Health-related quality of life in women with recurrent ovarian cancer receiving paclitaxel plus trebananib or placebo (TRINOVA-1).

BACKGROUND: To evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase III study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved progression-free survival (PFS) compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% confidence interval 0.57-0.77; P < 0.001). PATIENTS AND METHODS: HRQoL was assessed with the Functional Assessment of Cancer Therapy-Ovary [FACT-O; comprising FACT-G and the ovarian cancer-specific subscale (OCS)] and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate the influence of patient dropout on FACT-O and OCS scores over time. RESULTS: Of 919 randomized patients, 834 (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks, mean ± SD changes from baseline were negligible, with mean ± SD changes typically <1 unit from baseline: -2.4 ± 16.6 in the trebananib arm and -1.6 ± 15.2 in the placebo arm for FACT-O, -0.71 ± 5.5 in the trebananib arm and -0.86 ± 4.9 in the placebo arm for OCS, and -0.02 ± 0.22 in the trebananib arm and 0.02 ± 0.19 in the placebo arm for EQ-5D. Distribution of scores was similar between treatment arms at baseline and over the course of the study. In pattern-mixture models, there was no evidence that patient dropout affected differences in mean FACT-O or OCS scores. Edema had limited effect on either FACT-O or OCS scores in patients with grade ≥2 edema or those with grade 1 or no edema. CONCLUSIONS: Our results demonstrate that the improvement in PFS among patients in the trebananib arm in the TRINOVA-1 study was achieved without compromising HRQoL. CLINICALTRIALSGOV IDENTIFIER: NCT01204749.

Risk factors for bone pain among patients with cancer receiving myelosuppressive chemotherapy and pegfilgrastim.

PURPOSE: The purpose of this study was to evaluate risk factors for bone pain in patients receiving myelosuppressive chemotherapy and pegfilgrastim. METHODS: Individual patient data from 22 pegfilgrastim clinical trials were analyzed. Multivariable logistic regression models were used to evaluate risk factors associated with grade ≥2 bone pain and any grade bone pain in the first chemotherapy cycle and across cycles 1-6. RESULTS: Of the 1949 patients analyzed, 19 and 36 % had grade ≥2 and any grade bone pain, respectively, in cycle 1, and 28 and 51 % had grade ≥2 and any grade bone pain, respectively, across cycles 1-6. In cycle 1, history of bone pain (odds ratio (OR), 1.51; 95 % confidence interval (CI), 1.09-2.07) was associated with increased risk of grade ≥2 bone pain; age ≥65 years (versus <45 years; OR, 0.64; 95 % CI, 0.42-0.98), the European Union region (versus the USA region; OR, 0.32; 95 % CI, 0.20-0.52), colorectal cancer (versus breast cancer; OR, 0.14; 95 % CI, 0.05-0.41), and small-cell lung cancer (OR, 0.34; 95 % CI, 0.12-0.98) were associated with reduced risk of grade ≥2 bone pain. CONCLUSIONS: Potential risk factors for bone pain in patients receiving myelosuppressive chemotherapy and primary prophylactic pegfilgrastim identified in this study are younger age and history of bone pain. No other association with clinical factors and risk of bone pain was detected. Better understanding of risk factors for bone pain would be useful in identifying patients who may benefit from pain prevention strategies.

Adapted Finnish Migraine-Specific Questionnaire for family studies (FMSQ(FS)): a validation study in two languages.

BACKGROUND AND PURPOSE: The hypothesis of a genetic component in the etiology of migraine is getting a foothold. However, to explore genetic associations, precision in clinical phenotypization is crucial. For this reason, migraine-specific questionnaires, well discriminating between primary headaches, are required when large numbers of individuals need to be assessed. METHODS: We adapted and translated in two languages, German and Italian, the Finnish Migraine-Specific Questionnaire for use in family studies. RESULTS AND CONCLUSIONS: This adaptation proved to be reliable when differentiating from primary headaches, and to be in very good agreement with the standard for comparison. However, discriminating between migraine with and without aura still relays on a specialist evaluation. This article describes the validation of this questionnaire.

