Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

The impact of radical parotidectomy with immediate facial nerve reconstruction: a quality-of-life measure.

OBJECTIVE: Immediate facial nerve reconstruction is the standard of care following radical parotidectomy; however, quality of life comparisons with those undergoing limited superficial parotidectomy without facial nerve sacrifice is lacking. METHOD: Patients who underwent parotidectomy were contacted to determine quality of life using the University of Washington Quality of Life and Parotidectomy Specific Quality of Life questionnaires. A total of 29 patients (15 in the radical parotidectomy and 14 in the limited superficial parotidectomy groups) completed and returned questionnaires. RESULTS: Using the University of Washington Quality of Life Questionnaire, similar quality of life was noted in both groups, with the radical parotidectomy group having significantly worse speech and taste scores. Using the Parotidectomy Specific Quality of Life Questionnaire, the radical parotidectomy group reported significantly worse speech, eye symptoms and eating issues. CONCLUSION: Those undergoing radical parotidectomy with reconstruction had comparable overall quality of life with the limited superficial parotidectomy group. The Parotidectomy Specific Quality of Life Questionnaire better identified subtle quality of life complaints. Eye and oral symptoms remain problematic, necessitating better rehabilitation and more focused reconstructive efforts.

Identifying oncogenic drivers associated with increased risk of late distant recurrence in postmenopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study.

BACKGROUND: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. PATIENTS AND METHODS: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. RESULTS: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20-0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30-9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51-19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. CONCLUSIONS: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.

Association of baseline and change in tibial and femoral cartilage thickness and development of widespread full-thickness cartilage loss in knee osteoarthritis - data from the Osteoarthritis Initiative.

OBJECTIVE: To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. METHODS: Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N = 600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1 mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). RESULTS: Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR = 1.20; 95% CI: 1.11, 1.28 and OR = 1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57-0.70) and 0.63 (0.57-0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR = 1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58-0.72). CONCLUSION: Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL.

The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial.

Background: The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359).

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. PATIENTS AND METHODS: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. RESULTS: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. CONCLUSIONS: There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Quality of life predicts overall survival in women with platinum-resistant ovarian cancer: an AURELIA substudy.

BACKGROUND: Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic. PATIENTS AND METHODS: Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic. RESULTS: In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively. CONCLUSIONS: Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making. CLINICAL TRIAL REGISTRATION: NCT00976911.

Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Promising therapeutic results of the prostate-specific membrane antigen (PSMA) ligand have been shown when labelling with lutetium-177 (177Lu). We performed a systematic review and meta-analysis to assess the therapeutic response of 177Lu-PSMA in the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A systematic review was conducted using electronic databases up to December 2016. Two reviewers independently extracted data and assessed methodological quality. The main outcome of interest was antitumour biochemical response of 177Lu-PSMA, analysing two measures: 'any PSA decline' and '>50% decline' from baseline. A random-effects meta-analysis was used to calculate the pooled proportion across studies. The I2 statistic was calculated in each case to investigate the extent of heterogeneity across the studies. A sensitivity analysis was conducted removing two studies, which were presented as abstracts and proportions were summarised by chemical type (177Lu-J591/DKZ/I&T). All analyses were conducted using Stata v14. RESULTS: A total of 10 studies were included in the analysis giving a total sample size of 369, 220 (of 334 analysable) experienced any PSA decline. The pooled proportion of patients with any PSA decline was 68% (95% confidence interval (CI): 61-74). The I2 statistic was 39.1% (P=0.11) suggesting minor heterogeneity between results. The pooled proportion of patients with >50% PSA decline was 37% (95% CI: 22-52). The I2 statistic was 91.0% (P<0.001) suggesting substantial heterogeneity between results. On subgroup analysis, a higher proportion of patients in the 177Lu-DKZ/I&T subgroup had a PSA decline >50%, however, it can be seen that the 177Lu-DKZ/I&T subgroup had a substantial amount of heterogeneity across studies. CONCLUSIONS: This review suggests promising early results for the treatment of mCRPC, especially from patients treated with the more recently developed radioligands. Overall, our meta-analysis showed that approximately two-thirds of patients had a biochemical response. Randomised-controlled trials would be necessary to verify its effectiveness against current systemic therapies and create an ideal treatment protocol.

