Impact of risk-reducing salpingo-oophorectomy on lipid determinants, HbA1c and CRP.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is advised before 40-45 years of age for BRCA1/2 mutation carriers. This study describes the effect of RRSO on lipid determinants, hemoglobin A1c (HbA1c) and C-reactive protein (CRP). METHODS: A total of 142 women with increased risk of ovarian cancer were included, 92 premenopausal and 50 postmenopausal. Serum levels of low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol and total cholesterol, triglycerides, HbA1c and CRP were determined at three points in time: before (T0) and 6 weeks (T1) and 7 months (T2) following RRSO. The Hot Flush Rating Scale was administered at the same time points. RESULTS: In premenopausal women, levels of HDL-cholesterol, the cholesterol ratio and HBA1c increased significantly over time, although still staying within the reference range. In this group, hot flushes increased over time (p < 0.001). In postmenopausal women, no significant changes were observed following RRSO. At T2, serum LDL-cholesterol, triglycerides, HbA1c and CRP were significantly lower in premenopausal women compared to postmenopausal women, whereas HDL was increased. CONCLUSIONS: Seven months after RRSO, the lipid profile in premenopausal women had changed, although still staying within the reference range. For postmenopausal women, we did not observe any significant changes. Our results do not suggest a worsening of cardiovascular risk within 7 months of RRSO.

Conversion of unresponsiveness to immune checkpoint inhibition by fecal microbiota transplantation in patients with metastatic melanoma: study protocol for a randomized phase Ib/IIa trial.

BACKGROUND: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. METHODS: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. DISCUSSION: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08-02-2022).

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

Safety of hormone replacement therapy following risk-reducing salpingo-oophorectomy: systematic review of literature and guidelines.

Background: Women at high risk to develop ovarian cancer opt for risk-reducing salpingo-oophorectomy (RRSO) to reduce the risk by 80-96%. RRSO leads to a direct onset of menopause in premenopausal women. Hormone replacement therapy (HRT) can be used to mitigate menopausal symptoms after RRSO. However, it is unclear whether HRT in these women is safe in terms of breast cancer (BC) risk. Methods: We performed a literature search and investigated national guidelines on the use of HRT following RRSO in BRCA1 and BRCA2 mutation carriers. We analyzed differences and similarities between the guidelines and describe what these guidelines were based upon. Results: Seven articles regarding HRT following RRSO in BRCA1 and BRCA2 mutation carriers were identified. None of the included studies yielded any evidence that short-term use of HRT following RRSO increases the risk of developing BC or negates the protective effect of RRSO in BRCA1/2 mutation carriers without a personal history of BC. Eleven national guidelines were found and described. Conclusion: Short-term use of HRT after RRSO seems to be safe. The literature is more favorable toward estrogen alone. The ideal dosage and duration of use are unknown and remain to be investigated in future studies.

Does anti-Müllerian hormone predict change in menopausal symptoms following risk-reducing salpingo-oophorectomy? A prospective observational study.

OBJECTIVES: The aim of this study was to investigate whether serum anti-Müllerian hormone (AMH) predicts symptom burden after risk-reducing salpingo-oophorectomy (RRSO) in order to individualize counseling. METHODS: Patient-reported menopausal symptoms, sexual functioning, and psychological distress (depression and anxiety) were assessed 1 day before (T0) and 6 weeks (T1) and 7 months (T2) after RRSO. AMH was assessed before RRSO. Multivariable regression analysis was used to investigate the association between AMH and short-term and long-term change in symptom burden following RRSO. RESULTS: Ninety-one premenopausal women at high risk of ovarian cancer were included. Presurgical AMH was not related significantly to change in symptoms post RRSO. As a secondary outcome we found that regular menses before RRSO was associated specifically with long-term increase in hot flushes (sr = 0.40, p = 0.001; total R2 = 0.171) and depression (sr = 0.29, p = 0.012; total R2 = 0.132). Earlier receipt of chemotherapy was associated with long-term improvement in sexual functioning (sr = 0.24, p = 0.041; total R2 = 0.348). CONCLUSION: In this cohort, AMH was not a significant predictor of change in symptoms following RRSO. Regular menses prior to RRSO and earlier receipt of chemotherapy were significantly, but relatively weakly, associated with changes in outcomes 6 weeks and/or 7 months after RRSO.

Diagnostic validation and interpretation of longitudinal circulating biomarkers using a biomarker response characteristic plot.