Population isolates in South Tyrol and their value for genetic dissection of complex diseases.

The study of genetic isolates is a promising approach for the study of complex genetic traits. The small and constant population size, lack of migration, and multiple relationships between individuals in the isolate population could reduce the genetic diversity, and lead to increased levels of linkage disequilibrium (LD). We studied the extent of LD on Xq13 in six population isolates from South Tyrol in the Eastern Italian Alps. We found different levels of LD in our study samples, probably reflecting their degrees of isolation and their demographic histories. The highest values were obtained in Val Gardena (ranking among the highest levels of LD in Europe) and in Stelvio, which qualified as a microisolate according to historical information, and biodemographic and genealogical criteria. Phylogenetic analysis revealed that the two Ladin-speaking populations are genetically distant from each other, and from their German-speaking neighbours, and are characterized by a smaller effective population size than the neighbouring valleys. These peculiar characteristics suggest that South Tyrol could be a unique resource for the study of complex diseases, showing all the characteristics of isolated populations with the advantage of including, in a fairly homogeneous environment, two genetically differentiated sub-populations. This could allow investigators to gain an insight into the contribution of genetic heterogeneity in complex diseases.

Sentinel-node biopsy for axillary staging in breast cancer: results from a large prospective German multi-institutional trial.

PURPOSE: To analyse the reliability of sentinel-node biopsy (SNB) in a multicentre setting and define conditions for the routine use of the procedure. MATERIAL AND METHODS: SNB with consecutive axillary clearing was performed in 1124 breast cancer patients. The detection rate of a sentinel lymph node and its dependence on the choice of lymphography technique, patient selection, and technical procedure were analysed. The diagnostic performance of the sentinel-node method was compared to clinical, ultrasound-guided and histological staging. In order to study training effects all learning periods were included. RESULTS: Twenty-two institutions with a total of 89 surgeons participated in the trial. The detection rate (overall: 85.2%) was found to be related to the applied lymphography technique, the experience of the institution and various technical factors of the procedure itself. The false-negative rate (FNR, overall: 8.2%) was independent of patient selection and technical features. The FNR did not depend on experience in the application of the method, but seemed related to surgical accuracy to detect sentinel nodes. Compared to conventional staging procedures (palpation, ultrasound) SNB yielded highly reproducible results for the prediction of the axillary status even in a multicentre setting involving surgeons with different training status. CONCLUSION: SNB is suited as standard of care procedure. Measures of quality control appear more important than learning periods to minimize the FNR.

Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: a hospital-based study.

The genetic basis for nonmedullary forms of thyroid cancer (NMTC) is less well established than that of medullary thyroid cancer. However, epidemiological and family studies suggest that a proportion of NMTC may be due to inherited predisposition. To estimate the familial risk of thyroid cancer, we conducted a hospital-based case-control study at the Princess Margaret Hospital in Toronto, Ontario, Canada, and at 2 university hospitals in Montréal, Québec, Canada. We obtained pedigrees from 339 unselected patients diagnosed with NMTC and from 319 unaffected ethnically matched controls. Family histories of cancer were obtained from the cases and controls for 3292 first degree relatives of cases and controls. Seventeen cases (5.0%) and 2 controls (0.6%) reported at least one first degree relative with thyroid cancer. In relatives of patients with thyroid cancer, the incidence of any type of cancer (including NMTC) was 38% higher than in relatives of controls (incidence rate ratio, 1.4; 95% confidence interval, 1.1-1.7). The relative risk for thyroid cancer was 10-fold higher in relatives of cancer patients than in controls (incidence rate ratio, 10.3; 95% confidence interval, 2.2-47.6). Our findings suggest that hereditary or other familial factors are important in a small proportion of NMTC. Molecular studies are needed to determine the genetic basis of cancer susceptibility in these families.

Autoimmunity against p53 predicts invasive cancer with poor survival in patients with an ovarian mass.

