Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Phosphatidylethanolamine is progressively exposed in RBCs during storage.

BACKGROUND: It is well established that as a blood unit ages, fewer of the unit's red blood cells (RBCs) remain in circulation post-transfusion. The mechanism for clearance is not well defined. Phosphatidylethanolamine (PE) is a phospholipid that is primarily found on the inner leaflet of healthy cells, and is an important ligand for phagocytosis of dead cells when exposed. OBJECTIVES: The objective of the present study was to measure the change in PE exposure in donor RBCs over increasing storage ages using the novel PE-specific probe, duramycin. METHODS: Five adsol (AS-1) preserved RBC units were sampled weekly for 6 weeks and were labelled with duramycin. The percentage of PE exposed on red cells in each sample was determined using flow cytometry. Surface phosphatidylserine (PS) was evaluated for comparison. RESULTS: We found that RBCs in AS-preserved donor units increasingly exposed PE, from less than 1% in freshly processed RBCs, to nearly 20% at 42 days of storage and correlated with increased relative vesiculation or microparticle concentration and release of cell-free haemoglobin. By comparison, only 5% of cells exposed PS at 42 days. CONCLUSION: We conclude that exposure of PE in the RBC outer membrane was higher than that of PS during 42 days of storage and correlated significantly with increased vesiculation and release of haemoglobin.

Identification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set.

Multiple studies have identified loci associated with the risk of developing prostate cancer but the associated genes are not well studied. Here we create a normal prostate tissue-specific eQTL data set and apply this data set to previously identified prostate cancer (PrCa)-risk SNPs in an effort to identify candidate target genes. The eQTL data set is constructed by the genotyping and RNA sequencing of 471 samples. We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals. We analyse cis-acting associations where the transcript is located within 2 Mb (±1 Mb) of the risk SNP interval. Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates. Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes. This study provides a rich resource to study biological mechanisms underlying genetic risk to PrCa.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.

The effect of core suture flexor tendon repair techniques on gliding resistance during static cycle motion and load to failure: a human cadaver study.

The purpose of this study was to describe a modification of the Massachusetts General Hospital (MMGH) tendon repair and to compare it with three other suture techniques. Twenty human flexor digitorum profundus (FDP) tendons were randomly assigned to the modified Pennington (MP) suture and the MMGH suture. These were compared to the modified Kessler (MK) and Massachusetts General Hospital (MGH) sutures, using data from a previous study. All tendons were repaired with a similar epitendinous stitch and core sutures of 4-0 FiberWire. There was no significant difference in the normalized gliding resistance within the two-strand or four-strand core repair groups. The MP suture had significantly higher 2 mm gap force and ultimate load to failure than the MK suture. The MMGH suture had significantly higher 2 mm gap force and maximum failure ultimate load than the MGH suture. All repairs failed by knot unravelling.

Behavioral and physiological responsivity, sleep, and patterns of daily cortisol production in infants with and without colic.

To describe the behavioral and physiological responses associated with colic, the responses of 20 two-month-old infants with and 20 without colic were studied during a physical examination. Parents kept a diary of infant behaviors (including crying and fussing) for 3 days following the visit. Using Wessel, Cobb, Jackson, Harris, & Detwiler criteria, colic was defined as fussing/crying for 3 hr or more on each of the 3 days. Behavioral data coded by "blind" observers showed that during the physical exam, colic infants cried twice as much, cried more intensely, and were more inconsolable than were control infants. Despite these behavioral differences, heart rate, vagal tone, and cortisol measures indicated no appreciable difference in physiological responsivity for the two groups. At home, parents collected saliva cortisol samples at wakeup, midmorning, midafternoon, and evening for 2 days. In a finding similar to that shown by the laboratory data, the colic and control infants did not have different levels of daily average cortisol. These laboratory and home data provide no evidence of greater responsivity in the physiological substrate of difficult temperament for colic infants and are consistent with evidence of similarity in temperament once colic is resolved. At home, compared with control infants, colic infants did display a blunted rhythm in cortisol production. By diary, they also slept about 2 hr less per day than did control infants. Nighttime sleep was still significantly different when fussing/crying was statistically controlled. These data suggest that colic might be associated with a disruption or delay in the establishment of the circadian rhythm in activity of the hypothalamic-pituitary-adrenocortical axis and associated sleep-wake activity.

Dampening of the cortisol response to handling at 3 months in human infants and its relation to sleep, circadian cortisol activity, and behavioral distress.

The decrease in responsiveness of the hypothalamic-pituitary-adrenocortical (HPA) system is marked over the first months of life. Seventy-eight healthy infants (44 girls), 7 to 15 weeks old, were given a laboratory mock physical examination. Salivary cortisol samples were collected pre- and postexamination and at home. Behavioral state during the examination and home sleep/wake activity were measured. Subjects younger than 11 weeks showed an increase in pre- to postexamination cortisol, while older subjects did not. Further, there was no decrease in behavioral distress to the examination with age. Infants who showed an early- morning peak (EMP) in home cortisol levels were significantly older and were likely to be those who slept through the night. However, the presence of an EMP was not associated with a lack of cortisol response to the examination. The decrease in cortisol responsiveness witnessed around the age of 3 months is presumably due to other processes associated with age, and not with the expression of the day-night rhythm in basal cortisol.