BACKGROUND: Serum-based tumor biomarkers are used to monitor cancer treatment, while clear guidance on the clinical usage is often lacking. We describe a graphical presentation to support diagnostic accuracy studies and clinical interpretation of longitudinal biomarker data. METHODS: A biomarker response characteristic (BReC) plot was designed. To allow demonstration of the BReC plot application, software was developed that supported 1) dynamic generation of BReC plots, and 2) diagnostic accuracy studies of biomarker response-based medical tests. The BReC plot application was demonstrated using serial carcinoembryonic antigen (CEA) and Cyfra 21.1 results from 216 patients with metastasized non-small cell lung cancer, treated with Nivolumab in routine clinical practice. RESULTS: The developed software supported the generation of BReC plots and diagnostic validation of biomarker response-based medical tests by generating the sensitivity, specificity and predictive values. Obtained BReC plots showed a clear relationship between clinical outcome and CEA and Cyfra 21.1 responses. Furthermore, using BReC plots, CEA and Cyfra 21.1 based medical tests were designed with a sensitivity for detection of treatment failure of 0.34 and 0.35 and a specificity of 0.96. CONCLUSIONS: The BReC plot appears to support diagnostic validation studies and the interpretation of longitudinal biomarkers though further validation is warranted.

Impact of risk-reducing salpingo-oophorectomy in premenopausal women.

OBJECTIVES: To describe implications of premenopausal risk-reducing salpingo-oophorectomy (RRSO) on quality of life, endocrine symptoms, sexual function, osteoporosis, cardiovascular health, metabolic syndrome, cognitive impairment and safety of hormone replacement therapy. METHODS: We searched the following electronic databases: The Cochrane Library, EMBASE, PsycInfo, and MEDLINE. We selected controlled and uncontrolled trials of premenopausal women undergoing RRSO. Two authors independently assessed studies for inclusion. Reference lists of included reports were searched manually for additional studies. RESULTS: Surgical menopause leads to more menopausal complaints and sexual dysfunction than natural menopause. Overall quality of life is not affected by surgery. In the limited literature, there is no evidence that RRSO leads to more osteopenia in comparison with natural menopause at a young age. Cohort studies show a slight impaired cardiovascular health. Cognitive function decreases later in life in premenopausal oophorectomized women. Short-term hormone replacement therapy seems to decline postmenopausal complaints and does not seem to increase the risk for breast carcinoma in mutation carriers without a personal history of breast carcinoma. CONCLUSIONS: The conclusions of this systematic review are limited by the absence of randomized, controlled trials. There is growing evidence from observational studies that RRSO may impact negatively on all-cause non-survival endpoints.

Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer.

The extent of surgery and the decision for adjuvant treatment in patients with endometrial cancer (EC) depend on the presence of risk factors for lymph node metastases and disease recurrence. Postoperative markers such as myometrial infiltration and specific mutations can select patients for adjuvant treatment but will not influence surgical planning. A biomarker stratifying patients into low-risk and high-risk groups before surgery could identify patients who benefit from more extensive surgery. Therefore, we evaluated the correlation of serum biomarker HE4 with clinical and recently identified prognostic pathological variables and survival. Patients treated for endometrial cancer between 1994 and 2014 were included. Serum HE4 concentration was measured in preoperatively obtained samples. A total of 88 patients were eligible for analysis. The majority (64%) was diagnosed with endometrioid-type adenocarcinoma. Serum HE4 concentration is significantly associated with stage of disease (p = 0.001), deep myometrial invasion (p < 0.001), exact depth of myometrial invasion (≥4 mm) (p = 0.01), tumour-free distance to serosa (≤7 mm) (p < 0.001), extensive lymph vascular space invasion (p = 0.04) and cervical involvement (p = 0.001). HE4 concentration and nodal involvement were correlated, although not significant (p = 0.17). Serum HE4 is an independent prognostic factor for recurrence-free survival (HR 5.12 per 10-fold increase in HE4, 95% CI 1.54-17.1) and overall survival (HR 7.48 per 10-fold increase in HE4, 95% CI 1.76-31.7). HE4 is a prognostic marker in endometrial cancer and is helpful in addition to other variables for the preoperative risk stratification of patients with endometrial cancer.

New biomarkers in epithelial ovarian cancer: needed or redundant?

OBJECTIVE: For many years, intensive research has been dedicated to the development of sensitive biomarkers to detect various malignant diseases, including for the differentiation between a benign or malignant ovarian mass. One of these biomarkers is human epididymal protein 4 (HE4), which has been shown to have a higher specificity than, and comparable sensitivity to CA 125. HE4 is included in some predictive models. These new models have not yet been widely implemented in standard clinical care. The authors investigated the perceived need for new biomarkers and prediction models among Dutch gynecologists. MATERIALS AND METHODS: A web-based survey containing 38 questions was sent to all gynecologists (in training) registered by the Dutch Society of Obstetrics and Gynecology. RESULTS: 313 respondents completed the survey (23% response rate), of which 29% were specialized in or devoted at least part of their practice to oncology. Approximately two-thirds of the respondents indicated that there is a need for a new biomarker. Respondents indicated that they would use HE4 primarily as a diagnostic tool in the case of a pelvic mass (57%), followed by screening in case of risk factors (30%), detection of recurrent disease (23%), monitoring therapy response (22%), and as a prognostic factor (10%). Only 11% would not use HE4 at all. CONCLUSION: Evaluating the need for new technologies and diagnostics, including biomarkers, is important to avoid expensive research with min- imal clinical implications. In general, there is a perceived need for a new biomarker, if it can be used to improve the accuracy of diagnosis in patients with a pelvic mass.