Validation of preoperative cardiopulmonary exercise testing-derived variables to predict in-hospital morbidity after major colorectal surgery.

BACKGROUND: In single-centre studies, postoperative complications are associated with reduced fitness. This study explored the relationship between cardiorespiratory fitness variables derived by cardiopulmonary exercise testing (CPET) and in-hospital morbidity after major elective colorectal surgery. METHODS: Patients underwent preoperative CPET with recording of in-hospital morbidity. Receiver operating characteristic (ROC) curves and logistic regression were used to assess the relationship between CPET variables and postoperative morbidity. RESULTS: Seven hundred and three patients from six centres in the UK were available for analysis (428 men, 275 women). ROC curve analysis of oxygen uptake at estimated lactate threshold (V˙o2 at θ^L ) and at peak exercise (V˙o2peak ) gave an area under the ROC curve (AUROC) of 0·79 (95 per cent c.i. 0·76 to 0·83; P < 0·001; cut-off 11·1 ml per kg per min) and 0·77 (0·72 to 0·82; P < 0·001; cut-off 18·2 ml per kg per min) respectively, indicating that they can identify patients at risk of postoperative morbidity. In a multivariable logistic regression model, selected CPET variables and body mass index (BMI) were associated significantly with increased odds of in-hospital morbidity (V˙o2 at θ^L 11·1 ml per kg per min or less: odds ratio (OR) 7·56, 95 per cent c.i. 4·44 to 12·86, P < 0·001; V˙o2peak 18·2 ml per kg per min or less: OR 2·15, 1·01 to 4·57, P = 0·047; ventilatory equivalents for carbon dioxide at estimated lactate threshold (V˙E /V˙co2 at θ^L ) more than 30·9: OR 1·38, 1·00 to 1·89, P = 0·047); BMI exceeding 27 kg/m2 : OR 1·05, 1·03 to 1·08, P < 0·001). A laparoscopic procedure was associated with a decreased odds of complications (OR 0·30, 0·02 to 0·44; P = 0·033). This model was able to discriminate between patients with, and without in-hospital morbidity (AUROC 0·83, 95 per cent c.i. 0·79 to 0·87). No adverse clinical events occurred during CPET across the six centres. CONCLUSION: These data provide further evidence that variables derived from preoperative CPET can be used to assess risk before elective colorectal surgery.

The Effect of beta-blockade on objectively measured physical fitness in patients with abdominal aortic aneurysms--A blinded interventional study.

BACKGROUND: Perioperative beta-blockade is widely used, especially before vascular surgery; however, its impact on exercise performance assessed using cardiopulmonary exercise testing (CPET) in this group is unknown. We hypothesized that beta-blocker therapy would significantly improve CPET-derived physical fitness in this group. METHODS: We recruited patients with abdominal aortic aneurysms (AAA) of <5.5 cm under surveillance. All patients underwent CPET on and off beta-blockers. Patients routinely prescribed beta-blockers underwent a first CPET on medication. Beta-blockers were stopped for one week before a second CPET. Patients not routinely taking beta-blockers underwent the first CPET off treatment, then performed a second CPET after commencement of bisoprolol for at least 48 h. Oxygen uptake (.VO2) at estimated lactate threshold and .VO2 at peak were primary outcome variables. A linear mixed-effects model was fitted to investigate any difference in adjusted CPET variables on and off beta-blockers. RESULTS: Forty-eight patients completed the study. No difference was observed in .VO2 at estimated lactate threshold and .VO2 at peak; however, a significant decrease in .VE/.VCO2 at estimated lactate threshold and peak, an increase in workload at estimated lactate threshold., O2 pulse and heart rate both at estimated lactate threshold and peak was found with beta-blockers. Patients taking beta-blockers routinely (chronic group) had worse exercise performance (lower .VO2 ). CONCLUSIONS: Beta blockade has a significant impact on CPET-derived exercise performance, albeit without changing .VO2 at estimated lactate threshold and.VO2 at peak. This supports performance of preoperative CPET on or off beta-blockers depending on local perioperative practice. CLINICAL TRIAL REGISTRATION: NCT 02106286.

DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.

BACKGROUND: Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. PATIENTS AND METHODS: In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes. RESULTS: Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone. CONCLUSIONS: The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy. CLINICAL TRIAL: DOC-MEK (EudraCT no: 2009-018153-23).

Analysis of mobile phone design features affecting radiofrequency power absorbed in a human head phantom.

The US FCC mandates the testing of all mobile phones to demonstrate compliance with the rule requiring that the peak spatial SAR does not exceed the limit of 1.6 W/kg averaged over any 1 g of tissue. These test data, measured in phantoms with mobile phones operating at maximum antenna input power, permitted us to evaluate the variation in SARs across mobile phone design factors such as shape and antenna design, communication technology, and test date (over a 7-year period). Descriptive statistical summaries calculated for 850 MHz and 1900 MHz phones and ANOVA were used to evaluate the influence of the foregoing factors on SARs. Service technology accounted for the greatest variability in compliance test SARs that ranged from AMPS (highest) to CDMA, iDEN, TDMA, and GSM (lowest). However, the dominant factor for SARs during use is the time-averaged antenna input power, which may be much less than the maximum power used in testing. This factor is largely defined by the communication system; e.g., the GSM phone average output can be higher than CDMA by a factor of 100. Phone shape, antenna type, and orientation of a phone were found to be significant but only on the order of up to a factor of 2 (3 dB). The SAR in the tilt position was significantly smaller than for touch. The side of the head did not affect SAR levels significantly. Among the remaining factors, external antennae produced greater SARs than internal ones, and brick and clamshell phones produced greater SARs than slide phones. Assuming phone design and usage patterns do not change significantly over time, we have developed a normalization procedure and formula that permits reliable prediction of the relative SAR between various communication systems. This approach can be applied to improve exposure assessment in epidemiological research.

Sentinel node status predicts survival in thick melanomas: the Oxford perspective.

AIMS: To determine the prognostic value of SLNB in patients with thick melanoma in terms of overall survival (OS) and recurrence-free survival (RFS). METHODS: 136 patients with primary tumours (Breslow thickness ≥ 4.0 mm) underwent SLNB. OS and RFS were calculated and a multivariate Cox regression model used to determine the important prognostic factors for predicting OS and RFS. RESULTS: Median Breslow thickness was 5.5 mm and 60% were ulcerated. Median follow up was 4 years (95% CI = 4-5) with 54 patients having died at the time of analysis. 5-year OS for SLNB positive patients was 32%, compared to 78% for negative patients. The significant predictors of poorer OS were increasing age (p = 0.03), increasing Breslow thickness (p = 0.03) and SLNB positivity (p < 0.0001). 5 year RFS was significantly worse in the SLNB positive population compared to the negative patients (p < 0.0001); 27% versus 66% respectively. CONCLUSIONS: Patients with a thick melanoma and a positive SLNB have a significantly worse RFS and OS compared to those with a negative SLNB. Over three-quarters of patients with a negative SLNB survived five years. These findings have implications for the subpopulations included in adjuvant therapy trials and we advocate SLNB be recommended in patients with thick melanomas.

Variability and constraint in the mammalian vertebral column.

Patterns of vertebral variation across mammals have seldom been quantified, making it difficult to test hypotheses of covariation within the axial skeleton and mechanisms behind the high level of vertebral conservatism among mammals. We examined variation in vertebral counts within 42 species of mammals, representing monotremes, marsupials and major clades of placentals. These data show that xenarthrans and afrotherians have, on average, a high proportion of individuals with meristic deviations from species' median series counts. Monotremes, xenarthrans, afrotherians and primates show relatively high variation in thoracolumbar vertebral count. Among the clades sampled in our dataset, rodents are the least variable, with several species not showing any deviations from median vertebral counts, or vertebral anomalies such as asymmetric ribs or transitional vertebrae. Most mammals show significant correlations between sacral position and length of the rib cage; only a few show a correlation between sacral position and number of sternebrae. The former result is consistent with the hypothesis that adult axial skeletal structures patterned by distinct mesodermal tissues are modular and covary; the latter is not. Variable levels of correlation among these structures may indicate that the boundaries of prim/abaxial mesodermal precursors of the axial skeleton are not uniform across species. We do not find evidence for a higher frequency of vertebral anomalies in our sample of embryos or neonates than in post-natal individuals of any species, contrary to the hypothesis that stabilizing selection plays a major role in vertebral patterning.

