First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours.

BACKGROUND: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy. METHODS: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04. RESULTS: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses. CONCLUSIONS: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition. CLINICAL TRIAL REGISTRATION: NCT03267316.

A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies.

BACKGROUND: The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma. METHODS: In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I-III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I-III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III). FINDINGS: In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31-45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63-5·79] for a 25-unit increase in score, p<0·0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3·37 [95% CI 2·23-5·08], p<0·0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes. INTERPRETATION: Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters. FUNDING: Genomic Health Inc and Pfizer Inc.

In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?

BACKGROUND: The Oncotype DX recurrence score (RS) assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy in patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Patients with high RS tumors have substantial benefit, and patients with low RS tumors have minimal if any benefit from chemotherapy. Tumor size is used as a key parameter when selecting patients for neoadjuvant chemotherapy. The aim of this study was to assess the distribution of RS in patients selected for neoadjuvant chemotherapy primarily according to tumor size. PATIENTS AND METHODS: Patients with ER-positive and HER2-negative tumors that were node-negative or had no more than 1 positive node from three trials were included in this study. Oncotype DX was performed at Genomic Health, Inc., blinded to the clinical data. Descriptive statistics were calculated for distribution of RS for all cases. RESULTS: Of 277 patients, 96 met eligibility criteria, and 81 had sufficient material for analysis. Median tumor size was 40 mm (interquartile range [IQR], 30-50 mm). Grade I, II, and III were observed in 13, 49, and 17 cases, respectively. There was a wide distribution of RS with a median of 21.4 (IQR, 16.05-26.75). In total, 23 (28.3%) had high, 28 (34.6%) intermediate, and 30 (37%) low RS results. CONCLUSION: The RS may provide relevant information for neoadjuvant treatment decisions in select patients both in clinical practice and in studies. Inclusion of low RS disease patients in neoadjuvant trials will likely only dilute the ability to look at treatment effects.

The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients.

Oncotype DX testing is reimbursed in Israel for node-negative and node-positive (N1+; up to 3 positive nodes including micrometastases), estrogen receptor positive (ER+), breast cancer patients. This retrospective study evaluated the impact of Oncotype DX testing on treatment decisions in N1+/ER+ breast cancer patients. To this end, we compared treatments for all N+ patients for whom testing had been ordered with treatments for patients with similar characteristics where the test had not been available. The retrospective analysis included 951 patients (282 Oncotype DX, 669 controls), all of whom received endocrine therapy with or without chemotherapy. In Oncotype DX patients, 7.1, 37.0, and 100 % of those with low, intermediate, and high Recurrence Score results (Oncotype DX summary score) received chemotherapy, respectively (P < 0.0001, all comparisons). Chemotherapy use was lower in Oncotype DX patients versus controls (24.5 vs. 70.1 %). In a multivariate logistic regression analysis in which the probability of receiving chemotherapy was modeled as a function of Oncotype DX testing, age, tumor size, tumor grade, nodal status, and the interactions between Oncotype DX testing and the other covariates, Oncotype DX testing was associated with significantly lower odds of receiving chemotherapy (odds ratio 0.16; 95 % CI 0.11-0.24; P < 0.0001). In summary, our findings suggest that Oncotype DX testing has a significant impact on reducing chemotherapy use in N1+/ER+ breast cancer patients in Israel.

Liquid biopsy mutation panel for non-small cell lung cancer: analytical validation and clinical concordance.

Molecular testing for genomic variants is recommended in advanced non-small cell lung cancer (NSCLC). Standard tissue biopsy is sometimes infeasible, procedurally risky, or insufficient in tumor tissue quantity. We present the analytical validation and concordance study of EGFR variants using a new 17-gene liquid biopsy assay (NCT02762877). Of 144 patients enrolled with newly diagnosed or progressive stage IV nonsquamous NSCLC, 140 (97%) had liquid assay results, and 117 (81%) had both EGFR blood and tissue results. Alterations were detected in 58% of liquid samples. Overall tissue-liquid concordance for EGFR alterations was 94.0% (95% CI 88.1%, 97.6%) with positive percent agreement of 76.7% (57.7%, 90.1%) and negative percent agreement of 100% (95.8%, 100%). Concordance for ALK structural variants was 95.7% (90.1%, 98.6%). This assay detected alterations in other therapeutically relevant genes at a rate similar to tissue analysis. These results demonstrate the analytical and clinical validity of this 17-gene assay.

Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with only one functioning kidney.

BACKGROUND: About 2% of patients with a carcinoma in one kidney develop either metastases or a new primary tumor in the contralateral kidney. Often, renal cancers progress rapidly at peripheral sites and a metastasis to the second kidney may not be the patient's main problem. However, when an initial renal cancer is more indolent yet spreads to the formerly unaffected kidney or a new primary tumor forms there, local treatment may be needed. Stereotactic body radiotherapy (SBRT) has been demonstrated as a valuable treatment option for tumors that cause local symptoms. Presented here is a retrospective analysis of patients in whom SBRT was used to control primary or metastatic renal disease. PATIENTS AND METHODS: Seven patients with a mean age of 64 (44-76) were treated for metastases from a malignant kidney to its contralateral counterpart. Dose/fractionation schedules varied between 10 Gy x 3 and 10 Gy x 4 depending on target location and size, given within one week. Follow-up times for patients who remained alive were 12, 52 and 66 months and for those who subsequently died were 10, 16, 49 and 70 months. RESULTS: Local control, defined as radiologically stable disease or partial/complete response, was obtained in six of these seven patients and regained after retreatment in the one patient whose lesion progressed. Side effects were generally mild, and in five of the seven patients, kidney function remained unaffected after treatment. In two patients, the creatinine levels remained moderately elevated at approximately 160 micromol/L post treatment. At no time was dialysis required. CONCLUSION: These results indicate that SBRT is a valuable alternative to surgery and other options for patients with metastases from a cancer-bearing kidney to the remaining kidney and provides local tumor control with satisfactory kidney function.

Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib.

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit.Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer-specific survival (RCSS) were analyzed using Cox proportional hazards regression.Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15-39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant.Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407-15. ©2018 AACR.

The MAGIC survey in hormone receptor positive (HR+), HER2-negative (HER2-) breast cancer: When might multigene assays be of value?

BACKGROUND: A modest proportion of patients with early stage hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer benefit from adjuvant chemotherapy. Traditionally, treatment recommendations are based on clinical/pathologic criteria that are not predictive of chemotherapy benefit. Multigene assays provide prognostic and predictive information that can help to make more informed treatment decisions. The MAGIC survey evaluated international differences in treatment recommendations, how traditional parameters are used for making treatment choices, and for which patients treating physicians feel most uncertain about their decisions. METHODS: The MAGIC survey captured respondents' demographics, practice patterns, relevance of traditional parameters for treatment decisions, and use of or interest in using multigene assays. Using this information, a predictive model was created to simulate treatment recommendations for 672 patient profiles. RESULTS: The survey was completed by 911 respondents (879 clinicians, 32 pathologists) from 52 countries. Chemo-endocrine therapy was recommended more often than endocrine therapy alone, but there was substantial heterogeneity in treatment recommendations in 52% of the patient profiles; approximately every fourth physician provided a different treatment recommendation. The majority of physicians indicated they wanted to use multigene assays clinically. Lack of reimbursement/availability were the main reasons for non-usage. CONCLUSIONS: The survey reveals substantial heterogeneity in treatment recommendations. Physicians have uncertainty in treatment recommendations in a high proportion of patients with intermediate risk features using traditional parameters. In HR+, HER2- patients with early disease the findings highlight the need for additional markers that are both prognostic and predictive of chemotherapy benefit that may support more-informed treatment decisions.

Clinical outcomes in ER+ HER2 -node-positive breast cancer patients who were treated according to the Recurrence Score results: evidence from a large prospectively designed registry.

The Recurrence Score® is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 (N = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors ≤ 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18-30, and 10.2% Recurrence Score ≥ 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18-30, and ≥ 31 group, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant-recurrence rates for N1mi/1 positive node/2-3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated (n = 27) and 2.9% in chemotherapy-untreated patients (n = 352); P = 0.245. In Recurrence Score 18-30, recurrence rate in chemotherapy-treated patients (n = 102) was significantly lower than in untreated patients (n = 156) (1.0% vs. 9.7% P = 0.019); in Recurrence Score ≤ 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated (n = 89) and 4.4% in chemotherapy-untreated patients (n = 488); P = 0.521. In conclusion, our findings support using endocrine therapy alone in ER+ HER2-negative breast cancer patients with micrometastases/1-3 positive nodes and Recurrence Score < 18.

Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry.

The 21-gene Recurrence Score® (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS ≥ 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS ≥ 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS ≥ 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11-25 (n = 1037) (TAILORx categorization) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit.

Pooled analysis of prospective European studies assessing the impact of using the 21-gene Recurrence Score assay on clinical decision making in women with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative early-stage breast cancer.

PURPOSE: The 21-gene Recurrence Score assay (Oncotype DX) provides prognostic/predictive information in oestrogen receptor positive (ER+) early breast cancer, but access/reimbursement has been limited in most European countries in the absence of prospective outcome data. Recently, two large prospective studies and a real-life 5-year outcome study have been reported. We performed a pooled analysis of prospective European impact studies to generate robust data on impact of use in different clinical subgroups. METHODS: The analysis included four studies (French, German, Spanish, and British) in ER+ human epidermal growth factor receptor 2-negative breast cancer patients (n = 527). Node-positive patients were excluded. RESULTS: The analysis demonstrated that treatment recommendations changed in 32% of patients post-testing; chemotherapy recommendation rate decreased from 55% to 34%. Change rates in the individual studies ranged from 30% to 37%. The highest change rates were in patients originally recommended chemotherapy and in grade II tumours; there was no subgroup without a treatment recommendation change. Notably, 31% of patients with an intermediate Recurrence Score result had a treatment recommendation change suggesting that testing provides actionable information in this group. With the exception of the German study (where chemotherapy rates remained high [41%] post-testing), between-study variability in treatment recommendations decreased post-testing (chemotherapy: from 36-52% to 26-29%; hormonal therapy: from 48-64% to 71-74%). Physicians' confidence regarding treatment recommendations improved in all the studies after testing. CONCLUSION: Recurrence Score testing led to changes in adjuvant chemotherapy use in approximately a third of patients, to an overall reduced chemotherapy use, and to more homogeneous decision making.

West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment.

PURPOSE: The 21-gene Recurrence Score (RS) assay is a validated prognostic/predictive tool in early hormone receptor-positive breast cancer (BC); however, only a few prospective outcome results have been available so far. In the phase III PlanB trial, RS was prospectively used to define a subset of patients who received only endocrine therapy. We present 3-year outcome data and concordance analysis (among biomarkers/RS). PATIENTS AND METHODS: Central tumor bank was established prospectively from PlanB (intermediate and high-risk, locally human epidermal growth factor receptor 2-negative BC). After an early amendment, HR-positive, pN0-1 patients with RS ≤ 11 were recommended to omit chemotherapy. RESULTS: From 2009 to 2011, PlanB enrolled 3,198 patients with a median age of 56 years; 41.1% had node-positive and 32.5% grade 3 disease. In 348 patients (15.3%), chemotherapy was omitted based on RS ≤ 11. After 35 months median follow-up, 3-year disease-free survival in patients with RS ≤ 11 and endocrine therapy alone was 98% versus 92% and 98% in RS > 25 and RS 12 to 25 in chemotherapy-treated patients, respectively. Nodal status, central and local grade, the Ki-67 protein encoded by the MKI67 gene, estrogen receptor, progesterone receptor, tumor size, and RS were univariate prognostic factors for disease-free survival; only nodal status, both central and local grade, and RS were independent multivariate factors. Histologic grade was discordant between central and local laboratories in 44%. RS was positively but moderately correlated with the Ki-67 protein encoded by the MKI67 gene and grade and negatively correlated with progesterone receptor and estrogen receptor. CONCLUSION: In this prospective trial, patients with enhanced clinical risk and omitted chemotherapy on the basis of RS ≤ 11 had excellent 3-year survival. The substantial discordance observed between traditional prognostic markers and RS emphasizes the need for standardized assessment and supports the potential integration of standardized, well-validated genomic assays such as RS with clinicopathologic prognostic factors for chemotherapy indication in early hormone receptor-positive BC.

Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma.