Serum autoantibodies against the p53 protein (p53 AAb) were analysed with a newly developed enzyme-linked immunosorbent assay (ELISA) based on highly purified and renatured p53. In a hospital-based cohort study, preoperative sera from 113 patients with ovarian cancer, 15 patients with borderline tumours and 117 patients with benign tumours of the ovaries were studied. The prevalence of p53 AAb in patients with invasive cancer was 19% (21/113). No p53 AAb were found in patients with borderline lesions or benign tumours. The ELISA had a specificity for malignancy of 99% (1 of 117; false-positive from a patient with severe diabetes mellitus) and a likelihood ratio (LR+) for a positive test result of 21.7 (elevated CA125 and malignancy: LR+ 3.7). p53 AAb were only detectable in patients with immunohistochemical staining of nuclear p53 in the tumour (P = 0.006). Presence of p53 AAb positively correlated with tumour stage (P = 0.034) and grade (P = 0.009). Kaplan-Meier analysis showed both a shortened overall survival (P = 0.0016, log-rank) and relapse-free survival (P = 0.055) for p53 AAb-positive patients (median follow-up 22 months). High titres related to even worse prognosis. p53 AAb independently related to poor survival adjusting for stage (P = 0.026), grade (P = 0.029) and residual disease after surgery (P = 0.005). Preoperative findings of adnexal mass with serum p53 AAb are strongly suggestive of an aggressive invasive ovarian cancer.

Soluble CD44 splice variants and pelvic lymph node metastasis in ovarian cancer patients.

Alternative splicing of CD44 and aberrant levels of soluble CD44 protein in the serum of cancer patients has been correlated to tumor progression and metastasis. To examine the clinical value of CD44 serum levels (sCD44) in ovarian cancer we determined concentrations of the soluble, variable isoforms sCD44std, sCD44v5 and sCD44v6 with a sensitive ELISA. Pre-operative serum samples from 66 patients with histologically diagnosed invasive disease as well as sera taken from 40 healthy blood donors were analyzed. In sera of ovarian cancer patients we detected elevated concentrations of overall CD44 serum levels represented by sCD44std (p=0.001), but decreased levels of the specific isoforms CD44v5 (p=0.0002) and v6 (p=0.0001). This is the first report demonstrating that ovarian cancer patients with pelvic lymph node metastasis at the time of diagnosis showed specifically elevated sCD44v6 (p=0.073) serum concentrations in comparison to patients without lymph node involvement, whereas overall sCD44 serum levels did not differ. Decreased serum levels of sCD44v5 were found in progesterone receptor-positive tumors (p=0. 059) and postmenopausal patients (p=0.032). Increased concentrations of sCD44v6 were detectable in estrogen receptor-positive tumors but not significantly (p=0.138). Serum CD44v5 levels were associated with shortened relapse-free survival time. No association was found between serum CD44 isoforms and the classical clinicopathological parameters stage and grading or overall survival. CD44 splice variants are possibly involved in a complex interaction with the hormonal environment during tumorigenesis and metastasis of ovarian cancer.

Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in situ of the breast.

Five of 43 patients (11.6%) with ductal carcinoma in situ of the breast presented with p53 autoantibodies at diagnosis. Three seropositive patients demonstrated tumour sizes of < or = 5 mm. There was no association of p53 autoantibody status with age, clinical presentation, histological subtype, tumour size, grading, p53 immunohistochemistry or hormone receptor status.

p53 autoantibodies in patients with primary ovarian cancer are associated with higher age, advanced stage and a higher proportion of p53-positive tumor cells.

Autoantibodies (AAb) directed against the nuclear phosphoprotein p53 can be detected in patients with various forms of cancer. The objective was to determine the prevalence of p53 AAb at the time of diagnosis in ovarian cancer patients and to correlate the presence of p53 AAb with clinicopathological parameters. Sera of 83 patients were analyzed by an ELISA using p53 expressed from a human wild-type cDNA. p53 AAb were detectable at all stages. The overall prevalence was 46%. p53 AAb were more frequent in patients with higher age (p = 0.014), postmenopausal status (p = 0.050), or advanced tumor stage (p = 0.046). p53 AAb positivity was related to the proportion of cells positive in immunohistochemistry but not with the staining intensity. In bivariate analysis, patients with p53 AAb had a 1.96-fold risk for relapse (95% confidence interval 1.02-3.78).