Serum human epididymal protein 4 (HE4) as biomarker for the differentiation between epithelial ovarian cancer and ovarian metastases of gastrointestinal origin.

OBJECTIVE: About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of human epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated. METHODS: HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology. RESULTS: Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases. CONCLUSION: HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin.

A predictive model combining human epididymal protein 4 and radiologic features for the diagnosis of ovarian cancer.

OBJECTIVE: Ovarian cancer is the leading cause of death in women with gynecologic cancer. CA125 is the commonly used biomarker in the diagnosis of ovarian cancer, but has limitations in both sensitivity and specificity. Human Epididymal secretory protein (HE4) is a promising biomarker and is included in the Risk of Ovarian Malignancy Algorithm (ROMA) score, which is suggested to further increase the diagnostic accuracy than either marker alone. However, information from ultrasound and CT-scan is not included in this algorithm. This study evaluated the diagnostic accuracy of HE4 in the pre-operative diagnosis of ovarian cancer and the predictive values of biomarkers, ultrasound and CT-scan and combinations hereof. METHODS: HE4 and CA125 were measured in 361 subjects (34 benign, 147 ovarian cancer and 180 controls). Sensitivity, specificity and area under the curve (AUC) for CA125, HE4, ROMA and RMI scores were calculated using the receiver operating characteristic (ROC) methodology. The additional predictive value of ultrasound or CT-scan to the individual markers was analyzed using logistic regression. RESULTS: The sensitivity in predicting ovarian cancer of CA125 was 91% and of HE4 90%. The specificity was 65% and 97% respectively. HE4 demonstrated the highest discrimination (ROC-AUC=0.96), compared to ROMA, RMI and CA125 (AUC=0.95, 0.89 and 0.90 respectively). ROMA did not improve when it was combined with different ultrasound factors. The presence of intra-abdominal metastasis on CT-scan improved the discriminative potential of HE4 (p=0.0004). CONCLUSION: HE4 in combination with CT-scan may be incorporated in the diagnostic work-up in women with a pelvic mass.

Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours.

BACKGROUND: The aim of this prospective study was to examine whether discontinuation of proton pump inhibitors (PPIs) or replacement by H(2)-receptor antagonists (H2RA) resulted in a decrease of chromogranin A (CgA) levels in 196 patients with well-differentiated neuroendocrine tumours (NETs). METHODS: Patients with an unexpectedly high CgA level not connected with NET disease discontinued PPIs, or used H2RA instead; 2 weeks later CgA level was measured again. RESULTS: In all, 19 out of 196 (10%) patients showed unexpected elevated CgA levels, they all used PPI. In 11 out of 19 patients with no evidence of the disease, median CgA decreased from 390 µg l(-1) during PPI treatment to 56 µg l(-1) after discontinuation (P=0.003). In 8 out of 19 patients with stable disease, median CgA decreased from 618 to 318 µg l(-1) (P=0.012). In 12 out of 19 patients who ceased all acid inhibition, CgA levels decreased by 82%, while in the seven patients who replaced PPI by H2RA, CgA decreased by 77% (P=0.967). CONCLUSION: Proton pump inhibitor use causes falsely elevated CgA levels in patients with NET. We recommend to stop, or replace PPI by H2RA, to obtain a reliable CgA value.

An elevated progastrin-releasing peptide level in patients with well-differentiated neuroendocrine tumours indicates a primary tumour in the lung and predicts a shorter survival.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small-cell lung cancer. In well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. PATIENTS AND METHODS: Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess specificity and sensitivity in the identification of a primary tumour location. Cox proportional hazards models and Kaplan-Meier curves were constructed to determine the association of patients' characteristics and tumour markers with survival. RESULTS: For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a specificity of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). CONCLUSIONS: A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour.