BACKGROUND AND PURPOSE: We investigated the results of using stereotactic radiotherapy (SRT) for 58 patients with renal cell carcinomas (RCC) who were evaluated restrospectively for response rates, local control rates and side effects. PATIENTS AND METHODS: From October 1997 to January 2003, 50 patients suffering from metastatic RCC and eight patients with inoperable primary RCC received high-dose fraction SRT while placed in a stereotactic body-frame. The most common dose/fractionation schedules used were 8 Gyx4, 10 Gyx4 and 15 Gyx3 during approximately 1 week. RESULTS: SRT-treated tumor lesions regressed totally in 30% of the patients at 3-36 months, whereas 60% of the patients had a partial volume reduction or no change after a median follow-up of 37 months (SD 17.4) for censored and 13 months (SD 12.9) for uncensored patients. Side effects were generally mild. Of 162 treated tumors, only three recurred, yielding a local control rate of 90-98%, considering the 8% non-evaluable sites as defined here. For patients with one to three metastases, the time to new spread was 9 months. CONCLUSIONS: Our use of SRT for patients with primary and metastatic RCC yielded a high local control rate with low toxicity. Patients with one to three metastases, local recurrences after nephrectomy or inoperable primary tumors benefited the most, i.e. had fewer distant recurrences (13/23) and longer survival times compared to patients with >3 metastases (24/27 recurrences).

A Prospective Comparison of the 21-Gene Recurrence Score and the PAM50-Based Prosigna in Estrogen Receptor-Positive Early-Stage Breast Cancer.

INTRODUCTION: The 21-gene Recurrence Score(®) assay (Oncotype DX(®), Genomic Health, Inc.) is a validated predictor of recurrence risk/chemotherapy benefit in patients with estrogen receptor-positive (ER+) early-stage breast cancer treated with endocrine therapy. The Prosigna(®) assay (NanoString Technologies Inc.) is a validated prognosticator in postmenopausal patients with low-risk ER+ early-stage breast cancer treated with endocrine therapy. The assays were analytically/clinically developed and validated differently. This study focused on comparing recurrence risk estimates as determined by these assays and is the first blinded comparison of these assays on matched patient samples. METHODS: Sequential breast cancer specimens from postmenopausal, node-negative, ER+ patients treated at the Marin General Hospital were analyzed: first by the 21-gene assay then by the Prosigna assay in an independent lab blinded to the Recurrence Score results. RESULTS: The final analysis included 52 patients. Correlation between the Recurrence Score and the Prosigna assay results was poor (r = 0.08). Agreement between risk classifications based on these assays was 54%; 4/7 of patients classified as high risk by the Prosigna assay had low Recurrence Score results. Two tumors with high Recurrence Score results had low ER expression (close to positivity threshold); both of which had a low/intermediate Prosigna assay result. The Prosigna assay classified 73.1% and 23.1% of samples as luminal A and luminal B, respectively. A range of Recurrence Score results was observed within the subtypes; 83% of luminal B samples had a low Recurrence Score result. CONCLUSION: Consistent with prior comparisons between the 21-gene and other genomic assays, our study demonstrated substantial differences in the way patients are risk stratified, suggesting that the different assays are not interchangeable. FUNDING: Genomic Health, Inc.

Plasma proteins in a standardised skin mini-erosion (II): effects of extraction pressure.

BACKGROUND: A standardised suction technique has been used to sample plasma proteins in dermal interstitial fluid (IF) serially for 5 to 6 days from a suction-induced skin mini-erosion. Increased protein concentrations ascribed to inflammation have been shown from day 1 onward. In this study, we assessed the effect of two different extraction pressures on IF sample composition. METHODS: Total protein concentration and the concentrations of insulin, prealbumin, albumin, transferrin, IgG and alpha-2-macroglobulin were assessed daily in healthy volunteers. Samples were extracted at 50 mmHg and 200 mmHg below the atmospheric. RESULTS: At 0 h after forming the erosion, mean total IF protein content (relative to plasma) was lower in the samples extracted at -200 mmHg than at -50 mmHg (26 +/-13% (SD) vs 48 +/-9.8%; p < 0.05). There were no significant differences at 24, 48, 72 or 96 h. Of the individual proteins, expressed as area units (AU) for area under the curve (AUC) from 0-96 h, albumin was lower in IF sampled at -200 mmHg (2.49 +/- 0.68 vs 3.08 +/- 0.36 AU; p < 0.05), as was transferrin (1.91 +/- 0.52 vs 2.40 +/- 0.42 AU; p < 0.05). Extraction volumes were significantly higher at -200 mmHg (AUC diff: 60%; p < 0.05). CONCLUSIONS: Samples of IF extracted at 0 h at -200 mmHg contained lower protein concentrations, indicating an increased water fraction and an intact sieve function of the vascular wall. The difference in protein concentration extracted at higher and lower pressure from 24 h onward was less pronounced. Lower pressure should be used to sample substances of greater molecular size.