An evaluation of self-reported mobile phone use compared to billing records among a group of engineers and scientists.

Most epidemiologic studies of potential health impacts of mobile phones rely on self-reported information, which can lead to exposure misclassification. We compared self-reported questionnaire data among 60 participants, and phone billing records over a 3-year period (2002-2004). Phone usage information was compared by the calculation of the mean and median number of calls and duration of use, as well as correlation coefficients and associated P-values. Average call duration from self-reports was slightly lower than billing records (2.1 min vs. 2.8 min, P = 0.01). Participants reported a higher number of average daily calls than billing records (7.9 vs. 4.1, P = 0.002). Correlation coefficients for average minutes per day of mobile phone use and average number of calls per day were relatively high (R = 0.71 and 0.69, respectively, P < 0.001). Information reported at the monthly level tended to be more accurate than estimates of weekly or daily use. Our findings of modest correlations between self-reported mobile phone usage and billing records and substantial variability in recall are consistent with previous studies. However, the direction of over- and under-reporting was not consistent with previous research. We did not observe increased variability over longer periods of recall or a pattern of lower accuracy among older age groups compared with younger groups. Study limitations included a relatively small sample size, low participation rates, and potential limited generalizability. The variability within studies and non-uniformity across studies indicates that estimation of the frequency and duration of phone use by questionnaires should be supplemented with subscriber records whenever practical.

Measured radiofrequency exposure during various mobile-phone use scenarios.

Epidemiologic studies of mobile phone users have relied on self reporting or billing records to assess exposure. Herein, we report quantitative measurements of mobile-phone power output as a function of phone technology, environmental terrain, and handset design. Radiofrequency (RF) output data were collected using software-modified phones that recorded power control settings, coupled with a mobile system that recorded and analyzed RF fields measured in a phantom head placed in a vehicle. Data collected from three distinct routes (urban, suburban, and rural) were summarized as averages of peak levels and overall averages of RF power output, and were analyzed using analysis of variance methods. Technology was the strongest predictor of RF power output. The older analog technology produced the highest RF levels, whereas CDMA had the lowest, with GSM and TDMA showing similar intermediate levels. We observed generally higher RF power output in rural areas. There was good correlation between average power control settings in the software-modified phones and power measurements in the phantoms. Our findings suggest that phone technology, and to a lesser extent, degree of urbanization, are the two stronger influences on RF power output. Software-modified phones should be useful for improving epidemiologic exposure assessment.

Quantitative evaluations of mechanisms of radiofrequency interactions with biological molecules and processes.

The complexity of interactions of electromagnetic fields up to 10(12) Hz with the ions, atoms, and molecules of biological systems has given rise to a large number of established and proposed biophysical mechanisms applicable over a wide range of time and distance scales, field amplitudes, frequencies, and waveforms. This review focuses on the physical principles that guide quantitative assessment of mechanisms applicable for exposures at or below the level of endogenous electric fields associated with development, wound healing, and excitation of muscles and the nervous system (generally, 1 to 10(2) V m(-1)), with emphasis on conditions where temperature increases are insignificant (<<1 K). Experiment and theory demonstrate possible demodulation at membrane barriers for frequencies < or =10 MHz, but not at higher frequencies. Although signal levels somewhat below system noise can be detected, signal-to-noise ratios substantially less than 0.1 cannot be overcome by cooperativity, signal averaging, coherent detection, or by nonlinear dynamical systems. Sensory systems and possible effects on biological magnetite suggest paradigms for extreme sensitivity at lower frequencies, but there are no known radiofrequency (RF) analogues. At the molecular level, vibrational modes are so overdamped by water molecules that excitation of molecular modes below the far infrared cannot occur. Two RF mechanisms plausibly may affect biological matter under common exposure conditions. For frequencies below approximately 150 MHz, shifts in the rate of chemical reactions can be mediated by radical pairs and, at all frequencies, dielectric and resistive heating can raise temperature and increase the entropy of the affected biological system.