

PURPOSE: To investigate satisfaction with and perceived benefits of a model of needs-assessment related to rehabilitation (NARR) in women with early breast cancer after (neo)adjuvant chemotherapy. MATERIALS AND METHODS: Mixed methods were applied using survey (N = 200) along with interviews (N = 20). The survey included measurement of distress and self-assessed need of and satisfaction with the NARR. Type of experienced side/late effects were registered along with numbers of and reasons for referrals to rehabilitation. Individual semi-structured interviews were conducted. Quantitative data were analyzed using descriptive statistics, and qualitative data were analyzed with thematic analysis. RESULTS: Overall, 217 patients participated in a NARR and 200 (92%) accepted participation in the survey. Furthermore, 20/37 (54%) invited patients were interviewed. After the NARR, 39 patients (20%) were referred to rehabilitation. While satisfaction was high, findings regarding distress and need of the NARR were equivocal and indicated a need for talking about experiences throughout the cancer trajectory. CONCLUSIONS: While only 20% had rehabilitation needs, satisfaction with the NARR was high and patients benefitted from being confirmed in normality of their experiences. It is recommended to address patients' side/late effects after chemotherapy for early breast cancer to identify rehabilitation needs, reduce distress, and improve quality of life.

One fifth of patients with early breast cancer were referred to rehabilitation after needs-assessments conducted 2 months after chemotherapy termination.Higher distress and higher self-reported need were significantly associated with not working and experiencing a higher number of side effects/late effects.It is recommended to address patients' side effects/late effects, including psychological distress, after termination of chemotherapy for early breast cancer to identify rehabilitation needs, reduce distress, and ultimately improve quality of life.

High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): a phase I trial.

BACKGROUND: Consensus is that patients with locally advanced rectal cancer (LARC) should receive long-term chemoradiotherapy (CRT) before surgery. With the intent to offer the patients intensified concomitant chemotherapy (CT) to improve outcome and to assess tolerability and toxicity of oxaliplatin (Ox) a phase I trial of high dose pelvic radiotherapy (RT), fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed. METHODS: Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume (GTV) (60 Gy/30 fractions). Concurrent with RT patients received a daily dose of UFT 300 mg/m(2) plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m(2)/week from a start dose of 30 mg/m(2)/week to a maximum of 60 mg/m(2)/week. In addition, before and after CRT the patients received one course of TEGAFOX (UFT 300 mg/m(2) with l/leucovorin 22.5 mg Days 1-14 and Ox 130 mg/m(2) given on Day 1). Surgery was planned at least six weeks after the completion of the CRT. RESULTS: From May 2005 to March 2009, 18 patients with LARC (16 primary, two recurrent) were included in this phase I trial. Toxicity was low with only 5-17% grade 3-4 toxicity. Fifteen patients (83%) were operated (14 R0 resection and 1 R1 resection) after completion of CRT. Five (33%) patients had a pathological complete response (ypCR). When ypCR was combined with yp few residual cells, the rate was 60%. Thirteen patients are still alive December 2011. CONCLUSION: Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m(2)/week was feasible with low toxicity, high ypCR rates and promising OS in patients with non-resectable LARC.

Impact of Nonpharmacologic Interventions Targeting Sleep Disturbances or Disorders in Patients With Inflammatory Arthritis: A Systematic Review and Meta-Analysis of Randomized Trials.

OBJECTIVE: Patients with inflammatory arthritis have a high risk of sleep disturbances and disorders. The objective was to evaluate the evidence of nonpharmacologic interventions targeting sleep disturbances or disorders in patients with inflammatory arthritis. METHODS: A systematic search was undertaken from inception to September 8, 2020. We included randomized trials concerning nonpharmacologic interventions applied in adults with inflammatory arthritis and concomitant sleep disturbances or disorders. The primary outcome was the sleep domain, while secondary outcomes were core outcome domains for inflammatory arthritis trials and harms. The Cochrane Risk of Bias tool was applied, and the overall quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Effect sizes for continuous outcomes were based on the standardized mean difference, combined using random-effects meta-analysis. RESULTS: Six trials (308 patients) were included in the quantitative synthesis; 3 of these reported improvement in sleep in favor of the nonpharmacologic interventions. The meta-analysis of the sleep domains indicated a large clinical effect of -0.80 (95% confidence interval -1.33, -0.28) in favor of nonpharmacologic interventions targeting sleep disturbances or disorders. The estimate was rated down twice for risk of bias and unexplained inconsistency; this risk was assessed as corresponding to low-quality evidence. None of the secondary core outcomes used in contemporary inflammatory arthritis trials indicated a clinical benefit in favor of nonpharmacologic interventions targeting sleep. CONCLUSION: Nonpharmacologic interventions targeting sleep disturbances/disorders in patients with inflammatory arthritis indicated a promising effect on sleep outcomes, but not yet with convincing evidence.

MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.

Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum.

BACKGROUND: Until recently there has been no proven second-line therapy for patients with advanced gastro-esophageal cancer (GEC). Since 2004, Denmark has had a national health program where non-proven therapy can be offered to patients with advanced cancer, after approval by an expert panel appointed by the National Board of Health. This program has accelerated the introduction and implementation of new therapies in Denmark. Inspired by therapy in metastatic colorectal cancer, a combination of cetuximab and irinotecan (Cetiri) was chosen for second-line therapy in GEC patients. We report our experience with Cetiri as second-line therapy in patients with GEC. METHODS: All patients had histologically confirmed GEC and all patients had progressive disease during or after first-line platinum-containing chemotherapy. The patients received cetuximab 500 mg/m(2) on day 1 and irinotecan 180 mg/m(2) on day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was prospectively evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. RESULTS: From December 2007 to February 2009, 50 consecutive patients received Cetiri as second-line therapy. Median performance status (PS) was 1. The median number of courses was seven. Seven patients (14%) had a partial response. Median progression-free survival (PFS) was 3.3 months and overall survival (OS) was 5.5 months; two patients are still alive without progressive disease. Major toxicities were: diarrhea (8%), fatigue (10%), neutropenia (16%), and febrile neutropenia (2%). CONCLUSION: Cetiri every two weeks is a convenient and well-tolerated second-line regimen in GEC patients. A promising effect was seen in patients with PS 0-1 and in patients who developed a rash.

Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells.

We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around -110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity. Other short-chain fatty acids such as lactate, acetate, and butyrate could also induce MICA/B expression. We observed a striking difference in the molecular signaling pathways that regulate MICA/B. A functional glycolytic pathway was essential for MICA/B expression after exposure to propionate and CMV. In contrast, compounds with histone deacetylase-inhibitory activity such as butyrate and FR901228 stimulated MICA/B expression through a pathway that was not affected by inhibition of glycolysis, clearly suggesting that MICA/B is regulated through different molecular mechanisms. We propose that propionate, produced either by bacteria or during cellular metabolism, has significant immunoregulatory function and may be cancer prophylactic.

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.

Phase I study of docetaxel, oxaliplatin and capecitabine (TEX) as first line therapy to patients with advanced gastro-oesophageal cancer.

BACKGROUND: ECF (epirubicin, cisplatin, 5-FU) has been a standard first-line regimen in patients with advanced gastro-esophageal cancer (GEC). If cisplatin is substituted by oxaliplatin (Eloxatin®) - E) and 5-FU by capecitabine (X - Xeloda®) this regimen is easily administered with at least comparable efficacy and lower toxicity. Recent studies indicate that efficacy can be improved by adding docetaxel (Taxotere® - T) to CF. We initiated a phase I trial of T, short-time infusion of E and continuously X (TEX) as first-line therapy in GEC to establish the recommended dose (RD) for further therapy. MATERIALS AND METHODS: Patients were enrolled in cohorts of three at five dose levels. Patients had histologically confirmed GEC adenocarcinoma. Therapy was administered day 1 with escalating doses of docetaxel (60 mg/m² to 75 mg/m² iv as a 60 minutes infusion), oxaliplatin (85 to 130 mg/m² iv as a 30 minutes infusion) and oral capecitabine (1 000 to 1 250 mg/m²/day). TEX was repeated every third week for a maximum of eight cycles. Toxicity was evaluated according to CTCAE v3.0 and dose limiting toxicity (DLT) was evaluated after the first course of TEX. RESULTS: From June 2007 to April 2009, 23 consecutive patients received TEX. At dose level V, two of four patients experienced DLT and therefore we included additional seven patients at dose level IV. Only one of seven experienced DLT but dose-intensity was reduced to 75% in four of seven patients after three courses of TEX. Therefore we defined dose level III as RD. Efficacy was promising with response rate 38%, PFS 9.4 months and OS 12.5 months. CONCLUSION: The recommended dose of TEX (docetaxel 60 mg/m² iv day 1, oxaliplatin 115 mg/m² iv day 1 and oral capecitabine 1250 mg/m²/day continuously) every three weeks is easily administered in an out-patient setting. Efficacy is promising and will be evaluated in a phase II study.