Plasma proteins in a standardised skin mini-erosion (I): permeability changes as a function of time.

BACKGROUND: A standardised technique using a suction-induced mini-erosion that allows serial sampling of dermal interstitial fluid (IF) for 5 to 6 days has been described. In the present study, we studied permeability changes as a function of time. METHODS: We examined IF concentrations of total protein concentration and the concentration of insulin (6.6 kDa), prealbumin (55 kDa), albumin (66 kDa), transferrin (80 kDa), IgG (150 kDa) and alpha-2-macroglobulin (720 kDa) as a function of time, using an extraction pressure of 200 mmHg below atmospheric. RESULTS: At 0 h after forming the erosion, mean total IF protein content (relative to plasma) was 26 +/- 13% (SD). For the individual proteins, the relative mean concentrations were 65 +/- 36% for insulin, 48 +/- 12% for albumin, 30 +/- 19% for transferrin, 31 +/- 15%for IgG and 19.5 +/- 10% for alpha-2-macroglobulin. At 24 h, the total IF protein content was higher than at 0 h (56 +/- 26% vs 26 +/- 13%; p < 0.05, diff: 115%), as were some of the individual protein concentrations: prealbumin (50 +/- 24 vs 25 +/- 13%; p < 0.05), albumin (68 +/- 21 vs 48 +/- 12%; p < 0.05) and IgG (55 +/- 30 vs 31 +/- 15%; p = 0.05). ln the interval 24 h to 96 h the concentrations were relatively unchanged. CONCLUSIONS: The results indicate that fluid sampled at 0 h after forming the erosion represents dermal IF before the full onset of inflammation. From 24 h onward, the sampled fluid reflects a steady state of increased permeability induced by inflammation. This technique is promising as a tool for clinically sampling substances that are freely distributed in the body and as a model for studying inflammation and vascular permeability.

Prostasin, a potential tumor marker in ovarian cancer--a pilot study.

INTRODUCTION: Ovarian cancer is generally diagnosed at advanced stages of the disease; therefore, poor prognoses are typical. The development of tumor markers is thus of utmost importance. Prostasin is a protease that in normal tissues is highly expressed only in the prostate gland and seminal fluid. A previous study showed that prostasin is highly overexpressed in ovarian cancer cell lines. This study sought to evaluate the expression of prostasin in ovarian cancer. METHODS: Fresh tumor samples of ovarian epithelial cancer (n: 12) were analyzed for expression of prostasin mRNA (messenger ribonucleic acid) by conventional and real time quantitative PCR (polymerase chain reaction). As a standard control, a normal prostate sample was analyzed. RESULTS: Using conventional PCR, prostasin was detected in all but one sample. Using quantitative PCR, prostasin was over-expressed in all but one of the samples as compared to the control (prostate). CONCLUSIONS: These findings indicate that prostasin is overexpressed in many epithelial ovarian cancers. Further studies of prostasin as a potential biomarker for this disease are warranted.

Economic evaluations of leukemia: a review of the literature.

OBJECTIVES: Leukemia, together with lymphoma and multiple myeloma, are hematological malignancies, malignancies of the blood-forming organs. There are four major types of leukemia: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). There is a growing amount of literature of the health economic aspects of leukemia. However, no comprehensive review is yet performed on the health economic evidence for the disease. Hence, our aim was to review and analyze the existing literature on economic evaluations of the different types of leukemia. METHODS: A systematic literature search used electronic databases to identify published cost analyses and economic evaluations of leukemia treatments. After reviewing all identified studies, sixty studies were considered relevant for the purpose of the review. RESULTS: The identified studies were published after 1990, with a few exceptions. Many of the identified economic evaluations in leukemia, particularly for ALL and AML, may be defined as cost-minimization analyses, where only the costs of different treatment strategies are compared. In CML, a new treatment, imatinib, was introduced in 2001 and several cost-effectiveness analyses have since then been conducted comparing imatinib with previous first line treatments. CONCLUSIONS: This review indicates that there is a shortage of cost-effectiveness information in leukemia. The introduction of new therapies will stress the need for new economic evaluations in this group of diseases. More information about the total costs, that is, including indirect costs, and quality of life effects would be valuable in future evaluations in leukemia.