Soluble epidermal growth factor receptor (sEGFR) and carcinoembryonic antigen (CEA) concentration in patients with non-small cell lung cancer: correlation with survival after erlotinib and gefitinib treatment.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), a higher response rate can be achieved with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) when selection for therapy is guided by mutation analysis or gene amplification. However, both tests are complex and require tumour tissue. Simple methods to identify responders prior to EGFR-TKI treatment are urgently needed. This study aimed to define the relation between serum sEGFR levels, carcinoembryonic antigen (CEA) and survival in NSCLC patients treated with EGFR-TKIs. METHODS: Patients with stage III/IV NSCLC treated with gefitinib or erlotinib between July 2002 and December 2005 were reviewed. Levels of serum soluble EGFR (sEGFR) were determined by a sandwich quantitative enzyme-linked immunosorbent assay. A chemiluminescence immunoassay was used for CEA. The relation between sEGFR and survival was investigated. RESULTS: One hundred and two NSCLC patients, mainly stage IV (80%), were identified. Mean sEGFR at baseline was 55.9 µg/l (range 35.3-74.5 µg/l). The median CEA level was 11.1 µg/l (range <1.0-2938.0 µg/l). Median overall survival was 5.2 months (range 1-52 months). Decreasing log CEA values (HR 1.51, 95% CI 1.11-2.04, multivariate analysis) and increasing sEGFR values (HR 0.96, 95% CI 0.93-0.99, multivariate analysis) were both independently associated with prolonged survival. Higher levels of pre-treatment sEGFR were associated with lower risk of progressive disease within three months (p=0.04). CONCLUSIONS: Both baseline sEGFR and CEA levels in NSCLC patients receiving EGFR-TKIs showed a significant correlation with survival. To distinguish whether these factors have a predictive or a prognostic value, validation is warranted in an independent patient series containing a control arm without EGFR-TKI treatment.

Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models.

BACKGROUND: In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). PATIENTS AND METHODS: Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. RESULTS: SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5 x 10(-9), P = 1.1 x 10(-7) and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaike's Information Criteria (AIC) = 732, P = 5.2 x 10(-7)]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3 x 10(-11)) more robustly than the MSKCC model (AIC = 729, P = 1.3 x 10(-7)). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. CONCLUSIONS: Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.

S-100B protein and melanoma inhibitory activity protein in uveal melanoma screening. A comparison with liver function tests.

AIM: Our purpose was to determine whether S-100B or melanoma inhibitory activity (MIA) concentrations in the serum of patients with large uveal melanomas were better markers for the presentation of metastases than liver function tests. We also investigated whether increased marker levels were related to known clinical and histopathological prognostic parameters. METHODS: Total S-100B (A1B + BB) and MIA concentrations were measured in the sera from 104 patients with uveal melanoma prior to enucleation and in the sera from 50 healthy controls. Concentrations were also determined in the sera from 30 patients with known uveal melanoma metastases. Liaison Sangtec 100, an automated immunoluminometric assay measuring the total S-100B, and Roche MIA ELISA were used to quantify these proteins in serum. Results were compared with liver function tests [alkaline phosphatase, lactate dehydrogenase (LD), aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase]. RESULTS: The mean S-100B and MIA concentrations were significantly higher in patients with metastases compared to melanoma patients without metastases. At the time of enucleation, S-100B and MIA were not prognostic for metastases in uveal melanoma, but S-100B and LD were the best tests to predict the occurrence of metastatic disease during the follow-up period. CONCLUSIONS: In our study, the S-100B and MIA serum concentrations were not correlated with any tested established prognostic parameter. S-100B and LD showed better performance in identifying melanoma metastases than gamma-glutamyl transpeptidase and MIA. A prospective follow-up study is needed to evaluate S-100B and MIA in identifying early micrometastasis in uveal melanoma.

Comparison of four different assays for determination of serum S-100B.

BACKGROUND: S-100B determination has been shown to be clinically useful in the management of melanoma patients. After the development of a test for determination of the isoforms S100-A1B and S100-BB in serum (S-100B), several sensitive assays for the detection of serum S-100B have become available. We compared four S-100B assays, two automated (LIAISON Sangtec 100 and Elecsys S100) and two manual ones (Sangtec 100 ELISA and CanAg S100 EIA), with respect to clinical data, reference values and correlation. METHODS: In a total of 280 samples from 155 melanoma patients and 98 healthy individuals S-100B values were measured simultaneously with the different assays. RESULTS: The inter and intra coefficients of variation were best for the automated assays. The functional sensitivity of both manual assays was 0.15 microg/L. Method comparison revealed satisfactory correlation coefficients of 0.9 or higher, but the slopes ranged from 0.29 to 3.36. Except for the Sangtec 100 ELISA, the linearity between the assays was acceptable. The overall sensitivity for melanoma ranged from 37% (Elecsys S100) to 47% (LIAISON Sangtec 100) and the sensitivity increased with stage. ROC curves showed the best accuracy for the LIAISON Sangtec 100 assay. CONCLUSIONS: All assays gave satisfactory results, but it is advisable to improve the performance of the manual assays for better sensitivity. Agreement about an international reference standard is needed.