The regulation by gender, strain, dose, and feeding status of the induction of multiple forms of cytochrome P450 isozymes in rat hepatic microsomes by 2,4,5,2',4',5'-hexachlorobiphenyl.

2,4,5,2',4',5'-hexachlorobiphenyl (HCB) induces hepatic microsomal cytochromes P450 with a similar selectivity for responsive genes to phenobarbital (PB). CYP2Bl, CYP2B2, CYP2C6, CYP3Al, and CYP2Al each showed large strain differences in induction by HCB Fisher F344 >> Wistar Furth (WF) that were much more evident in female rats, paralleling previous observations with PB. These five P450s and epoxide hydrolase were, however, induced more effectively by HCB than by PB and strain differences were even larger. With HCB, strain differences in male rats were much more apparent than with PB. This change was not due to the greater HCB induction since a 2-fold lower induction was maintained even with a 10-fold lower dose of HCB. The sex and strain differences were seen both by immunoblot analysis and by form-selective enzyme activity assays. induction of CYP2B1, CYP2B2, and CYP3A1 by HCB was decreased 3-fold when starvation during the final 24 hr was replaced by continuous feeding. This effect was similar in each strain and therefore independent of the regulatory processes associated with the differential suppression of induction in WF rats. This modulation of induction by feeding was also seen with PB which caused only a 30% lowering of induction in continuously fed F344 rats. A 52-kDa microsomal protein (p52) was prominently induced by both HCB and PB after starvation, while minor induction of a 50-kDa microsomal protein (p50) also occurred after the same treatment. Furthermore, a 100-kDa microsomal protein (p100) was induced by HCB but not by PB and only in rats that were continuously fed. These results suggest that the induction of multiple forms of P450 following HCB treatment functions through the same PB-stimulated pathway that shows a strain-dependent endocrine (GH/T3/testosterone)-sensitive suppression mechanism. The induction of p5O, p52, and plOO by HCB suggests the presence of at least two additional hepatic response mechanisms for HCB.

Neonatal stress reactivity: predictions to later emotional temperament.

To investigate the relations among popular measures of neonatal stress and their link to subsequent temperament, 50 full-term newborns from a normal care nursery were examined responding to a heelstick blood draw. Baseline and heelstick measures of behavioral state, heart period, vagal tone, and salivary cortisol were obtained. Recovery measures of behavioral and cardiac activity were also analyzed. Mothers completed Rothbart's Infant Behavior Questionnaire when their infants reached 6 months of age. Baseline vagal tone predicted cortisol in response to the heelstick, suggesting that baseline vagal tone reflects the infants' ability to react to stressors. Greater reactivity to the heelstick (more crying, shorter heart periods, lower vagal tone, and higher cortisol) was associated with lower scores on "Distress-to-Limitations" temperament at 6 months. This finding was consistent with the expectation that the capacity to react strongly to an aversive stimulus would reflect better neurobehavioral organization in the newborn. Recovery measures of cardiac activity approximated and were correlated with baseline measures indicating the strong self-righting properties of the healthy newborn. Finally, vagal tone and salivary cortisol measures were not significantly related, suggesting the importance of assessing both systems in studies of the ontogeny of stress-temperament relations.

The stressfulness of separation among nine-month-old infants: effects of social context variables and infant temperament.

This manuscript reports on the results of 2 experiments dealing with behavioral and adrenocortical responses to separation among 9-month-old human infants. In both experiments the social context of separation was manipulated. The results of Experiment 1 yielded evidence of a statistically significant adrenocortical response to 30 min of separation under conditions in which the substitute caregiver responded sensitivity to infant distress, but was busy and relatively noninteractive when babies were not distressed during the separation period. Altering the behavior of the substitute caregiver such that she was warm, responsive, and interactive throughout the separation produced a significant reduction in adrenocortical activity and in negative affect. In fact, these measures were not significantly different than those obtained when the mother and infant remained together in the playroom (No Separation). In Experiment 2, the effects of group versus singleton care were examined using the less stressful mode of substitute caregiving as described above. No significant condition differences in behavioral distress or cortisol were found. Furthermore, neither condition elicited a significant increase in cortisol over basal levels. Finally, these data provide evidence that maternal reports of infant Distress to Limits temperament, using Rothbart's Infant Behavior Questionnaire, predict adrenocortical responses to separation, while reports of Fear of Novelty do not.

The effects of morning naps, car trips, and maternal separation on adrenocortical activity in human infants.

3 studies of adrenocortical activity in healthy 9-month-old infants were conducted to examine unanticipated results obtained in previous research. In the first study, morning naps were examined and found to be associated with significant decreases in salivary cortisol. These decreases were followed by a significant return to prenap cortisol concentrations. In the second study, riding for 40 min in the car was also shown to significantly lower salivary cortisol concentrations. This effect was obtained both for infants who did and who did not sleep during the car trip. In the third study, the effect of 30 min of maternal separation in the laboratory on salivary cortisol was compared to the effect of 30 min of play with mother present. Separation resulted in significantly higher salivary cortisol concentrations as compared to play with mother present. In general, correlations between cortisol and behavior were found to be nonsignificant under conditions that did not produce stress elevations in cortisol, while less positive, more distressed behaviour was significantly correlated with cortisol under separation or stress conditions.